Calcium Regulation by Calcium Antagonists - American Chemical

3 Effects of Calcium Inhibitory Compounds upon the Cardiovascular System WILLIAM W. MUIR

Downloaded by UNIV OF SYDNEY on May 3, 2015 | http://pubs.acs.org Publication Date: October 14, 1982 | doi: 10.1021/bk-1982-0201.ch003

Ohio State University, Department of Veterinary Physiology and Physiology, Columbus,OH43210

A diverse group of heterogeneous compounds have emerged which are advocated for the therapy of a variety of cardiovascular diseases including angina pectoris, hypertension, cardiac arrhythmias, obstructive forms of cardiomyopathy and ischemic heart disease. The therapeutic success of these compounds centers, in part if not totally, upon their ability to interfere with calcium metabolism. Drugs exhibiting the ability to inhibit the effects of calcium upon cardiovascular function have been classified as calcium antagonists, implying a receptor agonist-antagonist relationship. Verapamil, nifedipine, diltiazem and perhexiline are the most extensively studied of these compounds. The recent development of a new group of calcium inhibitory compounds, the 2-substituted 3-dimethylamino-5-,6methylenedioxyindenes, are believed to inhibit the intracellular regulatory protein calmodulin. Despite difficulties in determining the precise mechanism of action of drugs possessing calcium inhibitory activity, these compounds exert potent negative inotropic, chronotropic and dromotropic effects upon cardiac tissues. They are excellent coronary and peripheral vasodilators and preserve myocardial metabolism while preventing mitochondrial swelling during cardiac ischemia. Their antiarrhythmic activity in intact animals and isolated tissue preparations is closely linked to their ability to inhibit the slow inward calcium current, interfere with transmembrane sodium ion flux, and indirect effects. The development of s p e c i f i c a l l y designed and p r e c i s e experimental techniques coupled with an increased understanding 0097-6156/82/0201-0039$09.50/0 © 1982 American Chemical Society

In Calcium Regulation by Calcium Antagonists; Rahwan, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


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of the changes that occur i n myocardial metabolism during disease have been instrumental i n advancing c a r d i a c pharmacot h e r a p e u t i c s . Nowhere i n the science of pharmacology as i t r e l a t e s to c a r d i o l o g y has t h i s development been made more evident than i n the s y n t h e s i s and c l i n i c a l usage of adrenergic antagonists and a group o f compounds c o l l e c t i v e l y termed "calcium a n t a g o n i s t s " . The l a t t e r compounds have derived t h e i r name p r i m a r i l y because of the a b i l i t y of i o n i z e d calcium to reverse t h e i r e l e c t r i c a l and cardiodepressant e f f e c t s (_1, 2). Recently, s e v e r a l i n v e s t i g a t o r s have c r i t i c i z e d use of the term "calcium antagonist" i n f a v o r of more p r e c i s e a l t e r n a t i v e s i n c l u d i n g , "slow channel i n h i b i t o r " , and "calcium channel b l o c k i n g drugs"(2» 5)· The a c c e p t a b i l i t y of each of these expressions has been questioned, however, because of the absence of a proven a g o n i s t - r e c e p t o r r e l a t i o n s h i p and u n c e r t a i n t y surrounding the p r i n c i p l e mechanisms or l o c a t i o n whereby "calcium a n t a g o n i s t s " i n t e r f e r e with calcium-dependent f u n c t i o n s (6_, 7_)« In t h i s review and throughout the manuscript, the term "calcium i n h i b i t o r y compound" w i l l be used i n l i e u o f "calcium antagonist," "slow channel i n h i b i t o r , " and "calcium channel b l o c k i n g drug." An exhaustive d i s c u s s i o n of the many compounds e x e r t i n g calcium i n h i b i t o r y a c t i v i t y , t h e i r e f f e c t s upon c a r d i o v a s c u l a r f u n c t i o n , t h e i r mechanisms and s i g h t s of a c t i o n , and t h e i r s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s are beyond the scope of t h i s manuscript. For the sake of c l a r i t y , however, a b r i e f d i s c u s s i o n of the r o l e and importance of calcium i n e x c i t a t i o n - c o n t r a c t i o n c o u p l i n g i n c a r d i a c t i s s u e s and s e v e r a l proposed mechanisms o f a c t i o n of calcium i n h i b i t o r y compounds w i l l be reviewed. 2

C a * and E x c i t a t i o n - C o n t r a c t i o n Coupling Calcium i s e s s e n t i a l f o r the e x c i t a t i o n - c o n t r a c t i o n coupling process to occur i n c a r d i a c muscle. In comparison to s k e l e t a l muscle, where i n t r a c e l l u l a r calcium s t o r e s are extensive, myocardial s t o r e s of calcium are l i m i t e d . Two arguments are used to s t r e s s the importance of transmembrane Ca i n f l u x i n the e x c i t a t i o n - c o n t r a c t i o n coupling process. These are: l ) r e d u c t i o n i n the f o r c e of c a r d i a c c o n t r a c t i o n f o l l o w i n g the removal of C a from the p e r f u s i n g s o l u t i o n , and 2) uncoupling of e x c i t a t i o n - c o n t r a c t i o n i n heart muscle by lanthanum, (a substance which d i s p l a c e s r a p i d l y exchangeable membrane bound calcium, blocks calcium i n f l u x , but does not i t s e l f enter the c e l l ) (8, 10). Transmembrane calcium i n f l u x begins during r a p i d d e p o l a r i z a t i o n (phase 0) of c a r d i a c c e l l s and continues f o r s e v e r a l hundred m i l l i s e c o n d s t h e r e a f t e r (phase 2 ) . The transmembrane C a i n f l u x , which occurs during the c a r d i a c a c t i o n p o t e n t i a l i s too small to provide s u f f i c i e n t to i n i t i a t e c o n t r a c t i o n , but may c o n t r i b u t e to the e x c i t a t i o n - c o n t r a c t i o n coupling process i n three ways: l ) by 2 +

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maintaining i n t r a c e l l u l a r s t o r e s of calcium i n the sarcoplasmic reticulum; 2) by inducing ( " t r i g g e r i n g " ) the r e l e a s e of C a from the i n t r a c e l l u l a r sarcoplasmic r e t i c u l u m ; and 3) by modulating the r e l e a s e of C a from the sarcoplasmic r e t i c u l u m ( 1 1 , 13)· Support f o r the l a s t two of these hypotheses i s based upon s t u d i e s i n c a r d i a c f i b e r s from which the sarcolemma has been removed ("skinned" f i b e r s ) i n order to e l i m i n a t e membrane e f f e c t s , ( 1 4 , 15) and modulation of c a r d i a c a c t i o n p o t e n t i a l p l a t e a u and c o n t r a c t i o n by displacement of surface bound calcium with t r i - or d i v a l e n t c a t i o n s having i o n i c r a d i i s i m i l a r to that of C a (e.g., L a ? , C o , M n , N i ) (16, 17). Studies using "skinned" c a r d i a c f i b e r s i n d i c a t e that concentrations of s u b s t a n t i a l l y l e s s than required f o r c o n t r a c t i o n are capable of t r i g g e r i n g the r e l e a s e of C a from the i n t r a c e l l u l a r s a r c o t u b u l a r system (calcium induced calcium r e l e a s e ) (11, 15, 18). When the C a concentration within myocardial c e l l s i n c r e a s e s from r e s t i n g values of 10~7 M to 10~5 M , C a binds to troponin r e l e a s i n g troponins i n h i b i t o r y e f f e c t s upon myosin allowing muscular c o n t r a c t i o n to occur (19) (Figure l ) . Current b e l i e f contends that the development of c o n t r a c t i l e f o r c e i n c a r d i a c muscle i s determined by the amount of nonenergy dependent sarcolemmal C a binding. Extracellular Ca can bind to sarcolemmal p h o s p h o l i p i d s or an e x t e r n a l l a y e r of m a t e r i a l composed of g l y c o p r o t e i n , g l y c o l i p i d and mucopolysaccharide termed the " g l y c o c a l y x . " Q u a n t i t a t i v e l y , the binding of C a to the g l y c o c a l y x i s of secondary importance compared to that bound by p h o s p h o l i p i d elements. The g l y c o c a l y x does play a s i g n i f i c a n t r o l e i n the determination of myocardial c e l l C a permeability (20, 21). Upon a r r i v a l of the appropriate e l e c t r i c a l stimulus "["action potential), C a crosses the sarcolemma and i s the p r i n c i p a l c a t i o n r e s p o n s i b l e f o r a current c a l l e d the "slow inward c u r r e n t " ( l i ) ( 1 2 , 2 2 , 2 3 , 2 £ ) . Calcium i s conducted across the sarcolemma through channels or pores which are c o n t r o l l e d by the phosphorylation of sarcolemmal and s a r c o t u b u l a r p r o t e i n s . Cardiac sarcolemma and sarcoplasmic reticulum are phosphorylated by exogenous and endogenous c y c l i c adenosine y-5'monophosphate (cAMP)-dependent p r o t e i n kinases ( 2 5 , 26). Recently, another r e g u l a t o r y mechanism has been i d e n t i f i e d i n c a r d i a c sarcoplasmic r e t i c u l u m . Cardiac c o n t r a c t i o n was shown to be dependent upon a m u l t i f u n c t i o n a l r e g u l a t o r p r o t e i n c a l l e d calmodulin (27_, 28). Calmodulindependent phosphorylation of sarcoplasmic r e t i c u l u m i s dependent upon the presence of f r e e i n t r a c e l l u l a r C a (29, 3 0 ) · Both cAMP-dependent and c a l m o d u l i n - C a dependent phosphorylation of a p r o t e o l i p i d (phospholamban) of the p r o t e i n kinases, r e s u l t i n s t i m u l a t i o n of C a t r a n s p o r t and C a dependent ATPase a c t i v i t i e s of sarcoplasmic reticulum ( 3 0 , 31, 2 +

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52). The small amount of C a released from the sarcolemmalg l y c o c a l y x complex, t h e r e f o r e , serves as a t r i g g e r f o r calmodulin phosphorylation of c a r d i a c sarcoplasmic r e t i c u l u m resulting in C a r e l e a s e from the sarcolemmal-sarcotubular system and c a r d i a c c o n t r a c t i o n . A second mechanism separate from the slow channel, whereby Ca can enter the c a r d i a c c e l l , i s N a - C a exchange ( 5 5 ) · Movement of C a across the sarcolemma occurs v i a a N a - C a c a r r i e r system which i s dependent upon i n t r a c e l l u l a r Na concentration ( 5 4 ) · I n t e r v e n t i o n s which produce an i n c r e a s e i n i n t r a c e l l u l a r Na*" c o n c e n t r a t i o n (e.g., d i g i t a l i s ) stimulate the c a r r i e r to move Na out and C a i n t o the c e l l . The net inward movement of C a r e s u l t s i n an i n c r e a s e i n the f o r c e of c a r d i a c c o n t r a c t i o n . The r e l a t i v e magnitude and f u n c t i o n a l importance of the N a - C a exchange mechanism are u n c l e a r at t h i s time. 2 +

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Proposed Mechanisms and Sight of A c t i o n of Calcium I n h i b i t o r y Compounds i n Cardiac Muscle I t i s c u r r e n t l y accepted that calcium can enter the myocardial c e l l by three primary mechanisms i n c l u d i n g passive d i f f u s i o n ( e x t r a c e l l u l a r [Ca ]=10~3 M, r e s t i n g i n t r a c e l l u l a r [Ca ]=10~7 Μ ) , e l e c t r o g e n i c N a - C a exchange, and through voltage a c t i v a t e d time-dependent and independent i o n s e l e c t i v e channels or pores (55)· Voltage-dependent t r a n s f e r of calcium i o n i n t o the c a r d i a c c e l l i s c o n t r o l l e d by "gating mechanisms" and by phosphorylation of membrane p r o t e i n s (50, 55)· Alpha adrenergic, h i s t a m i n e r g i c , and s e r o t o n e r g i c receptors regulate the "gating mechanisms" r e s p o n s i b l e f o r C a f l u x through the sarcolemnal channels (25, 56). As p r e v i o u s l y s t a t e d , transscarcolemmal C a may p a r t i c i p a t e i n myocardial e x c i t a t i o n - c o n t r a c t i o n coupling and i n t r a c e l l u l a r calcium r e g u l a t i o n by l ) i n i t i a t i n g the e l e c t r i c a l event r e s p o n s i b l e f o r c o n t r a c t i o n ; 2) r e p l e n i s h i n g i n t r a c e l l u l a r calcium s t o r e s i n the sarcoplasmic reticulum; and 5) modulating the r e l e a s e of calcium from i n t r a c e l l u l a r s i g h t s . U n t i l r e c e n t l y , chemical compounds that antagnonized C a were b e l i e v e d to act by r e v e r s i b l y s e a l i n g s p e c i f i c C a channels at the membrane surface (sarcolemma-glycocalyx complex) of myocardial c e l l s ^ . D i v a l e n t and t r i v a l e n t c a t i o n s with r a d i i l a r g e r than the calcium i o n i n c l u d i n g Mn , N i , C o , and L a ^ w i l l block the i n f l u x of C a i n t o myocardial c e l l s by i n h i b i t i n g the passage of C a through membrane pores or channels (16, 56-59)· The l i s t of compounds purported to inhibit Ca i n f l u x i n c l u d e s a l a r g e number of s t r u c t u r a l l y r e l a t e d and u n r e l a t e d chemical compounds i n c l u d i n g papaverine, (40) diazoxide, (41) p e r h e x i l i n e , (42) lidoflazine, (45) prenylamine, (£) f e n d i l i n e , (4) verapamil, (58) methoxyverapamil (D-600), (58j d i l t i a z e m , (447 nifedipine, (45) n i l u d i p i n e , ( 4 6 ) n i s o l d i p i n e , (47) propafenon, (48) tiapaml, 2+

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( 4 9 ) ryanodine, (50) AHR-2666, (51) 2 - s u b s t i t u t e d 5dimethylamino-5,6-methylenedioxyindenes (MDl) (52, 53) and many others ( F i g u r e 2) (53, 54)· Recently, t h i s r e l a t i v e l y s i m p l i s t i c c l a s s i f i c a t i o n of calcium i n h i b i t i o n has been challenged by s t u d i e s which i n d i c a t e that many of the soc a l l e d "calcium a n t a g o n i s t s " may act i n t r a c e l l u l a r l y (58, 55-58). S e v e r a l arguments a r e used t o support the hypothesis of an i n t r a c e l l u l a r mechanism of a c t i o n i n c l u d i n g : l ) at 4 mM e x t r a c e l l u l a r potassium concentrations e x c i t a t i o n - c o n t r a c t i o n coupling i s predominantly dependent upon i n t r a c e l l u l a r calcium s t o r e s (59); 2) most calcium i n h i b i t o r y compounds demonstrate i n h i b i t i o n o f the c o n t r a c t i l e response ( e l e c t r i c a l - m e c h a n i c a l uncoupling) a t concentrations which do not a f f e c t the p l a t e a u phase of the c a r d i a c a c t i o n p o t e n t i a l (_1, 60, 61, 62) 5 ) ; s t u d i e s using mesenteric v a s c u l a r smooth muscle i n d i c a t e that low concentrations of calcium i n h i b i t o r y compounds i n t e r f e r e with phasic c o n t r a c t i o n s which are p r i n c i p a l l y dependent upon i n t r a c e l l u l a r calcium a c t i v i t y , while high concentrations o f calcium i n h i b i t o r y compounds i n t e r f e r e with t o n i c mechanical a c t i v i t y which i s dependent upon e x t r a c e l l u l a r calcium (58); 4) r a d i o l a b e l e d calcium (45ca) transmembrane f l u x i s not i n h i b i t e d by calcium i n h i b i t o r y compounds (5); 5) 2-n-propyl and 2-n-butyl MM bind to calmodulin and t r o p o n i n (M.T. P i a s c i k et a l . , manuscript i n p r e p a r a t i o n ) ; 6) Lineweaver-Burk p l o t s demonstrate that verapamil and D-600 do not compete with C a f o r the same membrane s i t e and that the onset of drug e f f e c t i s much slower than that of M n (58); and 7) the observation that the i n h i b i t i o n of transsarcolemmal C a f l u x by verapamil i s a d i r e c t f u n c t i o n of t i s s u e p r e p a r a t i o n pacing frequency independent of i t s d i r e c t negative i n o t r o p i c a c t i v i t y (65). The p r e c i s e mechanism and s i g h t of a c t i o n of most compounds categorized as calcium i n h i b i t o r y compounds, t h e r e f o r e , remains obscure. Future refinements i n experimental models and techniques w i l l undoubtedly w i l l lead to the c l a s s i f i c a t i o n o f calcium i n h i b i t o r y compounds based upon t h e i r primary mechanism of a c t i o n and s p e c i f i c s i t e ( s ) of a c t i o n ( e x t r a c e l l u l a r v s . intracellar). Because of the u n c e r t a i n t y surrounding the p r e c i s e mechanisms of a c t i o n of calcium i n h i b i t o r y compounds, I w i l l d e s c r i b e t h e i r c a r d i a c e l e c t r i c a l and mechanical e f f e c t s i l l u d i n g when p o s s i b l e to those compounds that are b e l i e v e d to act: l ) c o m p e t i t i v e l y with C a f o r s p e c i f i c calcium channels (e.g., C o , Mn , L a ^ , e t c . ) ; 2) at the c a r d i a c c e l l membrane and p o s s i b l y by one of s e v e r a l i n t r a c e l l u l a r mechanisms (e.g., verapamil, d i l t i a z e m , n i f e d i p i n e ) ; and 5) i n t r a c e l l u l a r l y (e.g., 2-n-propyl and 2-n-butyl MDl). 2 +

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Normal and Abnormal Cardiac E l e c t r i c a l

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Most s t u d i e s attempting to d e f i n e the e f f e c t s of calcium i n h i b i t o r y compounds upon c a r d i a c e l e c t r i c a l a c t i v i t y have


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focused upon the plateau phase of the c a r d i a c a c t i o n p o t e n t i a l . I n c a r d i a c and other e x c i t a b l e t i s s u e s , the a c t i o n p o t e n t i a l represents m u l t i p l e i o n i c transmembrane f l u x e s (35). Microelectrode and voltage clamp experiments have confirmed that two d i f f e r e n t inward currents are responsible f o r the development of the c a r d i a c a c t i o n p o t e n t i a l (Figure 3) (12, 24, 35_, 36, 5Z> 64)· A r a p i d inward current c a r r i e d by N a Tîna*î~ i s responsible f o r the i n i t i a l d e p o l a r i z a t i o n or spike of the c a r d i a c a c t i o n p o t e n t i a l . The t r a n s f e r of C a across the sarcolemma gives r i s e to a second inward current that with a small N a component i s r e f e r r e d to as the "slow inward c u r r e n t " (I -L). The a d j e c t i v e , slow, i s used because of the slow k i n e t i c s of calcium i o n t r a n s f e r compared to the r a p i d N a i n f l u x which occurs during the i n i t i a l d e p o l a r i z a t i o n . F o r d e s c r i p t i v e purposes, the cardiac a c t i o n p o t e n t i a l i s subdivided i n t o 5 d i s t i n c t phases. During phase 0, transmembrane conductance f o r the inward displacement of N a r a p i d l y increases ( r a p i d inward current I N + ) r e s u l t i n g i n rapid depolarization. As N a reaches i t s e q u i l i b r i u m p o t e n t i a l (+20-40 mV),*as p r e d i c t e d by the Nernst Equation, Na conductance decreases. Rapid i n a c t i v a t i o n of N a conductance coupled with the c e l l u l a r i n f l u x of c h l o r i d e i o n r e s u l t s i n a b r i e f period of r a p i d r e p o l a r i z a t i o n , r e f e r r e d to as phase 1. In Purkinje f i b e r s , r a p i d sodium i n a c t i v a t i o n i s delayed r e s u l t i n g i n a very l o n g - l a s t i n g d e p o l a r i z i n g o r inward current. During phase 0 when membrane p o t e n t i a l has d e p o l a r i z e d to a value of from -60 to -40 mV, the second slower inward current ( l i ) i s a c t i v a t e d . I ^ i s responsible f o r the p r o l o n g a t i o n of membrane d e p o l a r i z a t i o n o r p l a t e a u phase (phase 2) of the c a r d i a c a c t i o n p o t e n t i a l . Experimentally, d i v a l e n t ions with s i m i l a r r a d i i to that of C a , such as strontium ( S r ) and barium ( B a ) , have been used as charge c a r r i e r s f o r I j_. R e p o l a r i z a t i o n occurs when the sum of the outward currents exceeds that of the inward currents (56). At membrane p o t e n t i a l s l e s s negative than -40 mV, transmembrane conductance to K i n c r e a s e s . Increased K conductance and the r e s u l t a n t outward displacement of K coupled with a simultaneous decrease i n I j _ (calcium i n a c t i v a t i o n ) lead to c e l l u l a r r e p o l a r i z a t i o n (phase 3). Transmembrane conductance to K and i n t r a c e l l u l a r calcium a c t i v i t y are s i g n i f i c a n t f a c t o r s i n determining the rate of r e p o l a r i z a t i o n (65-68). F o r example, experimental o r pharmacologic manipulations which increase i n t r a c e l l u l a r calcium a c t i v i t y or increase membrane conductance to K markedly shorten a c t i o n p o t e n t i a l d u r a t i o n (69, 70)· The remaining phase of the c a r d i a c a c t i o n p o t e n t i a l i s r e f e r r e d to as phase 4· In r e s t i n g a t r i a l and v e n t r i c u l a r myocardium, phase 4 i s s t a b l e at a r e s t i n g membrane p o t e n t i a l ranging from between -80 to -95 mV. In cardiac t i s s u e s demonstrating spontaneous a c t i v i t y ( i . e . , s i n o a t r i a l [ S A ] node, a t r i o v e n t r i c u l a r [AV] node, s p e c i a l i z e d conducting [ P u r k i n j e ] +

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> ^

H CO-

COCM. II *

ΗΊ

3

ο 1 ο

-NO,

Ο

Γ

W

Τ ι

KjCCHjCHjOCMjCHjOl>c

y

cocMjCH ocM,cH CMj 2

2

lOL

Tiapamil

Niludipine Figure 2.

Structural formulas of some calcium inhibitory compounds. Continued on next page.

Perhexiline


3.

Inhibitory

MUIR

Compounds

OCH CH(CH)) t

and

the Cardiovascular

47

System

2


AHR-2666

OCM,

CH -CH2-ço 2

ù ùr*

-CHOH Ç H j

NH-CjH

7

Propafenone Diltiazem

^^-CMCH

2

CH

2

CM.

NHCHicH -^^

CM.

t

2-n-Butyl Methylenedioxyindene (MDl) Prenylamine OH OH

CH,,

OS

[OH , ,0

à Figure 2.

\

' II N O

HO

H

Fendiline

Ryanodine

Continued. Structural formulas of some calcium inhibitory compounds.

American Chemical Society Library 1155 16th St., N.W. Washington, D.C. 20036 In Calcium Regulation by Calcium Antagonists; Rahwan, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.


48

CALCIUM

REGULATION

BY CALCIUM

ANTAGONISTS

100msec TIME Figure 3. Action potentials recorded from Purkinje and SA nodal fibers. Note the absence of phase 1 and slurring together of phases 2 and 3 in the recording from the SA nodal fiber.


MUIR

3.

Inhibitory

Compounds

and the Cardiovascular

49

System

f i b e r s ) , phase 4 i s c h a r a c t e r i z e d by a gradual change i n the membrane p o t e n t i a l towards a l e s s negative o r threshold p o t e n t i a l from which an a c t i o n p o t e n t i a l i s generated. Phase 4 a c t i v i t y , c a l l e d d i a s t o l i c depolarization, i s responsible f o r the s o - c a l l e d "pacemaker current" of c a r d i a c c e l l s , and i n Purkinje f i b e r s has been a t t r i b u t e d to a decaying outward K current, termed I j ^ (71)* Recently an e n t i r e l y new mechanism f o r the pacemaker current and phase 4 a c t i v i t y i n Purkinje f i b e r s has been proposed (72, 75)· Phase 4 i s a t t r i b u t e d to a mixed current p r i n c i p a l l y generated by a c t i v a t i o n of an inward Na component rather than i n a c t i v a t i o n of 1^2 (75)* Acceptance of t h i s new concept has c l a r r i f i e d s e v e r a l important q u a l i t a t i v e d i f f e r e n c e s thought to e x i s t between phase 4 a c t i v i t y i n c e l l s of the SA node and H i s - P u r k i n j e system. The shape of the normal cardiac a c t i o n p o t e n t i a l v a r i e s considerably depending upon the recording s i g h t . C e l l s of the SA and AV nodes demonstrate a maximum d i a s t o l i c p o t e n t i a l of -60 mV compared to -90 mV recorded from Purkinje and muscle f i b e r s , a markedly reduced rate of r a p i d d e p o l a r i z a t i o n (phase 0), no phase 1 and a s l u r r i n g together o f phases 2 and 5· The c h a r a c t e r i s t i c , reduced, r e s t i n g membrane p o t e n t i a l and slow rate of phase 0 i n these t i s s u e s have l e d to the c o n c l u s i o n that phase 4 i s p a r t i a l l y dependent upon the inward displacement of calcium i o n and that phase 0 i s due to the inward movement of N a through p a r t i a l l y i n a c t i v a t e d f a s t channels and N a and C a through slow channels (74)· A l t e r a t i o n s i n normal impulse formation are due to normal and abnormal automaticity, a l t e r e d conduction, or both, and are responsible f o r abnormal e l e c t r i c a l a c t i v i t y and the many d i v e r s e arrhythmias that occur i n diseased hearts (75)« I n a d d i t i o n , there i s suggestive evidence that c a r d i a c arrhythmias r e s u l t from e l e c t r i c a l uncoupling of the v e n t r i c u l a r myocardium (76, 77)· E l e c t r i c a l uncoupling of c a r d i a c c e l l s occurs simultaneously with i n c r e a s e s i n i n t e r n a l c e l l u l a r r e s i s t a n c e and C a ^ concentrations (77, 78). Interventions that exaggerate i n c r e a s e s i n i n t e r n a l r e s i s t a n c e i n c l u d i n g hypoxia, ischemia, catecholamines, increases i n e x t r a c e l l u l a r C a ^ and increased s t i m u l a t i o n frequency also increase i n t r a c e l l u l a r Ca (75)· The c e l l u l a r e l e c t r o p h y s i o l o g i c changes that are b e l i e v e d to have an important r o l e i n the development of abnormal automaticity and conduction, and the development of c a r d i a c arrhythmias i n diseased hearts i n c l u d e v a r i a b l e reductions i n r e s t i n g membrane p o t e n t i a l , a l t e r e d a c t i o n p o t e n t i a l c o n f i g u r a t i o n and duration, unprovoked and t r i g g e r e d spontaneous a c t i v i t y , depression of c e l l u l a r e x c i t a b i l i t y and membrane responsiveness, prolongation of a c t i o n p o t e n t i a l r e f r a c t o r i n e s s and a c t i o n p o t e n t i a l s with a markedly reduced rate of r i s e of phase 0 (75)» Acute c e l l u l a r damage from any cause i s g e n e r a l l y a s s o c i a t e d with a l o s s of c e l l membrane i n t e g r i t y and a decrease i n i n t r a c e l l u l a r K concentration. +


+

+

+

2 +

+

+

2 +

+


CALCIUM

50

REGULATION

BY CALCIUM

ANTAGONISTS

These changes, combined with l o c a l i n c r e a s e s i n e x t r a c e l l u l a r K concentration, r e s u l t i n c e l l u l a r d e p o l a r i z a t i o n , a decreased rate of r i s e of phase 0, decreased a c t i o n p o t e n t i a l d u r a t i o n and p o t e n t i a l l y the development of calcium dependent (slow response) a c t i o n p o t e n t i a l s (75)* I n more chronic (hrs or days) s i t u a t i o n s , a f t e r e x t r a c e l l u l a r K concentration has returned t o normal, transmembrane p o t e n t i a l may be normal o r reduced, but a c t i o n p o t e n t i a l d u r a t i o n may be prolonged due t o decreases i n the transmembrane K concentration gradient and reductions i n membrane conductance t o K ( 7 5 ) · I n e i t h e r case, a reduction i n r e s t i n g membrane p o t e n t i a l r e s u l t s i n a c a r d i a c a c t i o n p o t e n t i a l more dependent upon C a for depolarization and predisposes the c a r d i a c c e l l to spontaneously o c c u r r i n g c y c l i c a l membrane o s c i l l a t i o n s ( d e p o l a r i z a t i o n induced automaticity) which may reach threshold and produce e x t r a d e p o l a r i z a t i o n s (75> 79» 80). Cardiac c e l l s that develop calcium dependent a c t i o n p o t e n t i a l s may a l s o demonstrate spontaneous o r t r i g g e r e d (dependent on a p r i o r i n i t i a t i n g a c t i o n p o t e n t i a l ) abnormal automaticity, delayed conduction patterns, and prolonged r e f r a c t o r i n e s s . A l l of these f a c t o r s are important i n the development of cardiac arrhythmias (80-83). Independent of disease induced e f f e c t s , pharmacologic i n t e r v e n t i o n s ( d i g i t a l i s , barium, catecholamines) can p o t e n t i a t e the slow inward C a current i n otherwise normal cardiac t i s s u e s and may t r i g g e r membrane o s c i l l a t i o n s which lead to abnormal c e l l u l a r automaticity and c a r d i a c arrhythmias (81). Drugs that demonstrate calcium i n h i b i t o r y a c t i v i t y d i s p l a y d i f f e r e n t c a r d i a c membrane e f f e c t s dependent upon t h e i r s t r u c t u r e , p h y s i c a l p r o p e r t i e s and c o n c e n t r a t i o n . Compounds which i n t e r f e r e with C a i n f l u x are expected to prolong the d u r a t i o n of the a c t i o n p o t e n t i a l . T h i s p r e d i c t i o n i s supported by evidence that decreased i n t r a c e l l u l a r C a a c t i v i t y may decrease the l a t e increase i n K conductance and p o t e n t i a l l y prolong the d u r a t i o n o f r e p o l a r i z a t i o n (phase 3) (69)· The f i r s t substances reported t o i n h i b i t I~± without i n f l u e n c i n g rapid d e p o l a r i z a t i o n (phase 0) were Mn2+, N i and C o (16, 17)» The e f f e c t s of the chemically complex calcium i n h i b i t o r y compounds upon I and a c t i o n p o t e n t i a l duration, however, are d i f f i c u l t to p r e d i c t because they may not act by a s i n g l e e l e c t r o p h y s i o l o g i c mechanism. F i n a l l y , i t has been suggested that the N a - C a exchange mechanism may be important i n p r o v i d i n g calcium f o r cardiac c o n t r a c t i o n (33.). M e t a l l i c cations (Mn , % , C o ) are known t o d i s p l a c e membrane bound which p a r t i c i p a t e s i n N a - C a exchange (34, 3 9 ) · The e f f e c t of the m a j o r i t y of calcium i n h i b i t o r y compounds on the Na -Ca exchange process i s u n c e r t a i n . +

+

+

+


2 +

2 +

2 +

2 +

+

2 +

+

2+

g

i

2

+

2 +

2 +

+

+

2 +

2 +

2 +


3.

MUIR

Inhibitory

Compounds

and

the

Cardiovascular

System

E l e c t r o p h y s i o l o g i c E f f e c t s of Calcium I n h i b i t o r y Agents i n Normal and Diseased Hearts E f f e c t s Upon A c t i o n P o t e n t i a l C o n f i g u r a t i o n and Automaticity* The one e l e c t r o p h y s i o l o g i c e f f e c t that a l l calcium i n h i b i t o r y compounds apparently share i n common i s i n h i b i t i o n of I j _ . The magnitude of t h i s e f f e c t i s dependent upon the potency and dose of the drug being i n v e s t i g a t e d . Furthermore, a number of compounds with calcium i n h i b i t o r y a c t i v i t y demonstrate m u l t i p l e membrane e f f e c t s dependent upon o p t i c a l isomerism. The (+)-isomers of racemic verapmil, D-600, and prenylamine demonstrate predominantly f a s t - c h a n n e l ( l f l ) i n h i b i t o r y e f f e c t s whereas, the (-)-isomers of these same compounds are predominantly i n h i b i t o r s of I j _ (45, 84, 85.)· I n t e r e s t i n g l y , only those calcium i n h i b i t o r y compounds which demonstrate e f f e c t s upon I * j are u s e f u l c l i n i c a l l y as a n t i a r r h y t h m i c s (45, 86-89;» Because of d i f f e r e n c e s i n drug potency, dose, and f o r m u l a t i o n , d e s c r i p t i v e experiments report that calcium i n h i b i t o r y compounds have v a r i a b l e e f f e c t s upon a c t i o n p o t e n t i a l c h a r a c t e r i s t i c s and c o n f i g u r a t i o n (^1, 60, 62, 90, 91, 92). In g e n e r a l , s e v e r a l statements can be made about compounds e x h i b i t i n g calcium i n h i b i t o r y a c t i v i t y . At drug concentrations, which begin to r e s u l t i n negative i n o t r o p i c e f f e c t s i n i s o l a t e d heart muscle p r e p a r a t i o n s , most calcium i n h i b i t o r y compounds cause l i t t l e or no change i n a c t i o n p o t e n t i a l amplitude, maximum upstroke v e l o c i t y of phase 0 ( V ) , or a c t i o n p o t e n t i a l d u r a t i o n at 100 percent r e p o l a r i z a t i o n . As drug c o n c e n t r a t i o n i s increased, gradual changes i n a t r i a l , v e n t r i c u l a r myocardium and P u r k i n j e f i b e r a c t i o n p o t e n t i a l c o n f i g u r a t i o n are observed. In a t r i a l and v e n t r i c u l a r myocardium, these changes i n c l u d e i n c r e a s e s i n the slope of the p l a t e a u (phase 2), a decrease i n a c t i o n p o t e n t i a l d u r a t i o n at 25 and 50 percent r e p o l a r i z a t i o n (ADP25 and A P D ^ Q ) and decreases, no change, or i n c r e a s e s i n A P D ^ Q Q . At s t i l l higher drug c o n c e n t r a t i o n s , the demarcation between phases 2 and 5 becomes i n d i s t i n g u i s h a b l e and A P D i s decreased at a l l p o i n t s during r e p o l a r i z a t i o n . A s s o c i a t e d with the changes observed i n A P D ] _ Q Q are s i m i l a r , but not p r o p o r t i o n a l , changes i n the e f f e c t i v e r e f r a c t o r y period (ERP); decreases i n A P D ^ Q Q r e s u l t i n i n c r e a s e s i n the E R P / A P D . In a d d i t i o n , s e v e r a l compounds (2-n-propyl and 2-n-butyl MDl, racemic verapamil, D-600, prenylamine) decrease V (45, 84, 91)* S i m i l a r but more pronounced changes are observed i n a c t i o n p o t e n t i a l s recorded from P u r k i n j e f i b e r s . Although s t u d i e s u s i n g voltage clamp techniques suggest that s e v e r a l of the calcium i n h i b i t o r y compounds (verapamil, D-600, and manganese) may a f f e c t background inward c u r r e n t s c a r r i e d by Na or time-dependent outward c u r r e n t s c a r r i e d by K (both of which could a f f e c t a c t i o n p o t e n t i a l d u r a t i o n ) , the changes that occur i n a c t i o n p o t e n t i a l c o n f i g u r a t i o n could be caused by v a r i a t i o n s i n the degree of i n t r a c e l l u l a r C a i n h i b i t i o n (95, 94)· Drugs which have profound depressant e f f e c t s upon i n t r a c e l l u l a r C a a c t i v i t y would be expected to s

+

a


s

a

m a x

m a x

+

+

2 +

2 +


CALCIUM

52

REGULATION

BY

CALCIUM

ANTAGONISTS

d r a m a t i c a l l y abbreviate phase 2 l e a d i n g to premature a c t i v a t i o n of the outward K c u r r e n t s and marked reductions i n A P D during a l l phases of r e p o l a r i z a t i o n . Compounds which have poor i n t r a c e l l u l a r Ca^ i n h i b i t o r y a c t i v i t y and which act p r i m a r i l y at the c e l l membrane by modulating the i n f l u x of C a 2 \ i n d i r e c t l y reduce i n t r a c e l l u l a r C a r e l e a s e from sarcoplasmic r e t i c u l u m . T h i s r e s u l t s i n minimal a b b r e v i a t i o n of phase 2, reductions i n A P D 2 5 and A P D ^ Q » d delayed a c t i v a t i o n of outward K c u r r e n t s , thereby prolonging APD^QO* Recently, we have had the opportunity to examine the i n v i t r o e l e c t r o p h y s i o l o g i c e f f e c t s of two calcium antagonists which are b e l i e v e d to act i n t r a c e l l u l a r l y (2-n-propyl and 2-n-butyl MDl) (55.) · A d d i t i o n of e i t h e r of these compounds at concentrations ranging from 10~7 to 10~5 M to Tyrode's s o l u t i o n superfusing canine P u r k i n j e f i b e r s r e s u l t s i n a c t i o n p o t e n t i a l changes c h a r a c t e r i s t i c of calcium i n h i b i t i o n , i n c l u d i n g decreases i n A P D 2 5 , A P D 5 0 and A P D ] _ o o * I* separate experiments, s i m i l a r concentrations of a quaternary d e r i v a t i v e of 2-n-butyl MDl were added to the s u p e r f u s i o n medium r e s u l t i n g i n s i g n i f i c a n t reductions i n A P D 2 5 , v a r i a b l e changes i n A P D ^ Q and increases i n A P D 1 0 0 (Figure 4 ) · These experiments suggest that the e l e c t r o p h y s i o l o g i c changes caused by calcium i n h i b i t o r y compounds are i n p a r t dependent upon i n h i b i t i o n of and the c u r r e n t s r e s p o n s i b l e f o r r e p o l a r i z a t i o n . Because of the n e g l i g i b l e e f f e c t s of 2-n-butyl MDl and i t s quaterinary d e r i v a t i v e upon phase 4 d e p o l a r i z a t i o n (discussed below), i t i s u n l i k e l y that i t i n t e r f e r e s with a c t i o n p o t e n t i a l r e p o l a r i z a t i o n by a l t e r i n g K e f f l u x , although t h i s aspect r e q u i r e s f u r t h e r study. +

+

2 +

a n


+

1

+

E f f e c t Upon Normal Automaticity 2 +

The e f f e c t s of many C a i n h i b i t o r y compounds on s i n o a t r i a l , a t r i o v e n t r i c u l a r , and P u r k i n j e f i b e r a u t o m a t i c i t y have been examined (45> 46, 95-100)» In general, i n v i t r o s t u d i e s suggest that the a d d i t i o n of C a i n h i b i t o r y compounds to s o l u t i o n s superfusing i s o l a t e d t i s s u e s r e s u l t s i n no change or a decrease i n spontaneous a c t i v i t y (98, 100). As p r e v i o u s l y s t a t e d , time-dependent outward c u r r e n t s c a r r i e d by K , and a c t i v a t i o n of an inward current c a r r i e d by Na and C a exert a s i g n i f i c a n t i n f l u e n c e on SA and AV node spontaneous a c t i v i t y (74)· Tyrodes superfused i n r a b b i t and guinea p i g and blood perfused canine sinus node preparations d i s p l a y the most pronounced negative chronotropic e f f e c t s to compounds which have the a b i l i t y to i n h i b i t Na and C a transmembrane f l u x . Verapamil, D-600, d i l t i a z e m and n i l u d i p i n e , i n a d d i t i o n to i n h i b i t i n g of I j _ induce changes i n Na and, i n d i r e c t l y i n K transmembrane f l u x r e s u l t i n g i n pronounced decreases i n spontaneous r a t e (46_, 91 > 102). In c o n t r a s t to t h e i r e f f e c t s upon SA and AV a u t o m a t i c i t y , calcium i n h i b i t o r y compounds do 2 +

+

+

+

2 +

2 +

+

s


+

MUIR

Inhibitory

Compounds

and the Cardiovascular


3.

53

System

2200V/sec

M200V/sec ^ O m V 50msec Figure 4. Action potentials recorded from Purkinje fibers before (A) and after 1 Χ ΙΟ Μ (Β), 1 χ 10~ M (C), and 1 X 10' M (D) 2-n-butyl MDl (top) and quaternary 2-n-butyl MDl (bottom). Note the obvious prolongation in APD in C(bottom). 6

5

4

100


CALCIUM

54

REGULATION

BY CALCIUM

ANTAGONISTS

not a f f e c t , or only minimally suppress, spontaneous a c t i v i t y i n normal Tyrodes o r blood superfused Purkinje f i b e r s (51, 60, 61, 62, 102). T h i s f i n d i n g i s not s u p r i s i n g i n view of the lack of importance of the inward C a current i n determining spontaneous a c t i v i t y i n normal Purkinje f i b e r s . Those calcium i n h i b i t o r y compounds that do e x h i b i t the a b i l i t y to depress spontaneous normal automaticity i n P u r k i n j e f i b e r s a l s o e x h i b i t e f f e c t s upon membrane N a conductance. N i f e d i p i n e , a compound b e l i e v e d to a c t p r i m a r i l y by i n h i b i t i n g C a i n f l u x , has no e f f e c t upon P u r k i n j e f i b e r automaticity (60). Verapamil, a calcium i n h i b i t o r y compound with both N a and C a inhibitory a c t i v i t y , has been reported to cause no change or decreases i n P u r k i n j e f i b e r a u t o m a t i c i t y (62). Both 2-n-propyl and 2-n-butyl MDl, and AHR-2666 demonstrate i n s i g n i f i c a n t e f f e c t s upon the slope of phase 4 but depress a u t o m a t i c i t y i n Purkinje fibers. Calcium antagonists that depress spontaneous a c t i v i t y without a f f e c t i n g phase 4 d e p o l a r i z a t i o n presumably a c t by s h i f t i n g the threshold f o r a c t i v a t i o n of the inward N a current i n a p o s i t i v e d i r e c t i o n (51)· 2 +

+

2 +


+

2 +

+

E f f e c t s Upon Abnormal Automaticity In c o n t r a s t to t h e i r n e g l i g i b l e e f f e c t s upon normal automatic mechanisms i n P u r k i n j e f i b e r s , calcium i n h i b i t o r y compounds depress abnormal automaticity induced by a v a r i e t y of experimental techniques (51, 60, 61, 62, 99-102). Calcium i n h i b i t o r y compounds are p a r t i c u l a r l y u s e f u l i n suppressing impulse formation due to i n t r i n s i c changes i n membrane conductance which r e s u l t i n c y c l i c a l , pacemaker-like o s c i l l a t i o n s of d i a s t o l i c p o t e n t i a l (51, 80, 91)· This type of a c t i v i t y i s most commonly observed i n depressed, p a r t i a l l y d e p o l a r i z e d f i b e r s and has been termed " d e p o l a r i z a t i o n - i n d u c e d a u t o m a t i c i t y " (105)· Depending upon t h e i r temporal r e l a t i o n s h i p to normally produced a c t i o n p o t e n t i a l s , membrane o s c i l l a t i o n s are c a l l e d e a r l y or delayed a f t e r d e p o l a r i z a t i o n s (104)· Delayed a f t e r d e p o l a r i z a t i o n s are a l s o c a l l e d o s c i l l a t o r y a f t e r p o t e n t i a l s , t r a n s i e n t d e p o l a r i z a t i o n s , low amplitude p o t e n t i a l s and enhanced d i a s t o l i c d e p o l a r i z a t i o n s (104)· A f t e r d e p o l a r i z a t i o n s that are dependent on a p r i o r i n i t i a t i n g a c t i o n p o t e n t i a l , reach threshold and i n i t i a t e rhythmic a c t i v i t y are c a l l e d " t r i g g e r e d " (85, 105)« A f t e r d e p o l a r i z a t i o n s and t r i g g e r e d a c t i v i t y have been recorded from SA and AV nodes, s p e c i a l i z e d a t r i a l and v e n t r i c u l a r (Purkinje) f i b e r s , a t r i o v e n t r i c u l a r valve l e a f l e t s , coronary sinus t i s s u e , and v e n t r i c u l a r myocardium (51, 75, 80, 105, 106). In a recent review, i t was pointed out that membrane o s c i l l a t i o n s can be produced by s t r e t c h , ischemia, hypoxia, c o o l i n g , drugs (catecholamines, d i g i t a l i s , C a , B a , a c o n i t i n e , v e r a t r i n e ) , elevated P 02> a l t e r a t i o n s i n the e l e c t r o l y t e content of s u p e r f u s i o n s o l u t i o n s , and spontaneously 2 +

2 +

C


3.

MUIR

Inhibitory

Compounds

and

the

Cardiovascular

System

o c c u r r i n g disease (75)· The calcium i n h i b i t o r y compounds which have demonstrated the a b i l i t y to reduce or e l i m i n a t e membrane o s c i l l a t i o n s i n c l u d e m e t a l l i c ions ( M n , N i , C o ) , verapamil, D-600, n i f e d i p i n e , n i l u d i p i n e , d i l t i a z e m , p e r h e x i l i n e , AHR 2666, 2-n-propyl and 2-n-butyl MDl and many others (51, 60, 61, 62, 99-108). Recent evidence suggests that t r a n s i e n t r e l e a s e of i n t r a c e l l u l a r C a from sarcoplasmic reticulum i s r e s p o n s i b l e f o r the membrane conductance changes which produce membrane o s c i l l a t i o n s (104)· I f t h i s theory i s c o r r e c t , the e f f i c a c y of calcium i n h i b i t o r y compounds i n reducing and a b o l i s h i n g membrane o s c i l l a t i o n s can be l i n k e d to t h e i r a b i l i t y to l i m i t i n t r a c e l l u l a r calcium r e l e a s e , transmembrane C a i n f l u x , or both. Since p a r t i a l a c t i v a t i o n of the background inward Na current i s b e l i e v e d to be somewhat r e s p o n s i b l e f o r membrane o s c i l l a t i o n s , calcium i n h i b i t o r y compounds which i n h i b i t Na transmembrane f l u x (verapamil, D-600, p e r h e x i l i n e , AHR 2666, 2-n-propyl and 2-n-butyl MDI's) may be p a r t i c u l a r l y u s e f u l i n a b o l i s h i n g abnormal rhythm disturbances due to membrane o s c i l l a t i o n s (79)· 2+

2 +

2 +

2 +

2 +


+

+

E f f e c t s Upon Conduction Diseased Hearts

of the Cardiac Impulse i n Normal and

Cardiac a c t i v a t i o n i s dependent upon the proper timing and sequencing of c a r d i a c e x c i t a t i o n . A l t e r a t i o n s i n the pathways or conduction v e l o c i t y which r e s u l t i n normal c a r d i a c a c t i v a t i o n could lead to abnormal conduction p a t t e r n s and disturbances i n c a r d i a c rhythm (75)· The r e l a t i v e potencies of calcium i n h i b i t o r y compounds i n depressing c a r d i a c conduction v e l o c i t y i n i s o l a t e d t i s s u e s i s dependent upon dose and the type of t i s s u e being i n v e s t i g a t e d . Normal a t r i a l and v e n t r i c u l a r muscle, and P u r k i n j e f i b e r s demonstrate l i t t l e or no response to the negative dromotropic e f f e c t s of calcium i n h i b i t o r y agents unless exposed to extremely l a r g e drug concentrations (62, 100, 102, 109)· Tyrode's or blood superfused SA and AV nodal t i s s u e s demonstrate dose dependent decreases i n conduction v e l o c i t y when exposed to calcium i n h i b i t o r y compounds (96-100, 102). Recordings from the upper and middle p o r t i o n s of the AV node i n d i c a t e that calcium i n h i b i t o r y compounds cause a r e d u c t i o n i n a c t i o n p o t e n t i a l amplitude and upstroke v e l o c i t y and i n c r e a s e the e f f e c t i v e r e f r a c t o r y p e r i o d (102)· The i o n i c mechanisms r e s p o n s i b l e f o r the e f f e c t s of calcium i n h i b i t o r y compounds upon conduction v e l o c i t y i n SA and AV nodal t i s s u e s remain undetermined although i n h i b i t i o n of I i i s conjectured to be r e s p o n s i b l e f o r the m a j o r i t y of changes based upon r e v e r s a l of these e f f e c t s by increasing extracellular C a or catecholamine a d m i n i s t r a t i o n (46, 102, 104)· s

2 +

The e l e c t r o p h y s i o l o g i c c o r r e l a t e s of the e f f e c t s of calcium i n h i b i t o r y agents upon conduction v e l o c i t y i n i s o l a t e d


55


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c a r d i a c t i s s u e s are observed i n i s o l a t e d whole heart preparations (electrograms), and s p e c i f i c i n t e r v a l s of the electrocardiogram recorded from i n t a c t animals (4-8, 95, 96, 98, 99, 110-115). Drug e f f e c t s are dependent upon d i v e r s e hemodynamic, metabolic, autonomic and r e f l e x changes. For example, i n v i t r o s t u d i e s i n d i c a t e that n i f e d i p i n e i s twice as potent as verapamil i n slowing AV nodal conduction when both are administered at equal negative chronotropic concentrations (95)* In v i v o s t u d i e s , on the other hand, i n d i c a t e that n i f e d i p i n e i n c r e a s e s heart rate and does not a f f e c t AV nodal conduction, while verapamil prolongs AV nodal conduction and produces second degree AV block (89, 111, 115)* Furthermore, verapamil exerts i t s negative dromotropic e f f e c t s i n both innervated and denervated hearts ( i l l ) . Studies i n p a t i e n t s i n sinus rhythm support these f i n d i n g s by i n d i c a t i n g that while verapamil has no e f f e c t upon the R-R, QRS and Q-T i n t e r v a l s of the electrocardiogram, i t d r a m a t i c a l l y prolongs both the a t r i a l to His (A-H) time and the P-R i n t e r v a l (59, 111)· Similar s t u d i e s using n i f e d i p i n e i n r e s t i n g human p a t i e n t s are unable to demonstrate d i s c e r n a b l e e f f e c t s upon SA and AV nodal or His P u r k i n j e conduction (96). The calcium i n h i b i t o r y compounds, d i l t i a z e m and p e r h e x i l i n e , demonstrate e f f e c t s i n i n t a c t hearts midway between those of verapamil and n i f e d i p i n e (_6, 98). S e v e r a l i n v e s t i g a t o r s a t t r i b u t e the d i f f e r e n c e s caused by calcium i n h i b i t o r y compounds i n i n t a c t animals to the magnitude of t h e i r in v i t r o f a s t (Na ) versus slow channel ( C a ) i n h i b i t o r y a c t i v i t y and t h e i r a b i l i t y to i n i t i a t e r e f l e x autonomic e f f e c t s (114, 115)* For example, verapamil i n h i b i t s both I j j and I j _ i n v i t r o , but demonstrates minimal autonomic e f f e c t s i n v i v o (62, 111?"» N i f e d i p i n e , however, depresses I j _ i n v i t r o and e l i c i t s strong r e f l e x sympathetic a c t i v i t y jln v i v o TÎ14)· Studies of these calcium i n h i b i t o r y compounds which are b e l i e v e d to act i n t r a c e l l u l a r l y (2-n-propyl and 2-n-butyl MDI's) upon a u t o m a t i c i t y and conduction i n SA and AV nodes and ischemic myocardium remain to be done. c

+

a

2 +

s

s

The e f f e c t s of calcium i n h i b i t o r y agents upon conduction v e l o c i t y and delayed a c t i v a t i o n i n normal hearts may be e n t i r e l y d i f f e r e n t from that observed i n ischemic myocardium. In c o n s t r a s t to depressant I i dependent conduction e f f e c t s i n SA and AV nodes of normal hearts, verapamil has demonstrated the a b i l i t y to reduce the degree of ischemia-induced conduction delay i n anesthetized dogs a f t e r l i g a t i o n of t h e i r l e f t a n t e r i o r descending coronary a r t e r y (109, 110). Recent s t u d i e s using n i f e d i p i n e , d i l t i a z e m , n i s o l d i p i n e and n i l u d i p i n e have y i e l d e d r e s u l t s suggesting a s i m i l a r e f f e c t upon ischemiainduced conduction delay (109, 116-124)· These r e s u l t s imply that calcium i n h i b i t o r y compounds f a v o r a b l y a f f e c t myocardial oxygen supply and demand presumably by improving oxygen supply to ischemic areas v i a coronary c o l l a t e r a l blood flow. Furthermore, i t has been argued that the a d m i n i s t r a t i o n of s


3.

MUIR

Inhibitory

Compounds

and

the

Cardiovascular

System

57

calcium i n h i b i t o r y compounds p r i o r to i n f a r c t i o n improves recovery of myocardial f u n c t i o n a f t e r coronary a r t e r y l i g a t i o n by decreasing i n t r a c e l l u l a r C a and energy demand during the ischemic p e r i o d (78, 122, 125). The r e l a t i v e potency of the v a r i o u s calcium i n h i b i t o r y compounds i n producing t h i s myocardial " s p a r i n g " or " s a l v a g i n g " e f f e c t has not been determined. 2 +


Antiarrhythmic A c t i v i t y Calcium i n h i b i t o r y compounds are used as antiarrhythmic drugs because of t h e i r d i v e r s e e f f e c t s upon c a r d i a c e l e c t r i c a l a c t i v i t y and experimental evidence which suggests that the slow inward current i s important i n the genesis of c a r d i a c arrhythmias (126). A v a r i e t y of p o t e n t i a l l y t o x i c compounds i n c l u d i n g a c o n i t i n e , barium, d i g i t a l i s and catecholamines have been used to produce abnormal e l e c t r i c a l a c t i v i t y i n i s o l a t e d t i s s u e p r e p a r a t i o n s i n order to demonstrate the e f f e c t i v e n e s s of calcium i n h i b i t o r y compounds i n suppressing abnormal a u t o m a t i c i t y . Experimental s t u d i e s i n i n t a c t animals i n d i c a t e that calcium i n h i b i t o r y compounds possess v a r i a b l e a n t i arrhythmic e f f e c t s against a v a r i e t y of c h e m i c a l l y - ( d i g i t a l i s , calcium, catecholimines) and mechanically- (coronary o c c l u s i o n ) induced v e n t r i c u l a r arrhythmias (79, 81, 109, 110, 127, 128, 129» ) · The importance of I j _ i n the genesis of v e n t r i c u l a r arrhythmias a s s o c i a t e d with these pharmacologic and mechanical manipulations i s assumed but remains s p e c u l a t i v e . The c l i n i c a l value of the v a r i o u s calcium i n h i b i t o r y compounds i n e f f e c t i v e l y c o n t r o l l i n g c a r d i a c arrhythmias caused by t o x i c concentrations of d i g i t a l i s and n a t u r a l l y - o c c u r r i n g disease (ischemia, i n f e c t i o n , hypoxia) i s a l s o disputed (1-26, 150)· I t i s noteworthy that calcium i n h i b i t o r y compounds with the a b i l i t y to i n h i b i t Ifl + possess the most potent antiarrhythmic a c t i v i t y against both experimental and c l i n i c a l arrhythmias (126). For example, n i f e d i p i n e exerts minimal, i f any, antiarrhythmic e f f e c t against ischemic induced arrhythmias i n i n t a c t animals (_6, 87, 1 5 1 ) · D i l t i a z e m and p e r h e x i l i n e , on the other hand, demonstrate v a r i a b l e a n t i a r r h y t h m i c e f f e c t s dependent upon t h e i r dose and the mechanism r e s p o n s i b l e f o r arrhythmia p r o d u c t i o n (ischemia, hypoxia, d i g i t a l i s , a c o n i t i n e ) (102, 126, 151, 152)» Only verapamil, which has been i n v e s t i g a t e d i n the l a r g e s t number of experimental and c l i n i c a l t r i a l s , has demonstrated c o n s i s t e n t a n t i a r r h y t h m i c a c t i v i t y against c a r d i a c arrhythmias r e g a r d l e s s of cause ( 1 5 5 ) · C l i n i c a l e l e c t r o p h y s i o l o g i c s t u d i e s i n d i c a t e that verapamil i s e f f e c t i v e i n combating s u p r a v e n t r i c u l a r arrythmias i n c l u d i n g a t r i a l premature d e p o l a r i z a t i o n s , paroxysmal a t r i a l t a c h y c a r d i a , AV nodal re-entrant paroxysmal s u p r a v e n t r i c u l a r t a c h y c a r d i a , a t r i a l f i b r i l l a t i o n and a t r i a l f l u t t e r ( 1 5 4 ) » Verapamil i s a l s o p o t e n t i a l l y b e n e f i c i a l i n e l i m i n a t i n g s

a



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recurrent s u p r a v e n t r i c u l a r t a c h y c a r d i a i n p a t i e n t s with accessory pathways and p r e - e x c i t a t i o n (135)· Verapamil i s most e f f e c t i v e i n c o n t r o l l i n g c i r c u s movement t a c h y c a r d i a i n v o l v i n g accessory pathways when retrograde conduction i s involved r a t h e r than when conduction i s antegrade. Verapamil w i l l not slow v e n t r i c u l a r r a t e during a t r i a l f i b r i l l a t i o n o r antegrade conduction over the accessory pathway. In a d d i t i o n , s i n c e l a r g e doses of verapamil may shorten the c a r d i a c a c t i o n p o t e n t i a l and the e f f e c t i v e r e f r a c t o r y p e r i o d , i n c r e a s e s i n v e n t r i c u l a r r a t e have been reported ( 1 5 4 , 135)· Recent experimental evidence using 2-n-propyl and 2-n-butyl MDl i n d i c a t e s that these compounds possess antiarrhythmic potency equivalent to that of verapamil without producing bradycardia, ECG changes or a t r i o v e n r i c u l a r block (52, 1 5 6 ) . I t w i l l be i n t e r e s t i n g to determine i f the MDI's are e q u a l l y as e f f e c t i v e i n combating arrhythmias i n p a t i e n t s with n a t u r a l l y o c c u r r i n g heart disease as they are i n experimental animals. In summary, compared to d i l t i a z e m , n i f e d i p i n e , and p e r h e x i l i n e , verapamil demonstrates the most c o n s i s t e n t r e s u l t s i n the c o n t r o l of both experimental and c l i n i c a l arrhythmias. In none of the s t u d i e s reported to date, however, has verapamil been uniformly s u c c e s s f u l i n r e - e s t a b l i s h i n g normal sinus rhythm i n a l l animals o r p a t i e n t s although there i s a marked r e d u c t i o n i n the frequency of e c t o p i c v e n t r i c u l a r d e p o l a r i z a t i o n s (126, 1 5 4 ) · The important d i r e c t antiarrhythmic e f f e c t s of the various calcium i n h i b i t o r y agents are the r e s u l t of a combined i n h i b i t i o n of both I f l a ^si (126). A d d i t i o n a l explanations f o r the d i r e c t antiarrhythmic e f f e c t s of calcium i n h i b i t o r y agents i n c l u d e h y p e r p o l a r i z a t i o n of the c a r d i a c c e l l membrane thereby reducing calcium c e l l u l a r i n f l u x and membrane o s c i l l a t i o n s (51, 60, 62, 1 1 0 ) , i n c r e a s e s i n calcium uptake or decreased calcium r e l e a s e from sarcoplasmic r e t i c u l u m or mitochondria (7_, 7 8 , 1 0 0 ) , s t i m u l a t i o n of the sodium-calcium pump promoting calcium e f f l u x ( 5 5 ) , i n t e r f e r e n c e with the i n t r a c e l l u l a r calcium receptor of c o n t r a c t i l e p r o t e i n s , and binding to i n t r a c e l l u l a r r e g u l a t o r y p r o t e i n s (M.T.Piascik et a l , manuscript i n p r e p a r a t i o n ) . E q u a l l y as important, and p o t e n t i a l l y more c l i n i c a l l y r e l e v a n t , are the i n d i r e c t mechanisms r e s p o n s i b l e f o r the antiarrhythmic a c t i v i t y of calcium i n h i b i t o r y agents, i n c l u d i n g coronary v a s o d i l a t i o n and subsequent i n c r e a s e s i n coronary a r t e r y blood flow ( 4 7 , 114, 124, 1 5 7 ) ; decreased c a r d i a c c o n t r a c t i l i t y , metabolism, and a r t e r i a l v a s o d i l a t i o n r e s u l t i n g i n decreases i n myocardial oxygen consumption and w a l l t e n s i o n ; (92) and r e f l e x a l t e r a t i o n s i n autonomic r e g u l a t i o n of heart rate~~(overdrive supression) and AV conduction ( 1 1 4 ) . +

a

n

d


3.

MUiR

Inhibitory

Compounds

and

the

Cardiac and Smooth Muscle Mechanical

Cardiovascular

System

Activity

Cardiac Muscle. Calcium i n h i b i t o r y agents may i n t e r f e r e with e x c i t a t i o n - c o n t r a c t i o n coupling processes i n myocardial or v a s c u l a r smooth muscle c e l l s by a number of mechanisms including: l ) i n h i b i t i o n of the slow inward current through d i r e c t competition f o r slow channels or i n t e r f e r e n c e with the membrane binding of C a ; 2) i n t e r f e r e n c e with the r e l e a s e and uptake of calcium by the various i n t r a c e l l u l a r o r g a n e l l e s ; and 5) a l t e r a t i o n of the a c t i v i t y of s p e c i f i c r e g u l a t o r y p r o t e i n s ( t r o p o n i n , calmodulin). I t i s i n t e r e s t i n g to note that most calcium i n h i b i t o r y agents are from 5 to 10 times more e f f e c t i v e i n reducing smooth muscle c o n t r a c t i o n than i n reducing the f o r c e of myocardial c o n t r a c t i o n . Furthermore, u n l i k e c a r d i a c muscle where tropomyosin and t r o p o n i n are b e l i e v e d to be the important r e g u l a t o r y p r o t e i n s , a substance c a l l e d calmodulin serves a predominant r o l e i n smooth muscle


2 +

(158,

139).

Experiments u t i l i z i n g i s o l a t e d superfused and blood perfused c a r d i a c t i s s u e p r e p a r a t i o n s and i s o l a t e d r a t , r a b b i t , and cat whole hearts a l l demonstrate the potent, c o n c e n t r a t i o n dependent, negative i n o t r o p i c a c t i v i t y of the calcium i n h i b i t o r y compounds ( 4 5 , 5 0 , 9 0 - 9 5 , 112, 115, 114, 118, 140, 141)· Studies comparing the r e l a t i v e negative i n o t r o p i c e f f e c t s of s e v e r a l of the calcium i n h i b i t o r y compounds i n d i c a t e that those compounds e x h i b i t i n g the most potent calcium i n h i b i t o r y e f f e c t s i n v i t r o are the most e f f e c t i v e i n reducing c a r d i a c c o n t r a c t i l i t y i n v i v o ( 6 ) . Of those compounds most f r e q u e n t l y compared, n i f e d i p i n e and n i l u d i p i n e e x h i b i t the most profound negative i n o t r o p i c a c t i v i t y followed by verapamil (levo isomer), d i l t i a z e m and p e r h e x i l i n e ( 8 8 , 8 9 - 1 4 2 ) . In i s o l a t e d guinea p i g , r a t , r a b b i t and cat p a p i l l a r y muscle p r e p a r a t i o n s , the a d d i t i o n of a calcium i n h i b i t o r y compound to the superfusing s o l u t i o n decreases i s o m e t r i c or i s o t o n i c t e n s i o n long before measurable changes i n the c a r d i a c a c t i o n p o t e n t i a l occur ( 5 0 , 8 9 , 9 2 , 118, 1 4 2 ) . The subsequent a d m i n i s t r a t i o n of catecholamines or i n c r e a s e s i n the extracellular C a c o n c e n t r a t i o n ( 2 . 5 to 5 · 0 mM) w i l l p a r t i a l l y reverse these e f f e c t s and o r i g i n a l l y served as the b a s i s f o r the hypothesis that calcium i n h i b i t o r y compounds l i m i t sarcolemmal C a f l u x v i a slow channels ( l ) . As p r e v i o u s l y suggested, i n t r a c e l l u l a r mechanisms are important i n d e t e r mining the c o n t r a c t i l e e f f e c t s of calcium i n h i b i t o r y compounds. Experiments conducted i n our l a b o r a t o r y , studying the e f f e c t s of 2-n-propyl or 2-n-butyl MDl i n i s o l a t e d Tryrodes superfused canine p a p i l l a r y muscle p r e p a r a t i o n s , demonstrate t h e i r a b i l i t y to uncouple e x c i t a t i o n - c o n t r a c t i o n c o u p l i n g at drug concentrations which do not reduce a c t i o n p o t e n t i a l c h a r a c t e r i s t i c s i n c l u d i n g a c t i o n p o t e n t i a l amplitude, r e s t i n g p o t e n t i a l , d u r a t i o n at 2 5 , 5 0 , 90 percent r e p o l a r i z a t i o n and the rate of r i s e of phase 0 ( d V / d t ) . I n t e r e s t i n g l y , at drug concentrations g r e a t e r than 5 X 10"-> M, v e n t r i c u l a r muscle 2 +

2 +

m a x


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CALCIUM

ANTAGONISTS

a c t i o n p o t e n t i a l d u r a t i o n s a c t u a l l y increased (Figure 5)· The e x p l a n a t i o n f o r t h i s l a t t e r e f f e c t i s u n c e r t a i n , although s i m i l a r changes appear to be evident upon c l o s e i n s p e c t i o n of f i g u r e s reported by other i n v e s t i g a t o r s using a v a r i e t y of calcium i n h i b i t o r y compounds ( l , 92). I t i s e s t a b l i s h e d that C a * and K are involved i n maintenance and t e r m i n a t i o n of the p l a t e a u phase of the cardiac action potential. Furthermore, i n t r a c e l l u l a r calcium c o n c e n t r a t i o n c o n t r o l s membrane K p e r m e a b i l i t y v i a the v a r i o u s conductance components f o r K (gK^, gK2, g l ) (69)· It i s also e s t a b l i s h e d that a c t i o n p o t e n t i a l d u r a t i o n and myocardial t e n s i o n development are i n t e g r a l l y r e l a t e d (13)· In view of previous observations and explanations f o r the e x c i t a t i o n c o n t r a c t i o n c o u p l i n g process and the e f f e c t s of calcium i n h i b i t o r y compounds upon the cardiac a c t i o n p o t e n t i a l of v e n t r i c u l a r muscle and P u r k i n j e f i b e r s , one p o s s i b l e e x p l a n a t i o n f o r the e f f e c t s observed i n v e n t r i c u l a r muscle preparations i s that low concentrations of calcium i n h i b i t o r y compounds reduce the amount of i n t r a c e l l u l a r f r e e calcium i n the v i c i n i t y of the K channel, thereby changing the channel's c o n f i g u r a t i o n r e s u l t i n g i n a r e d u c t i o n i n gK and delayed r e p o l a r i z a t i o n of the v e n t r i c u l a r muscle a c t i o n p o t e n t i a l . When elevated c o n c e n t r a t i o n s of calcium i n h i b i t o r y compounds are used, the p l a t e a u phase of the a c t i o n p o t e n t i a l i s d r a m a t i c a l l y abbreviated r e s u l t i n g i n reductions i n a c t i o n p o t e n t i a l d u r a t i o n during a l l phases of r e p o l a r i z a t i o n . Depending upon the c a r d i a c f i b e r type (Purkinje f i b e r or v e n t r i c u l a r muscle) and c o n c e n t r a t i o n of the calcium i n h i b i t o r y compound under i n v e s t i g a t i o n , q u a n t i t a t i v e and q u a l i t a t i v e changes i n a c t i o n p o t e n t i a l plateau and r e p o l a r i z a t i o n are to be expected, although c o n t r a c t i l e f o r c e i s i n v a r i a b l y reduced. Smooth Muscle. A l l known calcium i n h i b i t o r y compounds decrease smooth muscle tone i n both the coronary and peripheral c i r c u l a t i o n s (113, 114, 115, 140, 143-147)» Comparative s t u d i e s using dogs suggest that t h i s e f f e c t v a r i e s i n i n t e n s i t y but surpasses negative i n o t r o p i c a c t i v i t y (114, 145)» N i f e d i p i n e , verapamil and p e r h e x i l i n e e x h i b i t t h e i r most pronounced v a s o d i l a t o r e f f e c t s upon femoral a r t e r i a l blood flow followed by coronary, r e n a l , and mesenteric beds (44, 47, 115)· D i l t i a z e m and n i s o l d i p i n e p r e f e r e n t i a l l y d i l a t e the coronary bed (47)· The coronary smooth muscle r e l a x i n g e f f e c t s of the 2 - s u b s t i t u t e d aminoindenes c l o s e l y resemble that produced by verapamil and prenylamine (53, 113)· Two-n-butyl MDl, i n p a r t i c u l a r , demonstrates a 4 - f o l d g r e a t e r coronary a r t e r i a l v a s o d i l a t i n g than negative i n o t r o p i c e f f e c t ( 1 1 3 ) · E q u a l l y as i n t e r e s t i n g and p o t e n t i a l l y of g r e a t e r c l i n i c a l s i g n i f i c a n c e than t h e i r a b i l i t y to d i l a t e coronary a r t e r i e s , i s the a b i l i t y of s e v e r a l calcium i n h i b i t o r y compounds to a f f e c t r e g i o n a l myocardial p e r f u s i o n i n such a way as to i n c r e a s e blood flow to ischemic myocardium (47, 148, 149· 150). 2

+

+

+


x

+

+



3.

MUiR

Inhibitory

Compounds

and

the

Cardiovascular

System

Figure 5. Action potentials and developed tension recorded from canine papillary muscle before (A) and after 1 χ JO Μ (Β) and 1 X 10 M (C) 2-n-butyl-MDl. Developed tension decreased by 25% (B) and 80% (C). 6

s


61


62

CALCIUM

REGULATION

BY

CALCIUM

ANTAGONISTS

N i s o l d i p i n e , n i f e d i p i n e and verapamil have r e c e n t l y been shown to i n c r e a s e t o t a l coronary c o l l a t e r a l transmural blood flow to ischemic areas of myocardium (47)· Only d i l t i a z e m d i d not produce an i n c r e a s e i n t o t a l transmural blood flow w i t h i n the ischemic zone, although the r a t i o of blood flow i n the subendocardium versus that i n the subepicardium was s i g n i f i c a n t l y i n c r e a s e d . Recent s t u d i e s e v a l u a t i n g the e f f e c t s of n i f e d i p i n e i n dogs with experimentally induced acute myocardial ischemia and i n f a r c t i o n i n d i c a t e that the dosage of calcium i n h i b i t o r y compound u t i l i z e d may be c r i t i c a l i n determining whether or not a b e n e f i c i a l e f f e c t i s obtained (122). Dogs r e c e i v i n g n i f e d i p i n e , 13 yg/kg, demonstrated a 30 percent f a l l i n a o r t i c pressure, a 12 percent r i s e i n heart r a t e , and an extension of t h e i r i n f a r c t zone. Dogs r e c e i v i n g n i f e d i p i n e , 1 ug/kg, demonstrated a 12 percent f a l l i n a r t e r i a l blood pressure, no change i n heart r a t e , and an improvement of r e g i o n a l myocardial p e r f u s i o n suggesting l i m i t a t i o n of i n f a r c t s i z e . Together these s t u d i e s i n d i c a t e that drug, drug dose, dosage rate and method of a d m i n i s t r a t i o n are c r i t i c a l i n determining whether or not a favorable r e d i s t r i b u t i o n of blood flow to ischemic myocardium i s obtained. Calcium I n h i b i t o r y Compounds and Myocardial

Ischemia

Regardless of the e f f e c t s of calcium i n h i b i t o r y compounds upon t o t a l myocardial p e r f u s i o n and the d i s t r i b u t i o n of transmural blood flow, s e v e r a l groups of i n v e s t i g a t o r s have demonstrated that verapamil and d i l t i a z e m can prevent the consequences of myocardial ischemia, p a r t i c u l a r l y m i t o c h o n d r i a l s w e l l i n g and d e s t r u c t i o n (150-153)· Myocardial calcium l e v e l s i n ischemic dog hearts i n c r e a s e to 10 to 20 times normal l e v e l s (78, 154)« Increased i n t r a c e l l u l a r calcium i n c r e a s e s i n t r a c e l l u l a r energy u t i l i z a t i o n , decreases ATP, and impairs m i t o c h o n d r i a l f u n c t i o n (78). Recent evidence suggests that ischemia of myocardial t i s s u e r e s u l t s i n an i n c r e a s e i n i n o r g a n i c phosphate c o n c e n t r a t i o n which induces m i t o c h o n d r i a l s w e l l i n g and uncoupling of o x i d a t i v e phosphorylation mechanisms by s t i m u l a t i n g e n e r g y - d i s s i p a t i n g i n t r a m i t o c h o n d r i a l c y c l i n g of calcium (148). Furthermore, a d i r e c t r e l a t i o n s h i p e x i s t s between the accumulation of m i t o c h o n d r i a l C a and the development of c o n t r a c t u r e i n myocardial muscle s t r i p s and the degree of v e n t r i c u l a r muscle s t i f f n e s s i n i n t a c t hearts (155)· Pretreatment of t i s s u e p r e p a r a t i o n s or i s o l a t e d h e a r t s with a v a r i e t y of calcium i n h i b i t o r y compounds i n c l u d i n g verapamil, d i l t i a z e m , n i f e d i p i n e , prenylamine, f e n d i l i n e and bencyclane prevents m i t o c h o n d r i a l s w e l l i n g and uncoupling of o x i d a t i v e phosphorylation and reduces i n t r a c e l l u l a r calcium (155, 156, 157)· The net r e s u l t s of these e f f e c t s are an i n c r e a s e i n adenine n u c l e o t i d e s , t i s s u e ATP, c r e a t i n e phosphate and improvement i n c a r d i a c f u n c t i o n (78). 2 +


3.

MUIR

Inhibitory

Calcium I n h i b i t o r y

Compounds

and

Compounds and

the

Cardiovascular

System

Hemodynamics

A p p l i c a t i o n of the knowledge of the e l e c t r o p h y s i o l o g i c , negative i n o t r o p i c , and v a s c u l a r smooth muscle e f f e c t s of calcium i n h i b i t o r y compounds i n i s o l a t e d t i s s u e preparations to normal and diseased animals or human p a t i e n t s i s d i f f i c u l t . The net hemodynamic e f f e c t s of calcium i n h i b i t o r y compounds vary considerably depending upon t h e i r d i v e r s e pharmacologic a c t i v i t i e s independent of C a i n h i b i t i o n , t h e i r dose response c h a r a c t e r i s t i c s , and t h e i r a b i l i t y to i n i t i a t e or i n h i b i t c e n t r a l nervous system r e f l e x mechanisms. The a d m i n i s t r a t i o n of calcium i n h i b i t o r y compounds to anesthetized or conscious animals and humans with a v a r i e t y of c a r d i a c diseases i s associated with a dose dependent negative i n o t r o p i c e f f e c t and decrease i n myocardial oxygen consumption (88, 89, 95, 112, 114, 158, 159, 160). In general and at appropriate dosages, indexes of myocardial f u n c t i o n i n c l u d i n g l e f t v e n t r i c u l a r pressure, l e f t v e n t r i c u l a r end d i a s t o l i c pressure, l e f t v e n t r i c u l a r stroke work, the f i r s t d e r i v a t i v e of l e f t v e n t r i c u l a r pressure ( d P / d t ) , maximum v e l o c i t y of c o n t r a c t i o n ( V ) , and a d i a s t o l i c r e l a x a t i o n constant are decreased, whereas coronary sinus oxygen s a t u r a t i o n , l e f t v e n t r i c u l a r end s y s t o l i c diameter, and cardiac output are increased (95_, 114, 159, 161, 162, 163) · Heart rate changes are unpredictable (161, 162). Various review a r t i c l e s have reported that calcium i n h i b i t o r y compounds cause an increase, decrease or no change i n heart rate (4, 6_ 95^, 151» 160). As the dose of calcium i n h i b i t o r y compound increases, however, tachycardia g e n e r a l l y develops (161)· The hemodynamic changes described can be r e l a t e d to the a b i l i t y of calcium i n h i b i t o r y compounds to produce p e r i p h e r a l v a s o d i l a t i o n ( a f t e r l o a d reduction) and the i n t e r p l a y between d i r e c t drug mediated and r e f l e x events. Calcium i n h i b i t o r y compounds demonstrate l i t t l e or no e f f e c t on venous capacitance. The a d m i n i s t r a t i o n of n i f e d i p i n e i n t o the l e f t coronary a r t e r y of normal human volunteers, f o r example, produces decreases i n d P / d t , maximum v e l o c i t y of c o n t r a c t i o n , and l e f t v e n t r i c u l a r stroke work (161). In c o n t r a s t , the intravenous a d m i n i s t r a t i o n of n i f e d i p i n e i n t o the i n t a c t c i r c u l a t i o n of conscious dogs or normal human v o l u n t e e r s f a i l s to produce major changes i n l e f t v e n t r i c u l a r stroke work, d P / d t or mean a o r t i c blood pressure since v a s o d i l a t i o n i s r e f l e x l y counteracted by i n c r e a s e s i n cardiac output and heart rate (159, 162). Studies conducted i n human p a t i e n t s with congestive heart f a i l u r e i n d i c a t e that the d i r e c t negative i n o t r o p i c and chronotropic e f f e c t s of n i f e d i p i n e are masked by r e f l e x sympathetic a c t i v a t i o n (165)· The hemodynamic e f f e c t s of verapamil are reportedly more v a r i a b l e than those e l i c i t e d by n i f e d i p i n e . Studies conducted i n dogs and humans r e v e a l i n o t r o p i c and v a s o d i l a t o r e f f e c t s s i m i l a r to those of n i f e d i p i n e except that r e f l e x t a c h y c a r d i a


2 +

m a x

m a x

9

m a x

m a x


63


64

CALCIUM

REGULATION

BY

CALCIUM

ANTAGONISTS

i s l e s s l i k e l y to occur (95, 156, 159, 164). The reduced l i k e l i h o o d of verapamil induced t a c h y c a r d i a i s a t t r i b u t e d to a more prominent d i r e c t negative chronotropic e f f e c t (164)» Heart r a t e e f f e c t s s i m i l a r to those reported f o r verapamil have been reported to occur a f t e r the intravenous a d m i n i s t r a t i o n of d i l t i a z e m to human p a t i e n t s and i n dogs administered verapamil, d i l t i a z e m , and 2 - s u b s t i t u t e d aminoindenes (5£, 95_, 140, 165) » The s i d e e f f e c t s reported i n p a t i e n t s r e c e i v i n g calcium i n h i b i t o r y compounds are an extension of the hemodynamic a c t i v i t y of t h i s group of compounds and g e n e r a l l y r e l a t e to drug potency and d i l a t i o n of r e g i o n a l v a s c u l a r beds (56, 151, 160). Depending upon dose, p o s t u r a l hypotension, d i z z i n e s s , headache, AV conduction disturbances, pulmonary edema, heart f a i l u r e and c o n s t i p a t i o n can occur (_6, 151, 166). Cardiac arrhythmias are a p o t e n t i a l problem and i f already present, could become more severe (161). The m a j o r i t y of these s i d e e f f e c t s are most f r e q u e n t l y reported f o l l o w i n g n i f e d i n e a d m i n i s t r a t i o n although a g r e a t e r long-term experience with a l l the calcium i n h i b i t o r y compounds i s required before a d e f i n i t e c o n c l u s i o n can be made regarding t h e i r s a f e t y . Despite the l i m i t e d knowledge concerning the usage of calcium i n h i b i t o r y compounds i n p a t i e n t s , s e v e r a l authors have adopted g e n e r a l p o l i c i e s regarding t h e i r a d m i n i s t r a t i o n . I t i s suggested that calcium i n h i b i t o r y compounds not be used or administered with c a u t i o n to p a t i e n t s with s i g n i f i c a n t SA or AV node disease, l e f t v e n t r i c u l a r outflow o b s t r u c t i o n , low s y s t o l i c blood pressure, paroxysmal n o c t u r n a l dyspnea or orthopnea (166). T h i s l i s t of c o n t r a i n d i c a t i o n s i s c e r t a i n to i n c r e a s e as the calcium i n h i b i t o r y compounds become more popular. In c o n c l u s i o n , calcium membrane f l u x e s and v a r i a t i o n s i n i n t r a c e l l u l a r calcium a c t i v i t y play a p i v o t a l r o l e i n maintaining normal smooth muscle and myocardial c e l l f u n c t i o n . The slow inward current ( l i ) c a r r i e d p r i n c i p a l l y by C a serves as the mechanism whereby e x t r a c e l l u l a r Ca^ can enter the myocardial c e l l to i n i t i a t e or t r i g g e r e x c i t a t i o n c o n t r a c t i o n c o u p l i n g . Although the mechanism(s) of calcium i n h i b i t o r y compounds are disputed, the net e f f e c t of t h e i r a d m i n i s t r a t i o n i s a r e d u c t i o n i n i n t r a c e l l u l a r calcium a c t i v i t y l e a d i n g to a v a r i e t y of b e n e f i c i a l and p o t e n t i a l l y d e l e t e r i o u s e f f e c t s . Because of the a b i l i t y of calcium i n h i b i t o r y compounds to regulate calcium a c t i v i t y and, t h e r e f o r e , a v a r i e t y of c e l l u l a r f u n c t i o n s , they are p o t e n t i a l l y b e n e f i c i a l as therapy f o r a n g i o s p a s t i c angina (167, 168), angina due to mechanical coronary a r t e r y o c c l u s i o n ( p l a t e l e t aggregation) (169), c a r d i a c arrhythmias (126), a r t e r i a l hypertension (170), acute or chronic l e f t v e n t r i c u l a r f a i l u r e (166), myocardial ischemia and i n f a r c t i o n (158, 165), myocardial s a l v a g i n g ( c a r d i o p l e g i a ) (155), cardiomyopathy (171) and v a r i o u s v a s o s p a s t i c syndromes (172). Compounds demonstrating calcium i n h i b i t o r y a c t i v i t y r e q u i r e f u r t h e r development and refinement 2 +

S

+


3.

MUIR

Inhibitory

Compounds

and

the Cardiovascular

System

before current understanding of the e x c i t a t i o n - c o n t r a c t i o n c o u p l i n g process and the t o t a l usefulness of t h i s group of compounds as t h e r a p e u t i c agents can be f u l l y r e a l i z e d .

Literature Cited 1. 2. 3.


4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

Fleckenstein, A. "Calcium and the Heart", Academic Press, New York, 1971, pp 135-188. Fleckenstein, A. Annu. Rev. Pharmacol. Toxicol. 1977, 17, 149-166. Church, J.; Zsoter, T. T. Can. J. Physiol. Pharmacol. 1980, 58, 254-264. Henry, P.D. "Trace Metals in Health and Disease", Raven Press, New York, 1979, pp 227-233. Zsoter, T. T. Am. Heart J. 1980, 99, 805-810. Henry, P. D. Am. J. Cardiol. 1980, 46, 1047-1058. Nayler, W. G.; Poole-Wilson, P. Basic Res. Cardiol. 1981, 76, 1-15. Fabiato, Α.; Fabiato, F. Annu Rev. Physiol. 1974, 41, 473-484. Langer, G. A. J. Mol. Cell. Cardiol. 1980, 12, 231-239. Ringer, S. J. Physiol. (Lond) 1882, 4, 29-42. McDonald, T. F.; Dieter, P.; Wolfgang, T. Circ. Res. 1981, 49, 576-583. New, W.; Trautwein, W. Pfluegers Arch. 1972, 334, 24-38. Trautwein, W.; McDonald, T. F.; Tripath, O. Pfluegers Arch. 1975, 354, 55-74. Fabiato, Α.; Fabiato, F. Circ. Res. 1977, 40, 119-129. Fabiato, Α.; Fabiato, F. Ann. Ν. Y. Acad. Sci. 1978, 307, 491-522. Langer, G. Α.; Frank, J. S. J. Cell. Biol. 1972, 54, 441-455. Langer, G. Α.; Frank, J. S. Am. J. Physiol. 1979, 237, H-239-H246. Fabiato, Α., Fabiato, F. Nature 1979, 281, 146-148. Thorens, S.; Endo, M. Proc. Japan Acad. 1975, 51, 473-478. Frank, J. S.; Langer, G. Α.; Nudd, L. M.; Seraydarian, Κ. Circ. Res. 1977, 41, 702-714. Langer, G. Α.; Frank, J. S.; Philipson, Κ. D. Circ. Res. 1981, 49, 1289-1299. Beeler, G. W. Jr.; Reuter, H. J. Physiol. 1970, 207, 211-229. Gibbons, W. R.; Fozzard, H. A. J. Gen. Physiol. 1975, 65, 367-384. Reuter, H. J. Physiol. 1967, 192, 479-192. Wollenberger, Α.; Will, H. Life Sci. 1978, 22, 1159-1178. Wray, H. L.; Gray, R. R. Biochim. Biophys. Acta 1977, 461, 441-459.


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27.

Cheung, W. Y. Science 1980, 207, 19-27.

28.

Katz, S.; Remtulla, M. A. Biochem. Biophys. Res. Commun.

29.

B i l e z i k j i a n , L. M.; Kranias, E. G.; P o t t e r , J . D.; Schwartz, A. Fed. Proc. 1980, 1663, A b s t r a c t . B i l e z i k j i a n , L. M.; Kranias, E. G.; P o t t e r , J . D.; Schwartz, A. C i r c . Res. 1981, 49, 1356-1362. C o l l i n s , J . H.; Kranias, E. G.; Reeves, A. S.; Bilezikjian, L.M.; Schwartz, A. Biochem. Biophys. Res. Commun. 1981, 99, 796-803.

1978,

30. 31.

32.


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LePeuch, C. J . ; Haiech, J . ; Demaille, J . G. Biochemistry 1979, 18, 5150-5157. G l i t s c h , H. G.; Reuter, H.; Scholz, H. J. P h y s i o l . (Lond) 1970, 209, 25-43. Reuter, H. C i r c . Res. 1974, 34, 599-605. Coraboeuf, E.; Deroubaix, E.; Hoerter, J. Supp.1, C i r c . Res. 1976, 38, I92-I98. Diamond, J . M.; Wright, Ε . M. Annu. Rev. P h y s i o l . 1969, 1, 581-646. Kohlhardt, M.; Bauer, B.; Krause, H.; F l e c k e n s t e i n , A. P f l u e g e r s Arch. 1972, 335, 309-322. Payet, M. D.; Schanne, O. F.; R u i z - C e r e t t i , E.J.Mol. Cell. C a r d i o l . 1980, 12, 635-638. Rosenberger, L.; T r i g g l e , D. J. "Calcium in Drug A c t i o n " ; Weiss, G.B., Ed.; Plenum Press: New York, 1978; 3-31.

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51.

S a n g u i n e t t i , M. C.; West, T. C. J . Pharmacol. Exp. Ther. 1981, 219, 715-722. Bristow, M. R.; Green R. D. Eur. J. Pharmacol. 1981, 45, 267-279. O'Hara Naoki; Ono H.; Oguro K,; Hashimoto, K. J. Cardiovasc. Pharmacol. 1981, 3, 251-268. Kaufmann, R. Munch. Med. Wochenschr. 199 Suppl 1977, 1, 6-11. Nagao, T, Sato, M, Nakajima, H, Kiyomoto, A. Chem. Pharm. Bull. 1973, 21, 92-97. F l e c k e n s t e i n , Α.; Tritthart, H. S.; Doring, H. J . ; Byon, Y. K. Arzneim. Forsch. 1972, 22, 22-33. Kodama, I . ; H i r a t a , Y.; Toyama, J . ; Yamada, K. J. Cardiovas. Pharmacol. 1980, 2, 145-153. W a r l t i e r , D. C.; M e i l s , C. M.; Gross, G. J.; Brooks, H. L. J . Pharmacola. Exp. Ther. 1981, 218, 296-302. Ledda, F.; M a n t e l l i , L.; Manzini, S.; Amerini, S.; M u g e l l i , A. J. Cardiovasc. Pharmacol. 1981, 3, 1162-1173. Gmeiner, R.; Ng, C. K. J . Cardiovasc. Pharmacol. 1981, 3, 237-250. Sutko, J . L.; W i l l e r s o n , J . T. C i r c . Res. 1980, 46, 332-343. S i e g a l , M S.; Gliklich, J . I.; Mary-Robine, L.; Hoffmann, B. F. J. Pharmacol. Exp. Ther. 1979, 211, 606-614.


3.

MUIR

Inhibitory

Compounds

and

the Cardiovascular

System


52.

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70

133. 134. 135. 136. 137.


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Calcium Regulation by Calcium Antagonists - American Chemical

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