Postgraduate Medical Journal (July 1974) 50, 441-446.

Verapamil and the myocardiumWINIFRED G. NAYLER

D.Sc.

Cardiothoracic Institute,2 Beaumont Street,London, W.

DENNIS KRIKLERM.D., F.R.C.P., F.A.C.C.

Cardiovascular Division, Royal PostgraduateMedical School, Hammersmith Hospital,

London, W.12

SummaryAlthough many of the drugs which recently have beendeveloped for use in relieving angina pectoris displayP-adrenoceptor blocking activity this property cannotbe essential, because verapamil relieves angina pec-toris without blocking the cardiac p-adrenoceptors.Like propranolol, verapamil slows the heart and re-duces both the peak tension developed during systoleand the rate at which that tension is developed. Vera-pamil further resembles propranolol in that it improvescardiac efficiency, reduces the oxygen requirement ofthe heart and abolishes certain arrhythmias. Vera-pamil differs from propranolol, however, in that it doesnot antagonize the cardiac P-adrenoceptors and itdilates the coronary vessels. Verapamil probably owesits activity to its ability to interfere with the inwardsdisplacement of calcium ions across cardiac cellmembranes.

MANY of the drugs which have been developed duringthe past decade for use in the relief of angina pectorishave proved useful for the treatment of cardiacarrhythmias. Some of these compounds, e.g. pro-pranolol, oxprenolol and pindolol, exhibit I-adreno-ceptor blocking activity but others-for exampleveraoamil (Nayler et al., 1968a; Livesley et al., 1973;Krikler, 1974) do not. The mode of action of thesenewly developed drugs is perhaps most easily ex-plained if it is discussed in terms of the sequence ofevents which are involved in the contraction-relaxation cycle of cardiac muscle (Langer, 1968;Nayler, 1974) as well as in terms of the main deter-minants of myocardial oxygen consumption (Sarnoffet al., 1958; Braunwald, 1971). This in turn requiresan understanding of the subcellular organization ofthe cardiac muscle cell.

In cardiac as in skeletal muscle the fundamentalunit of muscle structure is the sarcomere, defined asthe distance between two adjacent Z bands. Z bandsare easily visible in the electromicrograph shown

Correspondence: Dr Winifred G. Nayler, CardiothoracicInstitute, 2 Beaumont Street, London, WIN 2DX.

in Fig. 1. Within each sarcomere the contractile pro-teins are arranged to form a regular, but interdigitat-ing array of thick (myosin) and thin (actin) filaments(Huxley, 1969). Contraction involves the regulateddisplacement of the actin along the relatively thickermyosin filaments such that whilst the length of eachactin and each myosin filament remains constant thedistance between adjacent Z bands changes. The dis-placement of the actin along the myosin filaments isa complex process (Katz, 1971) requiring the sequen-tial formation and activation of cross-bridges betweenthe adjacent filaments. Energy for the formation andactivation of these cross-bridges is derived from thehydrolysis of adenosine triphosphate (ATP). Therelevant ATPase enzyme forms part of the myosinmolecule. It is Mg2+-dependent and is activated byboth actin and Ca2+. The Ca2+-induced activationof the myosin ATPase enzyme is indirect and com-plex. It involves an interaction between Ca2+ andthe regulatory proteins (Katz, 1971; Nayler, 1974)within the myofilaments, as shown schematically inFig. 2.When Ca2 + is either absent or its concentration

falls below a critical level these regulatory proteins(troponin and tropomyosin) prevent actin fromactivating the myosin ATPase enzyme (Ebashi andEndo, 1968). When sufficient Ca2+ becomes avail-able, however, then this inhibiting effect of theregulatory proteins is suppressed and accordinglythe actin-induced activation of the myosin ATPaseenzyme can proceed. Now, provided that sufficientATP is available for hydrolysis, that the myosinATPase is active and that its various co-factors,including Mg2 +, are present, then, as shown schema-tically in Fig. 3, the transition from diastole to systoledepends simply upon an increase in the intracellularavailability of Ca2+. When the intracellular Ca2+concentration exceeds a critical level ofapproximately10-7M the rate at which the myosin ATPase enzymehydrolyses ATP is probably just sufficient (Weberand Herz, 1963) to provide the high energy phosphatebonds needed to facilitate cross-bridge formationand activation. Under conditions such as these the

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..,. *;

...::~~::::.::

:..,, -, :..-.:

*=-!..: :. ·:·:::

'S.. ....'S>.;,..

FIG. 1. Electromicrograph of part of the heart muscle cell. Note the Z bands, actin and myosin filaments,the sarcoplasmic reticulum and the cell membrane. (x 28,000.) Z = Z band; M = myosin; A = actin;SR = sarcoplasmic reticulum; CM = cell membrane.

Contractile proteins + Ca2+sensitive + ATP + Excitation(Actin +Myosin) 'regulatory' proteins

(Troponin+Tropomyosin) 2+CP Ca

Actin-induced activationof the myosin ATPase enzyme

ATP - ADP+ P + Energy

Activation of cross-bridgesbetween actin and myosin

Contraction

FIG. 2. Schematic representation of the events involved in the activationof contraction.

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Verapamlil and the myocardium 443

Activated by Ca2+ Ca2+ > 1O-7

Diastole Systole

Activated by removing Ca2+ Ca 1+IO-Mfrom the myofilaments

FIG. 3. Schematic representation of the involvement ofCa2+ in the systole - diastole - systole cycle in heartmuscle.

rate at which the muscle develops tension and under-goes shortening depends largely upon the intra-cellular availability of Ca2+, because this regulatesthe rate of ATP hydrolysis. The transition fromsystole to diastole reflects the reverse phenomenon-that is a reduction in the intracellular availability ofCa2+ (Schwartz, 1971) such that the regulatory pro-teins, troponin and tropomyosin, can re-exert theirinhibitory effect on the actin-reduced activation ofthe myosin ATPase enzyme.

Because of the relative importance of the rolewhich Ca ions play in regulating the transition fromdiastole > systole --- diastole, shown schemati-cally in Fig. 3, it is not surprising to find that con-siderable effort has been expended in experimentsaimed at establishing how the intracellular avail-ability of Ca2+ is regulated to facilitate either con-traction or relaxation as exhibited in the cardiac cycle.These studies have shown that resting heart musclecells have a potential difference of approximately 90mV, the inside being negative with respect to the out-side, and that the reversal of this transmembranepotential difference, such as that which (Fig. 4) occursduring the rising phase of a cardiac action potential,is accompanied by the influx of Ca2 + as well as Na4(Nayler and Merrillees, 1971). Some of the Ca2+which is involved in this influx is derived from theextracellular phase but some of it is probably dis-placed inwards from superficially located storagesites associated with the polysaccharides in the base-ment coat of the cell membrane (Langer, 1971;Nayler, 1973). When displaced inwards some of theseCa ions may activate contraction directly, but someof them probably function as a 'transmitter-like'

xERCGceSNUIG phase

:r.:.;S.:ar phase-,- 2+

NolXd b' *vopsgfiActvd by cchbw*

FIG. 4. Schematic representation of the Ca2+ and Na+influx associated with the rising and plateau phases of thecardiac action potential. Note that verapamil impedesthe influx of Ca2+.

substance, evoking the release of more Ca2 + fromintracellular storage sites. These intracellular storagesites are almost certainly associated with the sarco-plasmic reticulum, that fine lace-like network oftubules seen in Fig. 1, and which envelopes the myo-fibrils, crossing from sarcomere to sarcomere andcoming into close proximity to the cell membraneand its intracellular ramifications (Porter, 1961).This subcellular organelle can accumulate and storeCa2+ against a considerable concentration gradient(Schwartz, 1971). Presumably, therefore, it serves adual function:

(a) to provide a source of Ca2+ which can be re-leased into the vicinity of the myofibrils to facilitatecontraction;

(b) to provide a mechanism for retrieving Ca2from the sarcoplasm, to facilitate relaxation.That the catecholamines increase both the peak

tension developed during contraction and the rate atwhich that tension develops is now firmly established.These catecholamine-induced changes in contrac-tility almost certainly can be accounted for in termsof an increase in the amount of Ca2 + (Shigenbouand Sperelakis, 1972) which enters the cell during therising and plateau stages of the action potential,shown schematically in Fig. 4. Whether this catechol-amine-induced increase in the amount of Ca2 + whichbecomes available for interaction with the myo-fibrillar proteins results from the activation of amembrane-located adenyl cyclase enzyme is not yetfirmly established, but it is known that cardiac cellmembranes contain an active adenyl cyclase enzymecapable of converting ATP to 3' 5' AMP (Rubio,Berne and Dobson, 1973), and that under certainconditions 3' 5' AMP facilitates the transfer of Ca2 +

across isolated membranes (Kirchberger et al., 1972).

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444 W. G. Nayter and D. Krikler

Extracellulr phase

Activated by Inactivated byc h-eon

-i:!i:j:-..:: :..::"..........:.....::.:.jim::.:.::::......./.. .::......-::?:::

Introcellur..

..... .. ... ......

...

.. .. .. .. ...... . : .:......I

.s.. .. .'

...+co'-re*ukj

FIG. 5. Schematic representation of the pathways in-volved in activation by ,-adrenoceptor agonists and in-activation by P-adrenoceptor antagonists of the adenylcyclase enzyme. Note that in the presence of the 3' 5'AMP-dependent kinase 3' 5' AMP facilitates the uptakeof Ca2+ by the sarcoplasmic reticulum.

As well as increasing the peak tension developedduring contraction and the rate at which that tensionis developed the catecholamines accelerate the tran-sition from systole to diastole. Recent studies(Katz and Repke, 1973) have shown that this cate-cholamine-induced increase in the rate at whichcardiac muscle undergoes relaxation may be due toa 3' 5' AMP-dependent increase in the rate at whichCa2+ is accumulated by the sarcoplasmic reticulum.The scheme of events which may be involved in thisprocess is shown schematically in Fig. 5. By activat-ing the adenyl cyclase enzyme the catecholaminesincrease the intracellular availability of 3' 5' AMPand therefore, indirectly, increase the rate at whichCa2 + is accumulated by the sarcoplasmic reticulum.This in turn should facilitate the transition fromsystole --* diastole.The presently available 3-adrenoceptor antagonists

block many of these catecholamine-induced changesand therefore can be used clinically to protect themyocardium against the effects of excessive sympa-thetic stimulation (Nayler and Carson, 1973). Theseeffects ofsympathetic stimulation include, in additionto the enhanced contractile force and rate of tensiondevelopment, an increase in heart rate (Braunwaldand Chidsey, 1965). When it is recalled that the maindeterminants of myocardial oxygen consumption(Sarnoff et al., 1958; Braunwald, 1971) include rateof tension development, the peak tension developedduring systole and heart rate (Table 1) then it is notaltogether surprising to find that P-adrenoceptorantagonists are useful in limiting the myocardialdemand for oxygen (Hamer, 1968; Nayler andCarson, 1973) and therefore have proved useful forthe treatment of angina pectoris. The presently avail-

able P-adrenoceptor antagonists generally increasethe overall efficiency with which the heart performsuseful mechanical work (Nayler et al., 1967, 1968b).Some of them (Nayler et al., 1967) increase coronaryvascular resistance. Because of their P-adrenoceptorblocking activity, however, they deprive the heart ofsympathetically-mediated support.The use of P-adrenoceptor antagonists as anti-

arrhythmic compounds largely reflects their abilityto protect the heart against the effects of excessiveneurotransmitter release (Vaughan Williams, 1972).However, some of this antiarrhythmic activity, par-ticularly when high dose levels are established, mayinvolve the ability of these drugs to interact with thecell membrane in such a way as to render that mem-brane less permeable to various ions, including Na +and Ca2+ (Nayler et al., 1969). Interaction with thecell membrane to limit its permeability to Ca2 + is notthe prerogative of P-adrenoceptor blocking drugs;for example the drug verapamil, which although de-void of 3-adrenoceptor blocking activity, is useful forthe relief of angina pectoris and the relief of certainarrhythmias (Singh and Vaughan Williams, 1972;Krikler, 1974) and owes its activity to its ability toimpede the entry of Ca2+ into the cardiac musclecell (Fleckenstein, 1971; Nayler and Szeto,1972).

Like propranolol (Table 2) verapamil decreasescardiac contractility and heart rate (Nayler et al.,1968a). Like propranolol, therefore, it decreases themyocardial demand for oxygen (Nayler and Szeto,1972). However, in marked contrast to propranolol(Nayler et al., 1967) verapamil reduces coronaryvascular resistance (Nayler et al., 1968a). Both drugsincrease the efficiency with which the heart performsuseful mechanical work (Nayler et al., 1968a and b;Nayler and Szeto, 1972). These effects of propranololand verapamil are summarized in Tables 1 and 2.Despite the similarities which exist between thesedrugs verapamil differs from either propranolol,

TABLE 1. Effect of drugs on myocardial oxygen consump-tion and cardiac efficiency

Verapamil Propranolol Noradrenaline

Myocardial O2consumption

Cardiaccontractility T

Coronary blood thenflow t

Heart rate 4 tCardiac

efficiency

Where t denotes an increase and 4 a decrease.

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Verapamil and the iyocartilul 445

TABLE 2. Effect of drugs on contraction and relaxation inheart muscle stimulated to contract at a regular rate

Drug Verapamil Propranolol Noradrenaline

Peak developedtension

Rate of tensiondevelopment

Time required forrelaxation

Where t denotes an increase and, a decrease.

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