15

From Medical Department B, Rikshospitalet, and Institute of Pharmacology, University of Oslo, Oslo, Norway

Calcium, Calcium-antagonistic Drugs and the Heart

Knud Landmark and Helge Refsum

Cardiac electrophysiology with special reference to calcium The action potential of the cells in various parts of the heart are different (HOFFMAN & CRANEFIELD 1960; CRANEFIELD 1975) -I00

-

A Fig. 1 . Changes in the action potential as the cardiac impulse propagates from the sinus node and downwards to the atrium, artioventricular node, Bundle of His. Purkinie fibre, terminal Purkinie fibre and ventricle. From HOFFMAN & CRANE-

FIELD 1960.

(Fig. 1). The cardiac impulse arises in automatic cells in the sinus node. These cells have a low, unsteady resting potential. As the result of spontaneous diastolic depolarization the threshold potential is reached, resulting in an action potential. These action potentials show a very slow depolarization phase and a low conduction velocity. The atrial fibres immediately adjacent to the sinus node have a higher resting potential, a more rapid depolarization and a higher conduction velocity. When the action potentials reach the atrioventricular node, they undergo a drastic change. Here they resemble the action potentials of the sinus node, except that they do not exhibit automatic activity under normal conditions. As a result of the slow conduction velocity within the nodal fibres, the conduction time in the atrioventricular node represents approximately the half of the total PQ interval (Fig. 2). As the action potentials emerge from the lower portion of the bundle of His, they once again encounter fibres that have high resting potentials and high conduction velocities. The conduction velocity of Purkinje fibres can be as much as 100 times higher than that seen in the atrioventricular node. When the cardiac impulse reaches its final destination in fibres of the ventricular myocardium, it finds fibres that have high resting potentials, rapid depolarization and high conduction velocities.

.

16

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ties of the membrane with different ions carrying charges into and out of the cell. The initial, rapid depolarization (the fast component) is considered due to a large, but transient increase in the permeability of the cell membrane for sodium ions, resulting in a substantial increase of the sodium influx (NOBLE 1962; LANGER 1967; REUTER & BEELER 1969a). The maximum rate of the depolarization has been found linearly related to the external sodium concentration (DfiLhZE 1959; BRADY & WOODBURY 1960; HOFFMAN & CRANEFIELD 1960; WOODBURY 1962). The ability of the membrane to develop that large, rapid increase in permeability for sodium is dependent on the membrane potential, being inactivated by the depolarization (Fig. 3). Conduction velocity of impulses in cardiac muscle is directly related to the rate of depolarization in the same fibres (CONN & LUCHI 1964; SINGER et aE. 1967). *20,

a

0-

S

= d

Fig. 2. Schematic representation of the conduction

system above, and underneath are a standard electrocardiogram (SE) and a typical bipolar electrocardiogram (BE) recorded simultaneously. SAN is the sinus node, AVN the atrioventricular node, BH bundle of His and LB and RH the left and right branch respectively. AH is the conduction time through the atrioventricular node, HV the conduction time in the His-Purkinje system, A is a bipolar atrial electrogram and V is a bipolar ventricular electrogram. From NARULA et al. 1971. As in all excitable cells the electrolytes in cardiac muscle are unevenly distributed between the extracellular and the intracellular space (TRAUTWEIN 1963; LANGER 1968; TRAUTWEIN 1973). Cardiac cells have an intracellular concentration of potassium ions much higher than that of the extracellular fluid. The opposite is true for the concentration of sodium ions. In the resting state the cell membrane is more permeable to potassium than to other ions, and there is a tendency for potassium to move out of the cell. An equilibrium is reached at a voltage of about -60 to -90 mV. The inside is negative with respect to outside. The cardiac action potential results from a sequence of changes in the ionic permeabili-

c =

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Fig. 3. schematic representation of ion fluxes associated with the cardiac action potential. From NAYLER & MERRILLEES 1971.

The repolarization phase which follows after the depolarization, is a much slower process and has been explained by decreased sodium permeability and an increase of the potassium permeability, particularly towards the end of the action potential (FOZZARD & GIBBONS 1973; NOBLE 1975). The shape of the cardiac action potential, including the formation of a

17 plateau phase, can be satisfactory described in terms of different rates of change in sodium and potassium permeability (NOBLE 1962). However, during the past few years the demonstration of a slow inflow of positive ions (the slow component) during the plateau phase, has necessitated a modification of these notions. This flow is dependent on the extracellular calcium concentration, and the process has been interpreted as an inflow of calcium or calcium/ sodium ions which starts when the depolarization has reached a certain level (REUTER 1967; CARMELIET & VEREECKE 1969; ROUGIER et al. 1969; REUTER 1975). It has been suggested that the time course of the repolarization in mammalian cardiac prepara-

tions is predominantly determined by the inactivation of this slow ionic inward current (BEELER & REUTER 1970). LANGER (1968) has stated that the lowering of the extracellular calcium concentration decreases the outward potassium conductance which will prolong the plateau phase of the cardiac action potential. Further, ISENBERG (1975) has recently suggested that an elevation of the intracellular calcium concentration increases the potassium conductance. Increasing extracellular calcium concentrations shortens the time for the repolarization and thereby also shortens the effective refractory period (REFSUM & LANDMARK 1976) (Fig. 4 and 5).

1 L100 msec 2

5

8

[ c a + j0 (meq/l)

Fig. 4.Action potentials recorded from isolated rat atria at 2.0, 5.0 and 8.0 meq./l calcium, illustrating

shortening of the action potential duration with increasing external calcium concentrations. From REFSUM & LANDMARK 1976.

6o

r I

111 30 30 LO 50 60 70 80 90 EFFECTIVE REFRACTORY PERIOD ( m s e c l

Fig. 5. Relationship between the effective refrac-

tory period and the time for 90 per cent repolarizaand tion of the action potential at 2.0 (A),5.0 (0) 8.0 (0) meq./l of calcium. From REFSUM & LANDMARK 1976.

In the contractile fibres of the atrium and ventricle and in His-Purkinje fibres the two components (fast and slow) seem to be responsible for the depolarization (PAES DE CARVALHO et al. 1966 & 1969; FABIATO & FABIATO 1971). An other kind of cardiac action potential, known as the slow response (CRANEFIELD 1975), is seen under normal conditions in the cells of the sinus and atrioventricular node. The rate of depolarization is slow, and is related to influx of calcium or calcium/sodium ions (the slow component) (PAES DE CARVALHO et al. 1969). Tetrodotoxin (TTX) which blocks the influx of sodium ions, abolishes action potentials in the atrium, but not in the sinus node. Manganese ions which block the influx of calcium ions, have the opposite effect (LENFANT et al. 1968)

Fig. 6. Effect of tetrodotoxin (TTX) (B) and Mn++ions (C) on action potentials recorded from rabbit

atrium and sinus node, respectively. Tetrodotoxin inhibits the generation of action potentials in the atrium. but not in the sinus node. Mn++ions inhibits action potential generation in the sinus node, but not in the atrium. From LENFANT et a / 1968. (Fig. 6). In the isolated rabbit heart MnC12 depresses atrioventricular conduction without blocking conduction in the atrium of His bundle; on the other hand, TTX suppresses activity in the atrium or His bundle; but not in the artioventricular node (WATANABE 1970; ZIPES & MENDEZ 1973). Finally, URTHALER & JAMES (1973) found that in reserpinized dogs, selective perfusion with 'ITX failed to slow the sinus node and did not impair atrioventricular conduction. Catecholamines which enhance the calcium influx during the excitation (CARMELIET & VEREECKE

1969; MEINERTZ & SCHOLZ 1969; SHINEBOURNE et al. 1969; BEELER & REUTER 1970; ENTMAN 1970; PAPPANO 1970; KATZ & REPKE 1973), increase the veIocity of the depolarization in the fibres in the atrioventricular node (MATSUDA et al. 1958) (Fig. 7), thereby increasing atrioventricular nodal conduction (KRAYER et al. 1951; HOFFMAN et al. 1960; DAMATO & LAU 1970). Acetylcholine which reduces calcium influx (GROSSMAN & FURCHGOTT 1964; HODITZ & LCJLLMANN 19641, has the opposite effect (MATSUDA et al. 1958).

19

Fig. 7. Effect of

acetylcholine (A) and adrenaline (B)on action potentials recorded from fibres of the atrioventricular node. From MATSUDA et al. 1958.

Damaged and diseased cells in the atrium, ventricle and ventricular conducting system can generate an electrical response that differs fundamentally from that of their normal cells. In partly depolarized fibres inactivation abolishes the rapid sodium current and the slow response arises (CRANEFIELD et al. 1972). It has been suggested that many disturbances of cardiac rhythm are caused by fibres that show slow response activity, and that this slow response is due to a slow ionic inward current carried by calcium or calcium/sodium ions (SINGH & VAUGHAN WILLIAMS 1972; SURAWICZ 1974; CRANEFIELD 1975; ZIPES el al. 1975). Sympathetic activity may elicit slow response action potentials and cause re-entry which is associated with slow conduction and undirectional block (ROSEN & HOFFMAN 1973). It has previously been reported that in rabbit atria 66 per cent of sodium could be replaced without changing the sinus automaticity (HOFFMAN & CRANEFIELD 1960; TODA & WEST 1967). Inaddition, YAMAGISHI & SANO (1966) found that the slow diastolic depolarization of the pacemaker cells in the sinus node was not affected by high concentrations of TTX, which specifically blocks the fast sodium channel. However, a positive chronotropic action of extracellular calcium within a

certain concentration range, has been found in different species by several investigators (REITER & NOE 1959; FEINBERG et al. 1962; PARADISE 1963; SEIFEN et al. 1964; SCHAER 1964; TODA & WEST 1967, SEIFEN 1968; REFSUM 1975b; REFSUM et al. 1976). The rate of spontaneously beating rate atria is almost unchanged when the potassium concentration in the Ringer solution varies within the range from 1.325 to 10.6 meq./l (LANDMARK 1972a). This relative insensitivity towards an increase in the potassium concentration in rat sinus fibres is in accordance with observations made in isolated atria of other mammals (de MELLO & HOFFMAN 1960; TODA & WEST 1967; TODA 1969). However, arrhythmias of different origin have been found in some rat atrial preparations when these were suspended in a Ringer solution containing 1.325 meq./l of potassium (LANDMARK 1972a). This may be related to an unfavourable calcium/potassium ratio (GRUMBACH et al. 1954), to a disturbance of the repolarization observed upon a reduction in the potassium concentration (HOFFMAN & CRANEFIELD 1960), to an enhancement of automaticity by increasing the diastolic depolarization (SINGER & TEN EICK 1969), to a loss of intracellular potassium (KLEIN et al. 1960) or to a combination of these possibilities.

20 Calcium and excitation-contraction coupling in cardiac muscle The cardiac action potential triggers the initiation of the contractile response, but in addition it also serves as a determinant of contractility (KAVALER 1959; MORAD & TRAUTWEIN 1968; ANTON1 et aZ. 1969; REUTER & BEELER 1969b; WOOD et al. 1969; OCHI & TRAUTWEIN 1971; TRITTHART et al. 1973; TRAUTWEIN et al. 1975). One of the final steps in the chains of events inducing contraction, is an increase in the calcium concentration at the site of the contractile element. Since a calcium current is known to flow into the cell during the cardiac action potential, its role in the excitation-contraction coupling is of great interest. Excitation occurs at the cardiac cell membrane, whereas contraction is an intracellular phenomenon. The calcium ion acts as a mediator between the bioelectrical events at the cell surface and the intracellular biochemical processes which utilize ATP for contraction (HASSELBACH & WEBER 1965; EBASHI & E N D 0 1968; KATS 1970; CARMELIET et al. 1973). During excitation an increased transmembrane calcium influx takes place simultaneously with liberation of calcium from the sarcoplasmic reticulum. This rapid rise in free intracellular calcium initiates the splitting of ATP by the calciumdependent actinmyosin ATPase of the myofibrils so that phosphate-bound energy is transformed into mechanical work (FLECKENSTEIN 1971).

300

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Fig. 8. Effect of increasing the extracellular cal-

cium concentration on the contractile force of isolated rat atria. From LANDMARK 1972.

The concentration of calcium in the Ringer solution determines quantitatively the force of contraction of isolated cardiac muscle (REITER 1964; JORK et al. 1967; TODA 1969; LANDMARK 1972b) (Fig. 8). The presence of external calcium is of prime importance for the maintenance of cardiac contractility (RINGER 1882), and a proportionality between the changes in calciuminflux in cardiac muscle during depolarization and the changes in contractile force has been suggested (WINEGRAD & SHANES 1962; NIEDERGERKE 1963; LANCER 1968; REUTER & BEELER 1969b; CHAPMAN & TUNSTALL 1971). If calcium is removed, contractile force will decrease and finally cease; action potentials can, however, still be elicited (Fig. 9). The positive staircase

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Complete loss of contractility of isolated rabbit papillary muscle in a calcium-free Tyrode solution, while action potentials still can be elicited. Rapid recovery in normal Tyrode solution. From FLECKENSTEIN 1971.

Fig. 9.

21 phenomenon observed with an increase in the frequency of contractions is characteristic of the myocardium of most species. HAACKE et al. (1970) have demonstrated that in the isolated quinea-pig auricle, which displays a positive staircase phenomenon (Bowditch phenomenon), the amount of calcium entering the cell per single excitation is significantly decreased at rising frequencies. Hence, the positive inotropic effect of an increase in heart rate cannot be explained in terms of an increased quantity of inflowing calcium per beat, but probably by an increased release of stored calcium with the balance between the calcium influx or mobilization and calcium elimination being adjusted to a higher level (WOOD et al. 1969; KLAUS 1971). LITTLE & SLEATOR (1 969) have suggested that any additional calcium involved in larger contractions at higher frequencies comes from an increase in calcium ions available from intracellular stores. Relaxation occurs as the sarcoplasmatic reticulum pumps the calcium back into its lacunae (OLSON 1971).

Calcium-antagonistic drugs The role of calcium in the excitation-contraction coupling in cardiac muscle is illustrated by the fact that many substances with positive or negative inotropic effect exert this influence by either increasing or decreasing, respectively, the calcium supply to the contractile system. Positive inotropic substances e.g. adrenergic /+receptor stimulating agents, increase the amount of calcium available for the contractile element, whereas a number of negative inotropic substances inhibit excitation-contraction coupling due to a calcium-antagonistic effect (FLECKENSTEIN 1971 ; REFSUM & LANDMARK 1977). Bivalent ions e.g. cobalt, nickel, magnesium and manganese, compete with the calcium ions so that the excitation-contraction coupling may be abolished. However, this effect can be rapidly overcome by the administration of calcium chloride, and the original contractile strength can be obtained (KAUFMANN & FLECKENSTEIN 1965). A new group of extremely potent calciumantagonists has been synthesized. These drugs are able to block the transmembrane calcium conductivity of mammalian myocardial fibres

in a highly selective manner (FLECKENSTEIN 1971; FLECKENSTEIN et al. 1972). Thus, they interfere with the calcium supply to the contractile system during excitation, while the sodium-dependent excitatory process remains practically unaffected. It has been suggested that these drugs probably compete with calcium for a common receptor group or for a special carrier system in the cardiac cell membrane (KOHLHARDT et al. 1972; BAYER et al. 1975). Experiments with radioactive tracers, as well as measurements of the transmembrane calcium conductivity with voltage clamp technique, have demonstrated that verapamil (Isoptin), D600 (a verapamil derivative) and nifedipine (Adalat) all block selectively the transmembrane calcium influx into the excited heart muscle cell without affecting the simultaneous sodium influx which is connected with the depolarization (FLECKENSTEIN 1971; FLECKENSTEIN et al. 1972). A large number of drugs have calcium-antagonistic “side” effects e.g. certain of the adrenergic P-receptor blocking agents, anti-arrhythmic drugs and local anaesthetics (FLECKENSTEIN 1971). However, these drugs lack a distinct calcium specificity and do not discriminate between calcium and sodium fluxes, but may even interfere more with the sodium movements than the calcium transfer into the myocardial cells (TRITTHART et al. 1971).

Electrophysiological effects of calcium-antagonistic drugs It has previously been shown that verapamil did not effect the velocity of depolarization (dv/dt) of atrial, Purkinje and ventricular fibres (FLECKENSTEIN 1971; SINGH & VAUGHAN WILLIAMS 1972; CRANEFIELD et al. 1974), and that nifedipine did not alter the height and shape of the single fibre action potential of the cat papillary muscle (FLECKENSTEIN et al. 1972). As conduction velocity is related to dv/dt (CONN & LUCHI 1964; SINGER et al. 1967) the drugs have no depressant effects on intraatrial, His-Purkinje and intraventricular conduction times (NEUSS & SCHLEPPER 1971; HUSAINI et al. 1973; ROY et al. 1974; CAMERINI & SCARDI 1975; LANDMARK & AMLIE 1976). Verapamil causes a marked reduction of the con-

22 duction velocity within the atrioventricular node and a pronounced increase in the atrioventricular nodal refractoriness (BENDER & ZIMMERHOF 1967; NEUSS & SCHLEPPER 1971; HUSAINI et al. 1973; ROY et al. 1974; ZIPES & FISCHER 1974; LANDMARK & AMLIE 1976). The drug has been used successfully in the treatment of patients with paroxysmal supraventricular tachycardia and in reducing heart rate in atrial flutter and fibrillation (BENDER 1967; SCHAMROTH 1971; SCHAMROTH et al. 1972). HUSAINI et al.

A

1 mv[

(1973) have suggested that the explanation for this is the depressant effect on atrioventricular conduction, since paroxysmal supraventricular tachycardias are currently believed to be perpetuated by re-entry within the atrioventricular node (GOLDREYER & BIGGER 1969; GOLDREYER & DAMATO 1971). In the isolated rat heart nifedipine increases the PR interval, an effect which is pronounced at low extracellular calcium concentration (REFSUM et nl. 1976) (Fig. 10). However, in dogs nifedipine did not increase atrioventricular conduc-

B

C

SLhSLhu U

0.1 s o t Fig. 10. ECG tracings recorded from isolated rat hearts. A. Control ECG (5.0 meq./l of calcium). B. Effect of nifedipine (100 pg/I) in the presence of 5.0 meq./l of calcium. C. Effect of nifedipine (100 pg/l) in the presence of 2.0 meq./ of calcium. The PR interval is prolonged in B, and even more in C where also atrioventricular block occurs. From REFSUM et al. 1976.

tion time and refractoriness (TAIRA et al. 1975; AMLIE & LANDMARK, in prep.), and in neither of their patients, EKELUND & ATTERHBG (1 975) found any nifedipine-induced changes in atrioventricular conduction time at rest. It has been poposed that the virtual absence of a detrimental effect on the atrioventricular node of nifedipine in a wide range of doses can be ascribed to its greater preference to vascular smooth muscle (TAIRA et nl. 1975). It has been shown that verapamil depresses the plateau and prolongs the action potential of isolated dog cardiac Purkinje fibres, and that nifedipine causes a reduction in the time for 50 and 90 per cent repolarization of action potentials derived from isolated rat atria (REFSUM 1975a). These effects are most pronounc-

ed at lower calcium concentrations (Fig. 11). Nifedipine also reduces the effective refractory period of isolated rat atria, an effect which is most pronounced at lower calcium concentrations (Fig. 12). In vitro, verapamil (WIT & CRANEFIELD 1974) and nifedipine (REFSUM & LANDMARK 1975) by inhibiting calcium influx, causes a slowing of the sinus node discharge. This effect is more pronounced at lower calcium levels (REFSUM 1975b) (Fig. 13). The sinus node recovery time of isolated rat atria is increased by nifedipine (REFSUM 1975b). In vivo, the heart rate often increases after the administration of verapamil and nifedipine (ATTERHBG & EKELUND 1975; KIRCHHEIM & GROSS 1975). The nifedipine-induced rise in heart rate could be significantly reduced by pretreatment with a 8-

23

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1975a.

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adrenergic receptor blocker, propranolol, (SCHMIER et nl. 1975) and it has been claimed that the basic effects of nifedipine can be altered by an increase in the endogenous 8adrenergic drive (KRONEBERG 1975). Fibrillation of atrial muscle can be produced experimentally by several methods, including suitable times electrically stimulation (DIPALMA & SCHULTS 1950; BROOKS et nl. 1955; SZEKERES & LENARD 1960; LANDMARK 1971; REFSUM & LANDMARK 1972). In contrast to drugs with a quinidine-like effect (VAUGHAN WILLIAMS & SZEKERES 1961; LANDMARK 1971; REFSUM et nl. 1975; DAHL & REFSUM 1976), nifedipine does not influence the threshold for electrically induced atrial fibrillation (REFSUM 1975b). Arrhythmias of atrial and ventricular muscle can also be induced by increaseing the calcium concentration, while keeping the potassium concentration low (ARMITAGE et al. 1957, REFSUM 1975b; REFSUM et nl. 1976) (Figs. 14 and 15). These arrhythmias can be completely prevented by pretreatment with nifedipine (REFSUM 1975b; REFSUM et nl. 1976). Cal-

2 5 0 [ ~ a + + ]( ~m e q / l ) Fig. 12. Effective refractory period at increasing extracellular calcium concentrations in the absence (open symbols) and presence of nifedipine (100 pg/l( (closed symbols). From REFSUM & LAND-

MARK 1976.

cium ions at the cell membrane are believed to exert a “stabilizing” influence, and an increase in the threshold for electrical stimulation with an increase in the calcium concentration has been described in myocardial preparations of several species (GREINER & GARB 1950; WEIDMANN 1955; HOFFMAN & CRANEFIELD 1960; LANDMARK 1972). Experiments have shown that nifedipine has no effect on the excitability (REFSUM & LANDMARK 1975; REFSUM & LANDMARK 1976) (Fig. 16). This is consistent with the hypothesis that nifedipine only inhibits the transmembrane calcium influx during the excitation period, but

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Fig. 14. Atrial myograms showing effects of having increased the extracellular calcium concentration from 2.0 to 8.0 meq./l, while keeping the extracellular potassium concentration low, on the contractions of spontaneously beating, isolated rat atria. A. Irregularities of atrial rhythm. B. Bigeminal rhythm. C. Sudden atrial arrest. D. Brief periods of rapid atrial fibrillation. From REFSUM 1975b.

8

Fig. 13. Effect of increasing extracellular calcium

concentrations on the rate of contractions of spontaneously beating, isolated rat atria in the absence (0) and presence of nifedipine (100 &/I) (0). From REFSUM 1975b. 1

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Fig. 15. ECG tracings recorded from isolated rat hearts showing calcium-induced ventricular extrasystole (A) and ventricular fibrillation (B). From REFSUM et nl. 1976.

does not influence the calcium a t the cell membrane (FLECKENSTEIN 197 1; FLECKENSTEIN et al. 1972). Thus it is assumed that calcium-induced cardiac arrhythmias in vitro are caused by increased influx of calcium ions REFSUM 1975b: REFSUM et al. 1976).

25

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to-

solution

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Fig. 16. Threshold for electrical stimulation of iso-

lated rat atria at increasing extracellular calcium concentrations in absence (open symbols) and presence of nifedipine (100 p g / l ) (closed symbols). From REFSUM & LANDMARK 1976.

Contractile effects of calcium-antagonistic drugs Verapamil and nifedipine reduce the contractile force by reducing the calcium influx (HASHIMOT0 et 01. 1972; MAGNUSSEN & KUDSK 1974; REFSUM & LANDMARK 1975; LANDMARK & REFSUM 1977) (Fig. 17). This negative inotropic effect can be reduced or reversed by increasing the extracellular calcium concentration (FLECKENSTEIN 1971; REFSUM 1975b; REFSUM & LANDMARK 1977) (Fig. 18). Clinical trials have, however, demonstrated that verapamil in therapeutic doses has negligible effects on cardiac output. In patients with sinus rhythm receiving verapamil intravenously during cardiac catheterization, no significant haemodynamic effects were observed by RYDBN & S E T R E (1971). ATTERHOG & EKELUND (1975) noted a mild

cally stimulated, isolated guinea-pig papillary muscle by verapamil, and the reversal of this effect by isoproterenol. From FLECKENSTEIN 1971.

negative inotropic effect in 8 healthy middleaged men. There was no change in pre-ejection period, which indirectly reflects contractile force of the left centricle (PERLOFF & REICHEK 1972). The mild negative inotropic effect was abolished by exercise. In addition ROWE et al. (1971) have shown that verapamiI in a smaller dose increased cardiac output and left ventricular work in dogs. In those animals receiving pretreatment with a b-adrenergic blocking agent and reserpine, these effects were abolished, an observation which supports the hypothesis that catecholamines are released as response to verapamil. In the resting. unanaesthetized dog, sublingual application of nifedipine 10 mg reduced aortic mean blood pressure and caused a pronounced decrease in total peripheral resistance (-450/0), which induced a reflex rise in heart rate (+66%) and caused an increase in cardiac output of 61 per cent (KIRCHHEIM & GROSS 1975). The nifedipine-induced rise in heart rate could be

26

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Effects of calcium-antagonistic drugs on blood pressure and coronary flow

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Verapamil (KNOCH et al. 1963; TCHIRDEWAHN & KLEIPZIG 1973; CANTOR 1967; SANDLER et al. 1970; LIVESLEY et al. 1973; ANDREASEN et al. 1975; PERSSON et nl. 1977) and nifedipine (HAYASE et nl. 1971; cn LOOS & KALTENBACH 1972; KIMURA et Z al. 1972; KOBAYASHI et al. 1972; CAME200 RINI & SCARDI 1975; EBNER et al. 1975; c0 HAGEL 1975; LINKE 1975; MENNA et al. Q 1975) have been shown to be of clinical value in the treatment of angina pectoris. Both drugs 150 increase exercise tolerance in patients suffering Z from angina pectoris (ATTERHOG & PORJB 0 0 1966; ATTERHOG et al. 1975). Verapamil (BRITTINGER et al. 1969; ATTERHOG & L 100 EKELUND 1975) and nifedipine (HAYASE 0 et al. 1971; KIRCHHEIM & GROSS 1975) W c reduce blood pressure and total peripheral resistance. GRUN & FLECKENSTEIN (1975) Q 50 e have demonstrated that verapamil and nifedipine cause a relaxation of isolated coronary arteries, and it has also been found that both drugs may increase coronary flow in isolated perfused hearts (HAAS & HXRTFELDER 1962; HASHIMOTO rt al. 1972: KOSCHE et al. 1972; VATER et al. 1972; MAGNUSSEN & KUDSK 1974; REFSUM et al. 1976). Sublingual application of nifedipine 10 mg to unanaesthetized dogs caused an increase in Fig. 18. Effect of increasing extracellular calcium mean coronary flow by 91 per cent and a deconcentrations on the amplitude of contractions of spontaneously beating, isolated rat atria in the crease of mean coronary resistance by 56 per absence (0) and the presence of nifedipine (100 cent (KIRCHHEIM & GROSS 1975). In 6 &I) (0). From REFSUM 1975 b. patients with mild mitral stenosis without any clinical signs of coronary artery disease, K8HLER (1975) found a remarkable increase of coronary flow after sublingual or buccal adsignificantly reduced by pretreatment with a ministration of nifedipine 20 mg. LICHTLEN 8-adrenergic blocking agent (SCHMIER et al. (1975) have demonstrated that the increase in 1975). In patients, ANGELINO et al. (1975) coronary blood flow was most pronounced in and van den BRAND et al. (1975) observed a patients with mild coronary artery disease and slight increase in cardiac index after nifedipine normal resting flow values, but was minimal in 1 mg intravenously and 20 mg sublingualty. patients with severe, triple vessel disease and respectively. In 13 healthy individuals without extremely high resting resistance values. In clinical signs of cardiovascuIar disease, AN- dogs, verapamil lowers coronary vascular reGELSEN et al. (1975) found that 20 min. after sistance and increases myocardial blood flow sublingual application of nifedipine 10 mg, (ROWE et al. 1971). In 11 normal individuals stroke volume, cardiac output and peak aortic LUEBS et al. (1966) found that the drug signiflow increased. ficantly increased coronary blood flow. Howm

I

0

E

27 ever, in patients with arteriosclerotic heart disease the drug failed to increase or even reduced blood flow (LUEBS e t al. 1966; ZALESKI et al. 1967). The effects originally attributed to coronary artery dilatation therefore require alternative explanations. Myocardial oxygen demand is known to vary with heart rate, velocity of contraction and work performed by the left ventricle in overcoming pressure. Verapamil does not influence the rate- pressure product (PERSSON & F A G H E R 1977) and E K E L U N D & ATTERHOG (1975) found that after nifedipine 10 mg, exercise tolerance increased even though the rate-pressure product was increased by 11 per cent. Therefore it is probably unlikely that the observed clinical effects of verapamil and nifedipine in angina pectoris can be explained by a negative inotropic effect resulting in a decreased oxygen consumption as proposed by ANDREASEN et al. (1975) and EBNER (1975). In the case of verapamil PERSSON & F A G H E R (1977) concude that the mode of action of verapamil in angina pectoris remains to be solved, Four other papers are relevant to this discussion. S M I T H et al. (1975) found that verapamil reduced ST-segment elevation in dogs following acute coronary artery occlusion, and S I N G H et al. (1975) that its effects o n ST-segments occur without associated changes in collateral blood flow or the rate of anaerobic metabolism. S M I T H e t at. (1976) have shown that verapamil selectively depressed ischaemic myocardium, a finding which the authors felt might have clinical implications since injury can be decreased by reducing contractility and thereby myocardial oxygen consumption. Recently, REIMER e f al. (1977) have demonstrated that pretreatment which verapamil resulted in significantly less necrosis with minimal haemodynamic consequences following temporary artery occlusion in dogs. Attacks of Prinzmetal’s variant angina have frequently been attributed to functional stenosis (spasm) (OLIVIA et al. 1973; MacALPIN et at. 1973). It is interesting to note that nifedipine has been found to have excellent symptomatic effect in patients with this kind of angina pectoris ( E N D 0 et al. 1975; KODOMA et al. 1975; HOSODA & K I M U R A 1976).

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