Slow Response Action Potentials Research Articles

Somatostatin effects in isolated human atrial fibres

Effects of hypothalamic hormone somatostatin on the action potential and contractile force of 54 human atrial preparations obtained at cardiac surgery were studied with standard microelectrode techniques. In the atrial fibres responding to electrical stimuli with fast response action potentials in 4 mM [K]0 Tyrode solution (maximum rate of phase 0 depolarization greater than 50 V/s), somatostatin (10(-7) to 10(-6) M) reduced slightly the duration of action potential and decreased twitch force dose-dependently. In spontaneously active atrial fibres, somatostatin (10(-7) to 10(-6) M) abolished the action potentials in the preparations with low maximal diastolic potential (MDP, -48 +/- 2.8 mV), but induced only mild suppressive effect in the preparations with high MDP (-70 +/- 2.4 mV). When the fibres were depolarized in 27 mM [K]0 Tyrode solution, somatostatin decreased the maximum rate of depolarization and amplitude of the slow response action potentials induced by electrical stimuli. The delayed afterdepolarizations or triggered action potentials induced by high-frequency electrical drive in the presence of epinephrine were also suppressed by somatostatin. The above findings suggest that somatostatin may suppress the abnormal automaticity and the triggered activity in human atrial fibres through a reduction of cellular calcium.

Electrophysiologic Actions of Dibenzepin, a Tricyclic Antidepressant, on Canine Purkinje Fibers

Electrophysiologic effects of dibenzepin, a tricyclic antidepressant drug known experimentally to defibrillate the ventricles, were studied in canine Purkinje fibers with glass microelectrodes. In 11 normally perfused preparations the dose-response curve (10(-8)-10(-5) g/ml) revealed that the threshold concentration of this drug was 10(-7) g/ml, reducing the maximal rate of depolarization (MRD) from 930 to 876 V/s and overshoot from 32 to 30 mV, respectively (p less than 0.05). At 10(-6) g/ml, dibenzepin shortened action potential duration (APD) at 50 and 90% repolarization (APD50, APD90), respectively, from 290 to 248 ms and from 385 to 363 ms (p less than 0.001). At 10(-5) g/ml, it decreased the maximal diastolic potential (MDP) from -92 to -85 mV and further reduced MRD, overshoot and APD50 (p less than 0.01). The membrane responsiveness curve was shifted to more negative potentials, but its normalized curve (h infinity curve) remained unchanged. This drug did not alter slow response action potentials produced by 22 mM K+ and 10(-7) M isoproterenol. In six Purkinje fibers, hypoxia (100% N2) reduced MDP and MRD. Subsequent addition of dibenzepin further decreased MRD and shortened APD50. These results indicate that (a) dibezepin inhibits the fast Na+ current without changing its inactivation kinetics, thus suggesting a class 1 antiarrhythmic action; (b) it does not affect the slow inward current; and (c) the former action appears enhanced during hypoxia, possibly contributing to ventricular defibrillation.

The effects of doxorubicin on ventricular tachycardia.

Doxorubicin, in concentrations that have no effect on fast or slow response action potentials, has been shown to suppress ouabain-induced delayed afterdepolarizations. In this study, we used standard microelectrode techniques to determine the effects of doxorubicin on isolated canine Purkinje fibers. We studied automaticity induced at normal and low membrane potentials, conduction in normal and K+-depolarized Purkinje fibers, and triggered activity induced by ouabain and by experimental myocardial infarction. Doxorubicin, 50 microM, suppressed the triggered activity and the delayed afterdepolarizations that induced it, but had no effect on the other variables. We then studied the effects of intravenous doxorubicin, 16 to 64 mg/m2 body surface area, on ouabain-induced ventricular tachycardia and the ventricular tachycardia that occurs 24 hr after ligation of the left anterior descending coronary artery in the intact dog. There was no effect on the infarct-induced arrhythmia, but concentrations of doxorubicin that had no other effect on the electrocardiogram suppressed those ouabain-induced arrhythmias that appeared to have been triggered. The automatic arrhythmias induced by ouabain were not affected. Both the latter mechanisms were verified in studies of isolated Purkinje fibers that were obtained on completion of the intact animal experiments. These results indicate that agents having high selectivity for specific arrhythmogenic mechanisms can be useful adjuncts in discriminating among the mechanisms responsible for arrhythmias in intact animals.

Disopyramide phosphate effects on slow and depressed fast responses.

We studied the effects of disopyramide phosphate on explanted neonatal rat ventricle cells exhibiting depressed fast responses or naturally occurring slow response action potentials together with automatic activity. Disopyramide suppressed the spontaneous activity at a concentration of 2.5 micrograms/mL with a half-maximal value of 10 micrograms/mL. Before spontaneous activity was lost, there was an increase in beating rate possibly related to membrane depolarization. In depressed fast and slow response action potentials there was an increase in action potential duration (APD) which was consistently found both at the level of the plateau and at 90% repolarization. Comparison of the APD increase observed after disopyramide treatment and that after exposure to 20 mM tetraethylammonium suggested a block of a potassium conductance as a possible cause underlying the change in APD. The Vmax values of the depressed fast response decreased at constant membrane potential and this was attributed to the local anesthetic effect of the drug. In addition, we report two novel findings: (i) a decrease of Vmax of the slow response action potentials which may be secondary to membrane depolarization, and (ii) an increase in the duration of slow action potentials, possibly caused by inhibition of a potassium conductance.

Cardiotonic and Coronary Vasodilatatory Effects of Amrinone in the Canine Heart-Lung Preparation with a Support Dog as Compared with Those of Dobutamine

Analysis of the relative magnitude of the positive inotropic and chronotropic effects and the coronary vasodilating effects of amrinone conducted in the canine heart-lung preparation with a support dog in comparison with those of dobutamine demonstrated that amrinone was a preferential coronary vasodilator rather than a selective positive inotropic agent. An in vitro experiment in the canine papillary muscle suggested the initiation of the slow response action potential as a mechanism of the positive inotropic effect of amrinone.

Stimulation rate modulates effects of the dihydropyridine CGP 28 392 on cardiac calcium-dependent action potentials.

Calcium (Ca2+)-dependent action potentials were recorded from 22 mM potassium (K+)-depolarized guinea-pig papillary muscle at several different pacing frequencies in the absence and presence of CGP 28 392 (10 microM), a Ca2+ channel agonist. The maximum upstroke velocity (Vmax) of the slow response action potential was measured to determine relative changes in Ca2+ current as a function of pacing frequency. CGP 28 392 increased Vmax more than two fold at low rates of stimulation (1 or 12 pulses min-1), but had no significant effect on Vmax during rapid pulsing (200 pulses min-1). The enhancement of Vmax was dependent upon extracellular [K+]. Increasing extracellular [K+] from 22 mM to 27 mM suppressed the frequency-dependent agonist effects and increased the antagonist effects on Vmax. These results indicate that CGP 28 392 is a partial Ca2+-channel agonist and suggest that its effects on Ca2+ current are voltage-dependent.

Electrophysiologic effects of AHR 10718 on isolated cardiac tissues

We used microelectrode and blood superfusion techniques to study the electrophysiologic effects of a new antiarrhythmic compound, AHR 10718 (N′-2(diethylamino)ethyl)-N-(1-methylethyl)-N-2-(phenylsulfonyl)-ethyl)urea,(Z)-butanedioate) on the electrophysiologic properties of canine Purkinje fibers and papillary muscles. AHR 10718 (≥ 5 × 10 −6 M) induced a use-dependent decrease in V̇ max and significantly decreased Purkinje fiber conduction velocity and action potential duration. In addition, membrane responsiveness was depressed and the effective refractory period shortened. The effects of AHR 10718 were not highly dependent on [K +] 0. V̇ max of ventricular muscle action potentials also was reduced. However, in contrast to Purkinje fibers, ventricular muscle action potentials were significantly prolonged by AHR 10718 (≥ 5 × 10 −6 M). AHR 10718 had no effect on slow response action potentials induced by isoproterenol and high [K +] 0. AHR 10718 significantly decreased normal automaticity, catecholamine-enhanced automaticity, and abnormal automaticity induced by barium or myocardial infarction. It also suppressed triggered activity and reduced delayed afterdepolarization amplitude in ouabain-treated Purkinje fibers and infarcted myocardium. These studies suggest that AHR 10718 may be effective against arrhythmias resulting from conduction disturbances and certain forms of abnormal impulse initiation.

Effects of oximes, diacetylmonoxime, pyridine-2-aldoxime, and pyridine-2-aldoxime methochloride, on the electrical and mechanical activities of guinea pig cardiac ventricular muscles.

Effects of 3 oximes, diacetylmonoxime (DAM), pyridine-2-aldoxime (PAM) and pyridine-2-aldoxime methochloride (2-PAM), on the normal electrical and mechanical activities and on the slow response action potentials were examined in the guinea pig ventricular muscles. DAM and long-term exposure to high concentrations of PAM produced decreases in contractile force, action potential duration and slow response action potentials, whereas 2-PAM and low concentrations of PAM tended to increase these parameters. Thus, these 3 oximes did not act uniformly on cardiac muscle. It was speculated that DAM and high concentrations of PAM may act as slow channel inhibitors, whereas 2-PAM and low concentrations of PAM may act as slow channel activators.

Electrophysiological effects of cyclic GMP on canine cardiac Purkinje fibers.

The effect of cyclic 3'5'-guanosine monophosphate (8-bromo-cGMP) on action potential characteristics was investigated. Standard microelectrode techniques were used to study the effects of 8-bromo-cGMP on canine cardiac Purkinje fibers in vitro. Canine Purkinje fiber tissue preparations were exposed to increasing concentrations of 8-bromo-cGMP (10(-6), 10(-5), 10(-4) M). The action potential duration at 50% (APD50) and 90% (APD90) repolarization, resting membrane potential (RMP), action potential amplitude (APA), rate of rise of phase 0 (Vmax), spontaneous rate (SR), escape time (ET), and effective refractory period (ERP) did not change at these concentrations of 8-bromo-cGMP. The effect of 8-bromo-cGMP on isoproterenol (10(-7) M) treated Purkinje fibers was tested. Predictably, isoproterenol shortened APD and ERP and increased SR. APD or ERP shortening was not affected by 8-bromo-cGMP, but the increase in SR produced by isoproterenol was prevented. Eleven of sixteen Purkinje fiber preparations treated with isoproterenol alone became spontaneously arrhythmic, whereas none of six treated with 8-bromo-cGMP and isoproterenol became arrhythmic (p less than 0.05). Slow-response action potentials elicited by potassium depolarization and catecholamines were abbreviated and eventually abolished by 8-bromo-cGMP. In conclusion, 8-bromo-cGMP has no effect on action potential characteristics in normally polarized canine Purkinje fibers but depressed slow response action potentials. The effects of isoproterenol on SR are antagonized and the production of arrhythmias in this model are prevented by 8-bromo-cGMP.

Effects of timolol on action potential characteristics and automaticity in barium-depolarized canine cardiac Purkinje fibers.

To evaluate timolol's ability to antagonize the "slow response" in cardiac tissues, isolated canine cardiac Purkinje fibers were exposed to 0.25 mM barium chloride to induce membrane depolarization, spontaneous automaticity, and slow response action potentials. The effects of timolol on action potential parameters and the cycle length of spontaneous automaticity were tested at concentrations of 10, 100, and 500 micrograms/ml. Timolol significantly depressed the action potential and slowed automaticity only at 100 and 500 micrograms/ml but not at 10 micrograms/ml. Since verapamil and nifedipine have been reported to completely suppress activity in this model at concentrations of 0.2-2.0 micrograms/ml, we conclude that timolol has little direct slow response blocking potency.

Mechanisms for atrial arrhythmias associated with cardiomyopathy: a study of feline hearts with primary myocardial disease.

The cellular electrophysiologic and structural characteristics of arrhythmic and non-arrhythmic atria isolated from feline hearts with spontaneously occurring cardiomyopathy were studied. The animals were divided into three groups according to the degree of left atrial enlargement: mild (group I), moderate (group II), and severe (group III). The right atria were of relatively normal size. Microelectrode recordings showed that inexcitable cells were present in both left and right atria of all groups but were most numerous in the left atria of group III animals. Most inexcitable cells had low resting membrane potentials. There was also a significant reduction in resting membrane potentials, maximum rate of phase 0 depolarization, and action potential amplitude of excitable cells in left atria of animals in groups II and III, whereas action potentials of excitable cells in the right atria were normal. Acetylcholine or norepinephrine often restored excitability to cells that originally did not generate action potentials. Norepinephrine also caused slow-response action potentials as well as abnormal automaticity and triggered activity due to delayed afterpotentials. The diseased atria showed marked structural abnormalities, which were most pronounced in group III cats, including large amounts of interstitial fibrosis, cellular hypertrophy and degeneration, and thickened basement membranes. Therefore electrophysiologic abnormalities and concurrent changes in cell structure may be involved in the genesis of atrial tachyarrhythmias caused by cardiomyopathy.

Fetal canine cardiac Purkinje fibers: electrophysiology and ultrastructure.

We studied the ontogenesis of the transmembrane action potential and the ultrastructure of fetal canine Purkinje fibers. Fetal hearts were obtained from fetuses just after implantation to end gestation. Using standard microelectrode recording techniques, we found that action potential characteristics varied linearly over this period of development. Maximum diastolic potential (MDP) ranged from -65 to -85 mV; action potential amplitude (AMP) varied from 100 to 120 mV; maximum upstroke velocity (Vmax) increased from 200 to 550 V/s. Action potential duration measured to 50% repolarization (APD50) increased from 15 to 156 ms while duration measured at full repolarization (APD100) similarly increased from 75 to 236 ms. The relationship between external potassium concentration and membrane potential was equivalent across all stages of fetal development. Tetrodotoxin (TTX, 7.7 X 10(-7) to 1.6 X 10(-5) M) caused concentration-dependent decreases in AMP, Vmax, and APD50. Verapamil (1 X 10(-7) to 1 X 10(-5) M) decreased Vmax and APD50 in a concentration-dependent manner. The effects of both TTX and verapamil were statistically equivalent across all stages of fetal development. Ultrastructural studies of fetal Purkinje fibers showed that myocytes at the earliest stages of development (Purkinje fibers were not visually distinct at this time) were arranged as a tightly packed mosaic with a rounded shape, with a large amount of glycogen, small sparse mitochondria, and relatively large nuclei. Mitotic cells were observed frequently. Purkinje fibers when first identified grossly had fewer myofilaments than working myocardial cells and sarcomeres without M lines. By late gestation, intercalated disks appeared with an increase in surface areas; desmosomes occurred more frequently. Myofilaments are organized around Z bands into rudimentary sarcomeres that still lack M lines. These data indicate that, although the fetal canine Purkinje fiber undergoes marked developmental changes in ultrastructure, cellular electrophysiological changes are more subtle. The action potential has a qualitative appearance similar to those of the neonatal or adult fiber. At no time during fetal development could we find slow-response action potentials.

Acute coronary artery occlusion-reperfusion arrhythmias in pigs: Antiarrhythmic and antifibrillatory evaluation of verapamil, nifedipine, prenylamine and propranolol

The antiarrhythmic activity of the calcium entry blockers, verapamil, nifedipine and prenylamine, was assessed against arrhythmias occuring during 20 min of acute occlusion, or upon rapid reperfusion of the left anterior descending coronary artery (LAD) in anesthetized pigs. Propranolol, which may indirectly reduce calcium entry by blocking the facilitory action of catecholamines on slow channel conductance, was also evaluated for antiarrhythmic activity in this acute arrhythmia model. Only verapamil (0.2 mg/kg i.v.) reduced both the number of arrhythmias occuring during LAD occlusion and the incidence of ventricular fibrillation (VF) occurring after occlusion and reperfusion. Although both nifedipine (0.04–0.2 mg/kg i.v.) and propranolol (1–2 mg/kg i.v.) produced a slight but significant (P < 0.05) dose-dependent decrease in the incidence of VF during the occlusion period only, this protection was accompanied by a significant increase in ectopic activity. The increase in ectopic activity produced by propranolol (1.0 mg/kg i.v.) persisted even in combination with verapamil (0.2 mg/kg i.v.) which given alone decreased the ectopic frequency. Prenylamine up to 5 mg/kg was without significant antiarrhythmic or antifibrillatory activity. However, unlike verapamil and nifedipine, this drug produced only slight changes in heart rate or blood pressure which suggested the presence of only minimal calcium entry blocking action on myocardial and vascular tissue at the doses we employed. Because the relative antifibrillatory efficacies of verapamil and nifedipine paralleled the relative efficacies reported for depression of atrioventricular conduction, this may implicate the slow inward current channel in the etiology of VF occurring during acute myocardial ischemia. However, this selective antifibrillatory action of calcium entry blockers may be independent of effects on slow response action potentials, myocardial oxygen consumption, or their reported ability to reduce ischemic damage to the myocardium.

The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers.

In the "Na+ lag hypothesis" of cardiac glycoside action, [Ca++]i increases through sodium-calcium exchange following block of the sodium-calcium ATPase. This accumulation of [Ca++]i has been suggested to be responsible for digitalis-induced delayed after depolarizations and arrhythmias. We used standard microelectrode techniques to study the effects of adriamycin, 10-200 microM, on the canine Purkinje fiber transmembrane potential. Adriamycin, 10 and 50 microM, had no effect on the action potential other than inducing a 28% increase in duration at 50 microM (p less than 0.01). Adriamycin, 100 and 200 microM, further prolonged action potential duration and decreased amplitude and Vmax. We then studied the effects of adriamycin, 50 microM (a concentration that purportedly blocks sodium-calcium exchange), on ouabain-induced delayed afterdepolarizations and aftercontractions in Purkinje fiber and ventricular muscle. After initially increasing delayed afterdepolarization amplitude in five of nine Purkinje fibers, adriamycin reversibly reduced their amplitude in all nine, by 78%, at a drive cycle length of 500 msec (P less than 0.01). Adriamycin, 50 microM, had no effect on calcium ion-induced slow response action potentials, suggesting this concentration does not significantly reduce the slow inward current. In ventricular muscle, adriamycin, 50 microM, did not significantly reduce contraction but did depress aftercontractions (P less than 0.025). In sum: in concentrations that have no effect on the AP other than prolonging duration, adriamycin, 50 microM, reversibly depresses ouabain-induced delayed afterdepolarizations and aftercontractions; however, adriamycin, 50 microM, does not depress calcium ion-dependent action potentials. Although the action of adriamycin on delayed afterdepolarizations and aftercontractions is consistent with direct inhibition of the transient inward current and/or an indirect reduction via reduced activity of sodium-calcium exchange, whether either or both of these mechanisms is involved must be defined by further experimentation.

Dantrolene sodium: Effects on isolated cardiac tissues

The effects of dantrolene sodium on dog Purkinje fibers, cat atrial and ventricular muscles were studied. Action potential duration was significantly increased and contractility was significantly decreased by dantrolene in all three types of tissue. The plateau phase of Purkinje fiber and occasionally atrial action potential was slightly depressed. Dantrolene sodium had no significant effect on resting membrane potential, action potential amplitude or upstroke velocity of phase 0. The negative inotropic effects were most pronounced in Purkinje fibers, followed by atrial muscle while papillary muscles were least sensitive. Contractile force of Purkinje fibers was decreased by relatively the same amount at all frequencies of stimulation. At faster rates, atrial and ventricular muscle contractility was depressed relatively more than at slower rates. Slow response action potentials in cat papillary muscles were diminished slightly, but this effect was not significant. All drug effects took 10 to 15 min to develop, reached a steady state after 30 to 40 min, and were irreversible upon washout. Increasing the extracellular calcium concentration reversed the dantrolene-induced changes. These findings suggest that effects of dantrolene are mediated in part by a decrease in the intracellular free calcium concentration in cardiac tissues.

Frequency-dependent depression of Vmax of slow response action potentials by a high concentration of papaverine.

The maximum upstroke velocity (Vmax) of Ca2+-dependent action potentials was used to measure relative changes in the slow inward current (Isi) caused by 10(-4) M papaverine as a function of pacing frequency in K-depolarized guinea pig ventricular strips. Papaverine caused a pronounced frequency-dependent depression of Vmax presumed to be correlated with a decrease in the rate of recovery from inactivation of Isi. Papaverine (10(-4) M) tripled the time constants for the biexponential recovery from depression of Vmax (determined by a paired pulse protocol) relative to the control. Depression of Vmax by papaverine during a 1 Hz stimulus train preceded by a long rest period reached a new steady state within three depolarizations. Complete poststimulation recovery from the depression of Vmax was also relatively rapid, unlike that described for verapamil. Preparations exposed to Mn2+ (after pretreatment with Ba2+ to restore excitability) showed a depressed steady-state Vmax independent of frequency. It is concluded that the frequency-dependent blockers of Vmax (papaverine and verapamil) differ in their rates of association and dissociation with the slow inward channel.

Inhibition of myocardial K + channels by bromobenzoyl-methyladamantylamine, an adamantane derivative

The effect of bromobenzoyl-methyladamantylamine (BMA) on transmembrane potentials and contractility of atrial and ventricular myocardium of guinea-pig and cat, as well as on transmembrane ionic currents of the frog atrial trabeculae was studied using conventional glass microelectrode and double sucrose-gap voltage clamp techniques. BMA markedly prolonged the action potential duration, depolarized the cell membrane, reduced the rate of rise of the action potential and exerted a positive inotropic effect on non-clamped myocardial preparations. The drug-induced pacemaker activity in ventricular working muscle of cat. Moreover, BMA antagonized the effects of the K + channel activator acetylcholine in a dose-dependent manner. BMA was found to induced slow response action potentials in K +-depolarized ventricular myocardium of guinea-pig. In voltage clamp experiments, BMA reduced the outward K + current but had no effect on either rapid inward Na + or slow inward Ca 2+ currents. The results suggest that BMA is capable of selectively blocking the myocardial K + channels.

Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current.

beta-Adrenergic stimulation of the heart is thought to increase cardiac muscle contractility by activation of cyclic AMP-dependent protein kinase and concomitant increase in the phosphorylation of certain proteins (for refs see refs 1-6). Electrophysiological studies have shown that the stimulation of cardiac beta-adrenoreceptors, the external application of cyclic AMP or its analogues to Purkinje fibres, or the injection of cyclic AMP into single myocytes can increase the slow inward current (Isi) during the plateau phase of the action potential (AP). In heart muscle this current is mainly carried by Ca2+ (refs 10, 11) and it has been suggested that cyclic AMP-dependent phosphorylation of some component of the calcium channel increases the amount of Ca2+ which enters the cell during depolarization. We have investigated this hypothesis by examining the electrical responses of isolated guinea pig ventricular myocytes to pressure injections of subunits of the cyclic AMP-dependent protein kinase. We report here that injection of the catalytic subunit (C) resulted in a lengthening of the action potential duration (APD) and an increase in the height of the plateau as well as the amplitude of Isi. By contrast, the injection of regulatory subunit (R) shortened the APD of fast and slow response APs, an effect which was reversed by adrenaline.

Effects of lanthanum on the electrical and mechanical activities of frog ventricular muscle.

The effects of lanthanum on the resting membrane potential, action potential, membrane resistance, twitch tension, and potassium contracture were investigated and the localization of the drug was studied electron microscopically in isolated frog ventricular muscle. Lanthanum in concentration of 0.2 to 5 mM decreased the resting potential by about 5-8 mV, which was accompanied by an increase in the membrane resistance of about 43% for the depolarizing and 40% for the hyperpolarizing direction. Lanthanum caused a decrease in height and a prominent shortening of the action potential, and also, a depression of the plateau level. In addition, it increased the threshold for action potential generation depending on its concentration. The slow response action potential was inhibited by lanthanum in parallel with twitch inhibition. This finding suggests that the twitch inhibition resulted from the suppression of the slow inward calcium current. In contrast, potassium contracture was not inhibited by lanthanum. When the muscle preparation was treated with neuraminidase, the twitch inhibition caused by lanthanum was strongly depressed. Electron microscopic observation revealed that the precipitates of lanthanum were localized on the external lamina of myocytes as well as in the extracellular spaces but could never be found within the cytoplasm. No such precipitates could be detected in the neuraminidase-treated muscle. From these results it is suggested that lanthanum takes the place of calcium at the membrane surface: it modifies permeabilities to sodium, potassium and calcium ions and the excitation-contraction coupling of the ventricular muscle by replacing calcium bound to the membrane-surface.

Inotropic actions of isoproterenol in cat ventricular muscle. Effects of extracellular potassium.

The inotropic actions of isoproterenol in cat papillary muscles or trabeculae bathed in a salt solution containing 4 mM KCl were compared to those in similar muscles bathed in a salt solution containing 22 mM KC1. Although isoproterenol evoked the same increase in force of contraction in both groups of muscles, the time course of contraction differed markedly. In muscles bathed in 4 mM KC1, isoproterenol caused a concentration-dependent decrease in time-to-peak force, but in muscles bathed in 22 mM KCl, isoproterenol caused a concentration-dependent increase in time-to-peak force. These data suggest that ventricular muscle activated by slow response action potentials may utilize a different mechanism of excitation-contraction coupling than do muscles activated by Na-dependent action potentials.