Slow Response Action Potentials Research Articles

Cardiac Electrophysiologic Effects of McN-5691, a New Calcium-Channel Blocking Antihypertensive Agent

The purpose of this study was to evaluate the cardiac electrophysiological effects of McN-5691, a new calcium-channel blocking antihypertensive drug. In anesthetized dogs, the primary electrophysiological effect of McN-5691 was dose-related prolongation of AV-nodal conduction time and refractoriness (0.1-1.0 mg/kg i.v.), which correlated with McN-5691 plasma levels. There were no significant effects on atrial or ventricular conduction times, QTc, or ventricular monophasic action potential duration. This profile was similar to that of verapamil. McN-5691 caused concentration-related, rate-dependent reductions in Vmax and amplitude of slow-response action potentials in guinea pig papillary muscle: ED-20% for depression of Vmax was 0.72 +/- 0.32 microM. Verapamil was more potent in depressing these action potentials: ED-20% for depression of Vmax was 0.03 +/- 0.01 microM. McN-5691 also caused rate-dependent reduction in Vmax and amplitude of canine Purkinje fiber action potentials, but only at relatively high concentrations: ED-20% for depression of Vmax was 55 +/- 12 microM. McN-5691 also reduced the action potential duration (0.3-30 microM) without affecting the slope of phase 4 depolarization and the maximum diastolic potential. Verapamil also reduced Vmax in Purkinje fibers (ED-20% for depression of Vmax was 32 +/- 3 microM) and shortened the action potential duration. The results show that McN-5691 has cardiac electrophysiological effects consistent with blockade of the slow inward calcium current, and that this activity occurs at concentrations well below those having local anesthetic activity. In addition, its lower potency in comparison to verapamil in depressing slow responses suggests a lesser propensity for negative inotropic effects.

Study of the effects and mechanisms of berberine on slow-response action potentials

The effects of berberine on slow-response action potentials (SAP) of guinea pig papillary muscles were studied. SAP was elicited by histamine in a high concentration of potassium solution (27 mmol). The results showed that berberine (24.5 μmol) was able to increase action potential amplitude, maximum rate of depolarization, action potential duration 50, action potential duration 100 (n = 16, p < 0.01) and effective refractory period (n = 10, p < 0.01) of SAP by 6.2%, 21.1%, 50.1%, 47.2% and 92.2%, respectively, but did not affect the resting membrane potential (RMP). To the above parameters, except APD 100, berberine was no longer to induce any significant change by pretreating with propranolol. The results suggested that the effects of berberine on slow-response action potentials were mainly related to the facilitating of slow calcium inward current, which might result from stimulating the beta-adrenoceptor.

Negative inotropic effects of amiodarone on isolated guinea pig papillary muscle

The aim of the study was to investigate the inotropic effects on isolated papillary muscle of acute and chronic exposure to amiodarone. Papillary muscles were obtained from untreated and amiodarone pretreated guinea pigs, and tension recording and conventional glass microelectrode techniques were used to assess the effects of amiodarone. Guinea pigs of either sex weighing 300-500 g were used: 65 untreated and 18 amiodarone pretreated (20 mg.kg-1.d-1 for 3 1/2 weeks). Acute amiodarone exposure (4.4 X 10(-6)-1.1 X 10(-3) mol.litre-1) caused a concentration dependent negative inotropic effect, which was also frequency dependent (0.1-5 Hz), with greater effect at higher stimulation frequencies. Time to peak tension and resting tension increased, while rate of development and relaxation of twitch contraction were slower. Amiodarone caused a dose dependent depression or abolition of slow response action potentials and of contraction in both untreated and amiodarone pretreated specimens. In amiodarone pretreated muscle, contractile forces did not differ significantly from control preparations. Chronic exposure to amiodarone attenuated the negative inotropic effects of acute amiodarone superfusion. The negative inotropic action of amiodarone may reflect a decrease in Na+ influx via Na+ channels and/or Ca2+ influx via Ca2+ channels, and/or an impairment of Ca2+ sequestration, alone or in combination. The differences in contractile response in relation to acute and chronic amiodarone exposure may be relevant to clinical actions of amiodarone.

Possible Increases in Potassium Conductance by Apamin in Mammalian Ventricular Papillary Muscles

Apamin, a bee venom polypeptide, is reported to block the Ca2+-dependent K+ channel in smooth muscle, hepatocyte, and neuroblastoma cells. In embryonic chick hearts, it was found to block the Ca2+ channel. We report here that apamin (10(-9)-10(-7) M) hyperpolarizes the resting membrane potential and shortens the duration of the action potential (AP) in the fast response of adult guinea pig ventricular papillary muscles. This peptide also depresses the isoproterenol or Ba2+-induced slow response APs in the presence of high K+ (21.6 mM) Tyrode solution, without affecting the resting potential. The most striking effect of apamin on the slow response was to shorten the duration of AP with only slight decreases in the maximal rate of increase (Vmax) of the AP, a nonlinear measure of Ca2+ currents. These findings suggest that apamin increases membrane K+ conductance in the mammalian ventricular myocardium. However, in enzymatically isolated single ventricular cells and at wide range of concentrations (10(-7)-10(-11) M), apamin did not affect the AP configuration and did not alter the membrane Ca2+ or K+ current, perhaps because of a loss of apamin sensitivity secondary to enzymatic digestion of the tissue with collagenase.

Platelet-activating factor: lack of direct action on guinea pig myocardium and possible transmitter release from cardiac sympathetic nerve endings at high concentrations

Microelectrode and mechanical studies were performed with isolated guinea pig myocardium (right ventricular free walls and papillary muscles) to examine the effects of platelet-activating factor (PAF) and lysophosphatidylcholine (LPC). Low concentrations of PAF (10(-8) to 10(-6) M, a range equivalent to the blood concentrations that produce marked hypotension in vivo) had no effects on action potential configuration and contractile force. High concentrations (10(-5) to 10(-4)M) of PAF and LPC per se elicited slow response action potentials with concomitant contraction (restored contraction) in the myocardium depolarized with elevated K+ (25 mM); they also augmented slow responses and restored contractions produced by a low concentration of isoproterenol (10(-8) M). Although these results suggested there was an increase in slow Ca current, the slow responses and restored contractions thus produced were greatly suppressed or abolished by the addition of a beta-adrenoceptor blocking agent, sotalol (10(-5) M), and by pretreatment with reserpine (5 mg/kg i.p., 24 h prior). In accordance with our previous conclusions, the present results suggest that direct cardiac action is not involved in the mechanisms of hypotension produced by PAF. It was also shown that high concentrations of PAF and LPC may act nonspecifically as amphiphilic compounds to induce transmitter release from sympathetic nerve endings, which may in turn augment the Ca current channels in the myocardial cell membrane.

Electromechanical Effects of Protamine in Isolated Human Atrial and Canine Ventricular Tissues

Effects of protamine sulfate (1-100 mg%) on the electrical and mechanical activities of isolated dog ventricular tissues and human atrial fibers were studied. In dog Purkinje fibers, 10 mg% protamine reduced markedly the maximum diastolic potential and the rate of phase 0 depolarization. Eventually, slow response action potential developed at a depolarized level and the twitch force declined abruptly. The depolarization and the negative inotropy were reversed by increasing [Ca])o or [K]o but not by tetrodotoxin. When Purkinje fibers were depolarized in 27 mM [K]o Tyrode solution plus 0.5 microM epinephrine, higher concentrations of protamine (30 mg% or above) were required to depress the slow response action potentials and twitch, in contrast to the action of verapamil and diltiazem (1-30 microM). Dog ventricular and human atrial muscle fibers were more resistant to the depressant effects of protamine. In human atrial fibers, however, 10 mg% protamine was able to depress significantly the oscillatory afterpotentials and aftercontractions induced by epinephrine and theophylline. The present findings suggest that the depolarization and decline in force of cardiac tissues induced by protamine, at a concentration about twice of the maximum clinically relevant dose, may be explained by the development of slow response action potentials as a result of decrease in membrane K+ and Na+ conductances.

Positive inotropic action of novel vasoconstrictor peptide endothelin on guinea pig atria.

Endothelin (ET), a novel 21-amino acid peptide isolated from the culture supernatant of porcine aortic endothelial cells, has been shown to be the most potent of all known vasoconstrictor substances. The purpose of the present study was to investigate the effects and the mode of actions of ET on the heart. ET exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atria of guinea pigs. The ET-induced response was of slow onset and characteristically long lasting. The half-maximal effective dose of the ET-induced response was about 1 nM, indicating that ET is one of the most potent cardiotonic substances. The response was presumably caused through direct actions of ET on the myocytes, since adrenergic, histaminergic, and serotonergic antagonists showed no effect on the response. The dose-response relationship of ET for the positive inotropic effect was displaced to the right in a parallel fashion by 0.3 microM nicardipine. In the left atria depolarized with 22 mM KCl, ET produced gradually increasing contractions in conjunction with the slow response action potentials in response to the electrical pacing. These results suggest that the ET-induced response on the left atria is intimately related to the influx of extracellular Ca2+.

Positive inotropic effect of calcitonin gene-related peptide mediated by cyclic AMP in guinea pig heart.

The mechanism of cardiac actions of rat calcitonin gene-related peptide (CGRP) was analyzed on isolated guinea pig hearts. CGRP exerted a positive inotropic effect in a dose-dependent manner on the electrically driven left atria but not on the ventricles. Immunohistochemical studies demonstrated that CGRP-like immunoreactive nerves were distributed densely in the myocardia of the atria but only sparsely in those of the ventricles. The CGRP-induced augmentation of the contraction was accompanied by the shortening of the time to peak force and the increase in the relaxation velocity. The positive inotropic response to CGRP was significantly enhanced by isobutylmethylxanthine and was attenuated by adenosine. CGRP increased the action potential amplitude and prolonged action potential duration at the level of 50% repolarization in the left atria. In the preparations, which were partially depolarized with an increase in extracellular potassium, CGRP induced slow response action potentials. These electrophysiological results indicate that CGRP causes an increase in the slow inward Ca2+ current. The cyclic AMP content in the left atria significantly increased following the addition of CGRP, the time course of which was nearly consistent with that of the augmentation of the contractile force. In the membrane preparation of the atria, the activity of adenylate cyclase was enhanced by CGRP in a dose-dependent manner. These effects of CGRP are qualitatively similar to those of beta-adrenoceptor stimulation. It is concluded that the CGRP-induced response in the guinea pig atria is attributed to the activation of adenylate cyclase via stimulation of its specific receptor and the subsequent increase in the intracellular cyclic AMP level.

Cellular Electrophysiological Properties of a New Aminosteroid Antiarrhythmic Agent, SC-35135

SC-35135 is a structurally unique class I antiarrhythmic agent previously shown to suppress arrhythmias produced by a two-stage coronary artery ligation or by administration of ouabain, but to be arrhythmogenic at high doses. SC-35135 was evaluated in guinea pig papillary muscle using standard microelectrode techniques to record transmembrane action potentials. SC-35135 markedly blocked Vmax (maximum rate of membrane depolarization) as a function of pacing frequency in the concentration range of 3 x 10(-6) to 3 x 10(-5) M, and was without effect on action potential duration. The effective refractory period was significantly shortened only at the highest concentration tested (3 x 10(-5) M). Rate constants for the onset of Vmax block determined at two stimulation rates, 60 and 200 pulses/min, were 0.17 +/- 0.052 and 0.06 +/- 0.005 (action potentials)-1, respectively, in the presence of 10(-5) M SC-35135. The recovery from Vmax depression following a train of stimuli was very slow in the presence of SC-35135. The average time constant for the recovery from block of Vmax after addition of 10(-5) M SC-35135 was 10.2 +/- 0.94 s. SC-35135 caused both a concentration- and stimulation frequency-dependent hyperpolarizing shift in the half point of the relationship between Vmax and resting membrane potential. Slow response (Ca current-dependent) action potentials were not changed by SC-35135 at concentrations less than or equal to 3 x 10(-5) M, indicating a lack of class IV antiarrhythmic activity. The results of these experiments indicate that SC-35135 has electrophysiological properties similar to other previously studied aminosteroid antiarrhythmics such as amafolone and CCI 22277. Its onset and recovery kinetics also resemble the well known class IC antiarrhythmics flecainide, lorcainide, and encainide. The arrhythmogenic activity of SC-35135 has prevented further development of this compound.

Action potentials of cardiac muscle in healing infarcts: Response to norepinephrine and caffeine

Previous studies have shown that the muscle fibers that survive on the epicardial surface of a 5- or 14-day-old infarct in canine hearts have reduced or absent plateau phase during repolarization. Since the absence of a plateau phase could be related to a decrease in the slow inward current, we determined whether norepinephrine (NE) (3.13 x 10(-5) M) or caffeine (2.5 to 5.0 mM) restored the reduced plateau phase of action potentials of fibers from the 5- to 14-day infarct (4 mM K+). In addition, we compared the slow inward current-mediated slow response action potentials induced by NE or caffeine in K+ depolarized fibers from the 5- and 14-day infarcts to those induced in control fibers. Our results show that NE and caffeine had little or no significant effects on repolarization or the plateau area of action potentials of fibers from infarcted preparations. In addition, NE and caffeine both induced slow response action potentials in normal fibers, but in some fibers from infarcts, these agents failed to elicit slow responses. In other fibers from infarcts, NE and caffeine induced slow response action potentials but they had reduced mean areas when compared to the control potentials. In conclusion, the alteration and absence of slow responses in fibers from infarcted preparations suggest that there may be a chronic abnormality in the slow Ca current channel in fibers from the 5- and 14-day infarct.

Effects of hypoxia with mild acidosis and reoxygenation on slow response action potentials in canine myocardial tissues

We studied slow response action potentials (SRAP) in canine ventricular muscle tissue during hypoxia (and mild acidosis) and reoxygenation. Slow responses were initiated by perfusing the tissue with a solution containing 27 mM KCl and 10(-6) M norepinephrine. The tissue was stimulated at 0.5 Hz, 20V and 4ms (duration of the pulse). Microelectrode techniques were used to record action potential and mechanical activity was recorded with a force displacement transducer. Hypoxia and mild acidosis progressively diminished the amplitude and duration of these SRAPs, whereas reperfusion/reoxygenation progressively increased their amplitude even more than that in the control (prehypoxic value). Action potential duration (APD) increased (at all levels) during reperfusion compared to that in hypoxia and mild acidosis but APD remained shorter than the control (prehypoxic level). The effects of hypoxia (and mild acidosis) and subsequent reoxygenation seem similar to that of elevating the extracellular calcium (increased inward current). From these experiments one cannot, however, distinguish the effects of hypoxia on inward current from those on the outward currents.

Adrenoceptor‐mediated changes of excitation and contraction in ventricular heart muscle from guinea‐pigs and rabbits.

1. The influence of alpha-adrenoceptor stimulation on mechanical and electrophysiological parameters was investigated in ventricular preparations from guinea-pigs and rabbits. Action potential and force of contraction were measured in papillary muscles and ionic currents were measured in isolated myocytes. 2. The effects of alpha-adrenoceptor stimulation were compared with those of beta-adrenoceptor stimulation. 3. In the guinea-pig the stimulation of alpha-adrenoceptors caused a small increase in the force of contraction (less than 10% of the response to beta-adrenoceptor stimulation) which was not accompanied by any increase of the slow calcium inward current. beta-Adrenoceptor stimulation produced large increases in both force of contraction and slow inward calcium current. The noradrenaline-induced increase in the slow inward calcium current was not affected by phentolamine. 4. In the rabbit, alpha-adrenoceptor stimulation produced large increases in the force of contraction (about two thirds of those seen in response to beta-adrenoceptor stimulation). Whereas beta-adrenoceptor stimulation also produced large increases in both maximal upstroke velocity of slow-response action potentials and slow inward calcium current, there was almost no change of both parameters in response to alpha-adrenoceptor stimulation. 5. We conclude that, first, the contribution of alpha-adrenoceptors to adrenoceptor-mediated changes of force of contraction is minimal in the guinea-pig ventricle, and second, the pronounced changes of force of contraction in the rabbit ventricle in response to alpha-adrenoceptor stimulation are unrelated to changes in the slow inward calcium current.

Cardiac electrophysiologic effects of AHR 5360C

We used microelectrode and blood superfusion techniques to study the cardiac electrophysiologic effects of a new drug, AHR 5360C, which has antihypertensive and calcium channel blocking properties in several experimental models. AHR 5360C, 10 −7 M significantly depressed the amplitude of the slow response action potential in canine Purkinje fibers. The fast response action potential was also depressed in a dose-dependent fashion, but with a threshold concentration of 5 × 10 −6 M. AHR 5360C decreased normal automaticity and barium-induced abnormal automaticity at concentrations of 5 × 10 −6 and 10 −5 M respectively, as well as ouabain-induced delayed afterdepolarizations at a threshold concentration of 10 −6 M. In blood superfusion studies, i.v. administration of AHR 5360C, 0.3 mg/kg, significantly reduced blood pressure. Doses of 1.0 mg/kg induced a high degree of A-V block, further reduction of blood pressure, and no physiological changes in heart rate and in the blood superfused fibers. In conclusion, AHR 5360C has calcium blocking properties that depress A-V conduction at concentrations that do not affect the sodium-dependent fast response action potential.

Inhibition by amiodarone of slow response action potentials and contraction in guinea pig ventricular muscle

1. 1. Effects of an antiarrhythmic agent, amiodarone (AM), on slow response action potentials and contraction of guinea pig ventricular muscle were examined. 2. 2. AM (4.4 × 10 −5 M, 1.1 × 10 −4 M) significantly inhibited the maximum upstroke velocity of slow response action potentials and contraction. 3. 3. As for action potential duration (APD), higher concentration (1.1 × 10 −4 M) of AM significantly shortened the APD, while low concentration (4.4 × 10 −5 M) had little effect on it. 4. 4. These findings strongly suggest that AM blocks slow inward current inflow via Ca 2+ channels in the ventricular muscle.

Suppressive effects of somatostatin in dog Purkinje fibres.

1. The effects of somatostatin (SS, 1 nM-3 microM) on the electrical and mechanical activities of isolated Purkinje fibres of the dog were studied. 2. In most Purkinje fibres driven electrically in normal [K]o Tyrode solution, SS decreased the force of contraction slightly and had very little effect on the fast response action potential. However, in sensitive fibres SS induced a moderate reduction of action potential duration and contractile force in normal [K]o and depressed the slow response action potentials in high [K]o. 3. In spontaneously beating Purkinje fibres, SS decreased the regular rhythms slightly but abolished bursts of fast rhythms at a concentration as low as 1 nM. 4. When the fibres were depolarized in the presence of 0.2 mM barium or in Na-free solution, SS suppressed the Ca-dependent slow response action potentials. 5. These findings suggest that SS may suppress abnormal automatic activity of dog Purkinje fibres through a reduction of transmembrane Ca influx or a modulation of intracellular calcium.

Voltage- and use-dependent block of the inward calcium current by MCI-176, a new non-dihydropyridine calcium antagonist, in canine ventricular muscles and single ventricular cells of the guinea-pig.

Effects of MCI-176, 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-isopro pox y-4(3H)- quinazolinone hydrochloride, on action potentials of canine ventricular muscles and on membrane currents of single ventricular cells of the guinea-pig heart were studied with the microelectrode and the patch-clamp ("whole-cell recording") methods. In canine ventricular trabeculae, MCI-176 (10(-5)-10(-4) M) decreased the plateau potential, the action potential duration at 30%-repolarization and the maximum rate of rise of the action potential; and it also decreased the amplitude and the duration of the slow response action potential in a concentration-dependent manner. Those effects were much more apparent at higher stimulus frequency. Under voltage clamp condition of single ventricular cells of the guinea-pig heart, MCI-176 (3 x 10(-5) M) decreased the inward calcium current (ICa) by 25-30% when the membrane potential was held at the resting membrane potential, and the drug abolished it when the membrane potential was held at -30 mV. MCI-176 added at rest decreased ICa ("initial block") and reduced it further with repetitive depolarizations in a beat-to-beat fashion. MCI-176 facilitated the reduction of ICa by increasing the clamp pulse frequency. These results indicate that MCI-176 decreases ICa of mammalian ventricular muscles in a voltage- and use-dependent manner.

Arrhythmogenic effects of theophylline in human atrial tissue

We studied the effects of theophylline on the transmembrane action potential and the contractile force of human atrial fibers obtained from the hearts of 15 patients, undergoing corrective open-heart surgery. Atrial fibers were perfused with Tyrode solution and driven electrically at a constant rate of 60 beats per min. Theophylline (0.1–1 mM) steepened the diastolic depolarization, increased the amplitude of oscillatory potential during diastole and facilitated the development of spontaneous slow response action potentials. These arrhythmogenic effects of theophylline were suppressed after diltiazem (0.1–0.3 μM) pretreatment. The present findings provide the electrophysiologic evidence that abnormal atrial automaticity as a result of triggered activity may be the underlying cause for atrial ectopic activity and multifocal atrial tachycardia in patients taking theophylline.

Electrophysiologic Effects of McN-4130, a New Antiarrhythmic Compound, on Isolated Cardiac Tissue

McN-4130 has antiarrhythmic efficacy in a number of animal models of ventricular arrhythmia and fibrillation. We used standard microelectrode techniques to characterize the electrophysiological effects of McN-4130 on isolated cardiac tissue. In canine Purkinje fibers, McN-4130 reduced the maximum rate of depolarization (Vmax) and shortened action potential duration at 50% repolarization (APD50) in a concentration-dependent manner (2-10 microM). These effects occurred without significant changes in membrane potential. APD100 tended to prolong with continued superfusion with McN-4130. The depression of Vmax was rate dependent and accompanied by increases in conduction time. The reductions in Vmax and APD50 induced by McN-4130 did not reach a steady-state until 90-150 min of superfusion. At 10 microM, fibers became inexcitable within 60-90 min. In addition, the effects on the action potential were not readily reversible. McN-4130 depressed membrane responsiveness in Purkinje fibers. It shortened the effective refractory period slightly but had a much greater effect on APD50. McN-4130 also reduced Vmax in ventricular muscle preparations. In contrast to its effects on the Purkinje fiber action potential, McN-4130 prolonged the duration of the ventricular muscle transmembrane potential and effective refractory period. Slow-response action potentials induced by high [K+]o and isoproterenol were not affected by McN-4130 at concentrations up to 10 microM. McN-4130 (2 and 4 microM) had no significant effect on normal Purkinje fiber automaticity. However, continued exposure to McN-4130 at 4 microM induced early afterdepolarizations and triggered activity in five of eight spontaneously discharging fibers. In guinea pig papillary muscle, McN-4130 caused marked rate-dependent depression of Vmax at concentrations that caused minimal tonic depression of Vmax. These results indicate that McN-4130 has effects at the cellular level that are similar to those of other potent local anesthetic antiarrhythmic agents. These effects may contribute to the antiarrhythmic and antifibrillatory activity of McN-4130.

Electrophysiology and ultrastructure of eustachian ridge from cat right atrium: a comparison with SA node

Intracellular microelectrode and electron microscopic techniques were used to investigate and correlate the electrophysiology of subsidiary pacemaker activity with the presence of cells having ultrastructural characteristics of pacemaker cells i.e. P cells, in Eustachian ridge tissue isolated from cat right atrium. In addition, the electrophysiological characteristics of subsidiary pacemaker activity and the ultrastructural characteristics of P cells in Eustachian ridge were compared to those of SA node obtained from the same hearts. Action potential recordings and morphological analysis were restricted to the endocardial site of earliest activation. Electrophysiological recordings revealed that spontaneously active Eustachian ridge tissues generate slow response action potentials with pacemaker characteristics similar, although not identical, to those of SA node. These included a relatively steep diastolic slope, low maximum diastolic potential (-70 mV), rate of rise (5.5 V/s), take-off potential (-52.5 mV), a relatively large overshoot potential (+7.7 mV) and a spontaneous cycle length (948 ms) about twice as long as SA node (434 ms). Morphological analysis revealed cells with ultrastructural characteristics of P cells, that were restricted to the endocardial site of earliest pacemaker activation. Morphological measurements indicate that Eustachian ridge P cells are not significantly different from P cells in SA node of the same hearts. However, Eustachian ridge P cells exhibit a unique apposition of subsarcolemmal cisternae between cells not seen in SA node. We conclude that pacemaker cells within the Eustachian ridge generate stable, spontaneous activity via slow response pacemaker action potentials. Cells responsible for this subsidiary pacemaker activity are most likely P cell types that are similar, although not identical, to P cells in SA node.

Abnormal pacemaking is modulated by sarcoplasmic reticulum in partially-depolarized myocardium from dilated right atria in humans

Fifty human atrial specimens removed at time of cardiac surgery were studied in vitro. Thirty-four samples were selected as presenting partial cell depolarization and exhibiting slow response action potentials. Twenty of these preparations were automatic whereas 14 were not. Neither mean maximum diastolic potential (-52.8 +/- 1.3 mV and -49.3 +/- 2.2 mV respectively) nor maximum rate of depolarization (Vmax) (1.1 +/- 0.1 V/s and 1.3 +/- 0.8 V/s) significantly differed between these two groups. Abnormal automaticity due to phase 4 depolarization occurred in 12/13 preparations dissected from markedly dilated atria whereas it occurred in only 2/10 preparations sampled from non-dilated atria. A statistically significant relationship between in vitro abnormal pacemaking and atrial dilatations was found. We investigated the effects on abnormal pacemaker depolarization and automaticity of a reduction in the extracellular Na and Ca and of sarcoplasmic reticulum (SR) inhibitors. Abnormal pacemaker depolarization appeared to be much more sensitive to a reduction in the extracellular Na than in the extracellular Ca. Both Sr and Mg slowed the automatic rate. Ryanodine 3 X 10(-6) M, a specific SR inhibitor, irreversibly lengthened the spontaneous basic cycle duration to about 300% of control. Epinephrine up to 10(-4) M was ineffective in accelerating the residual spontaneous rhythm that persists after ryanodine action, although epinephrine markedly enhanced the overshoot and Vmax of the slow responses. It is concluded that, in the human atrial myocardium, abnormal pacemaking that develops at low level of membrane potential: is promoted by chamber dilatation; is strongly modulated by SR-dependent processes.