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We compared the cardiac electrophysiological actions of two types of H1-receptor antagonists--the piperidines, astemizole and terfenadine, and the nonpiperidines, chlorpheniramine and pyrilamine-in vitro in guinea pig ventricular myocytes and in vivo in chloralose-anesthetized dogs. Astemizole and terfenadine significantly increased action potential duration of guinea pig myocytes. This concentration-dependent prolongation of action potential duration was reverse frequency dependent and led to development of early afterdepolarizations, which occurred more frequently at higher concentrations and slower pacing frequencies. Astemizole and terfenadine potently blocked the rapidly activating component of the delayed rectifier, IKr, with IC50 values of 1.5 and 50 nmol/L, respectively. At 10 mumol/L, terfenadine but not astemizole blocked the slowly activating component of the delayed rectifier, IKs (58.4 +/- 3.1%), and the inward rectifier, IK1 (20.5 +/- 3.4%). Chlorpheniramine and pyrilamine blocked IKr relatively weakly (IC50 = 1.6 and 1.1 mumol/L, respectively) and IKs and IK1 less than 20% at 10 mumol/L. Astemizole and terfenadine (1.0 to 3.0 mg/kg IV) significantly prolonged the QTc interval and ventricular effective refractory period in vivo. Chlorpheniramine and pyrilamine (< or = 3.0 mg/kg) did not significantly affect these parameters. Block of repolarizing K+ currents, particularly IK1, by astemizole and terfenadine produces reverse rate-dependent prolongation of action potential duration and development of early afterdepolarizations, delays ventricular repolarization, and may underlie the development of torsade de pointes ventricular arrhythmias observed with the use and abuse of these agents.

We examined the effects of stellate ganglia stimulation on the phase-dependent chronotropic and dromotropic responses to brief vagal bursts in open-chest anesthetized dogs. Stellate stimulation affected the phasic vagal effects on heart rate by shortening the latent period, shifting the phase at which maximum decrease in heart rate occurred to earlier phases, and reducing the maximum decrease in heart rate. These effects were due primarily to an increase in the basic heart rate. No significant sympathetic-parasympathetic interaction occurred for heart rate, indicating that accentuated antagonism did not occur with brief vagal bursts. Stellate stimulation primarily decreased the amplitude of the phasic vagal effects on atrioventricular nodal conduction, regardless of the underlying heart rate, and a significant sympathetic-parasympathetic interaction was associated with this effect. The peak of the phase-dependent vagal effects on heart rate and atrioventricular nodal conduction were phase-shifted with one another. From these findings, we postulate the small changes in sympathetic tone might shift the predominant phase-dependent vagal effect from one on heart rate to one on atrioventricular nodal conduction. Furthermore, our results suggest that dynamic vagal control of heart rate and atrioventricular node conduction involves both phase-dependent and phase-independent factors. Sympathetic activity appears to affect only the phase-independent factor(s) in the control of heart rate, whereas it affects both phase-dependent and phase-independent factors in the control of atrioventricular node conduction.

Dynamic heart rate control by parasympathetic nervous input involves feedback mechanisms and reflex bursting of efferent cardiac vagal fibers. Periodic vagal bursting induces phasic changes in sinoatrial cycle length and can entrain the pacemaker to beat at periods that may be identical to those of the vagal burst. We investigated the electrophysiological basis of these phenomena in isolated sinus node preparations (rabbit, cat, and sheep). In the presence of propranolol (3.9 X 10(-6)M), relatively brief (50-150 msec) trains of stimuli, applied onto the endocardial surface of the preparation, activated postganglionic vagal terminals and induced a brief hyperpolarization of sinoatrial pacemaker cells. This vagally mediated hyperpolarization could alter the pacemaker rhythm by an amount that depended on its duration and its position in the cycle, as well as on the duration of the free-running pacemaker period. When the free-running period was sufficiently long and the hyperpolarization was induced sufficiently early in the spontaneous cycle, a "paradoxical" acceleration of the pacemaker rhythm ensued. Phasic changes were plotted on phase-response curves, constructed by scanning systematically the sinoatrial pacemaker period with single or repetitive vagal trains. These phase-response curves enabled us to predict the entrainment characteristics and the levels of synchronization of the pacemaker to the vagal periodicity. The overall data explain the cellular mechanisms involved in the phasic effects of brief vagal discharges on sinoatrial periodicity, and provide conclusive evidence for the prediction that repetitive vagal input is capable of forcing the cardiac pacemaker to beat at rates that can be faster or slower than the intrinsic pacemaker rate. These data should improve our knowledge of the dynamic control of heart rate by neural reflexes and aid in our understanding of rhythm disturbances generated by the interaction of the cardiac pacemaker with vagal activity.

We studied the cardiac effects of amantadine, an antiviral and anti-Parkinson drug. Amantadine hydrochloride (100--800 microM) produced significant changes in the electrophysiological properties of isolated ventricular muscle preparations from frog, rabbit, cat, dog, and calf. At relatively low concentrations (100--300 microM), the drug increased action potential duration, decreased action potential amplitude and maximum diastolic potential, and induced phase 4 depolarization. Amantadine also caused subthreshold diastolic depolarizations, apparent upon cessation of stimulation in all preparations studied. The amplitude of the diastolic depolarizations increased as a function of time and/or concentration of drug, eventually reached threshold, and spontaneous activity ensued. In the steady state, amantadine-induced spontaneous activity was rather stable, and the rate was dependent upon the amantadine and external potassium concentrations, as well as the membrane potential. In the absence of stimulation, amantadine-induced spontaneous activity occurred abruptly or could be triggered by a single stimulus, often occurring in a "bursting" fashion that appeared to originate from multiple discrete foci. All actions of amantadine were rapidly reversed upon washout. Propranolol had no effect on the actions of the drug. Amantadine-induced spontaneous activity was unaffected by lidocaine, diminished by TTX, and reduced or abolished by verapamil. The results indicate that amantadine can directly alter the membrane properties of ventricular muscle, possibly due to an effect on potassium conductance. Furthermore, amantadine can be used as a tool to study the ionic basis of ventricular automaticity and to model cellular mechanisms of ventricular rhythm disturbances.

Previous studies have shown that antegrade conduction through damaged His Purkinje tissue may be suppressed following rapid ventricular pacing (overdrive suppression of conduction). We studied this phenomenon using isolated Purkinje fibers placed in a three-chamber bath. Superfusates for the left, middle, and right segments of the fiber were altered to produce action potentials that resembled those of normal bundle branch, damaged His bundle, and normal His bundle, respectively. To produce anisotropic conduction, the left segment of the fiber was adjusted to be three to four times longer than the right segment. Pacing the right segment at intermediate rates produced maximal action potential amplitude in the middle segment and 1:1 right-to-left conduction, whereas pacing at faster or slower rates reduced action potential amplitude and produced block. Pacing the left segment at fast or slow rates also reduced action potential amplitude in the middle segment, but conduction was maintained (anisotropy). After rapid or slow left segment pacing, action potential amplitude in the middle segment remained low during subsequent right segment pacing at intermediate rates, and transient block occurred (overdrive or underdrive suppression of conduction). With time, action potential amplitude normalized and conduction resumed. In other more severely depressed preparations, conduction block occurred even at intermediate right segment pacing rates prior to left segment pacing. Under these conditions, pacing the left segment at intermediate rates increased action potential amplitude in the middle segment and temporarily permitted 1:1 conduction at intermediate right segment pacing rates (overdrive facilitation of conduction).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have suggested that maintained vagal stimulation or acetylcholine infusion results in a fade of responses in the sinoatrial node but not in the atrioventricular node, implying different muscarinic receptor subtypes in the two regions. We investigated this hypothesis in 23 isolated rabbit atrial preparations made quiescent by continuous superfusion with verapamil (1 microgram/ml). Transmembrane potentials were recorded simultaneously from cells in the sinoatrial pacemaker region and from the "N" region of the atrioventricular node. Postganglionic vagal stimulation was achieved by the application of trains of pulses (50-150 microseconds; 10-20 V; 200 Hz). Simultaneous application of long-lasting (1-10 sec) vagal trains produced hyperpolarizations which were nearly identical for both nodal regions. Maximal hyperpolarizations (approximately or equal to 24 mV for sinoatrial node; 26 mV for atrioventricular node) were reached about 500 msec after initiation of the vagal train. Thereafter, hyperpolarizations faded, following a biphasic time course, and thus displaying two different time constants, one fast (tau fast = 580 msec for sinoatrial node; 550 msec for atrioventricular node), and one slow (tau slow = 9.2 sec for both sinoatrial and atrioventricular nodes). Hyperpolarizations during brief (200-msec) but repetitive vagal trains also faded biphasically, but approached a steady state much more rapidly than responses to long-lasting trains. Recovery from hyperpolarization decay occurred rather slowly and was linear. Our results demonstrate that the membrane potential responses to vagal stimulation in the atrioventricular node are indistinguishable from those in the sinoatrial node, and suggest that similar muscarinic receptors are operative in both regions. These phenomena may play an important role in the response of the cardiac conducting system to direct or reflexly mediated vagal input.

We examined the effects of quinidine (5-20 microM) on transmembrane action potentials and ionic currents of isolated canine ventricular myocytes. Collagenase treatment of canine ventricular tissue produced a yield of 40-60% healthy cells. Myocytes had normal resting and action potentials as measured using conventional microelectrodes. Quinidine decreased Vmax, amplitude, overshoot, and the duration of action potentials stimulated by passage of brief current pulses through the recording pipette. Recovery was complete after washout except that action potential duration was prolonged compared with control. A discontinuous single microelectrode voltage ("switch") clamp was used to measure ionic currents. Quinidine irreversibly reduced steady-state outward current as measured with three different voltage clamp protocols. Quinidine reversibly decreased peak calcium current as well as the slowly inactivating and/or steady-state inward currents in the plateau voltage range, presumably both "late" sodium (tetrodotoxin-sensitive) and calcium (tetrodotoxin-insensitive) currents. The effect on calcium current showed both tonic and use-dependent block. Thus, quinidine has a multitude of actions on both inward and outward currents, which combine to produce the net effect of quinidine on action potential configuration.

Effects of brief vagal bursting on pacemaker periodicity and intranodal conduction were studied by recording transmembrane potentials in isolated rabbit sinoatrial preparations. Postganglionic vagal terminals were activated by applying brief (50- to 150-msec) trains of pulses (duration, 100 mu sec; frequency, 200 Hz) to the endocardial surface of the node. Sympathetic effects were prevented by superfusion with Tyrode's solution containing propranolol (1 microgram/ml). Vagal trains applied singly every 10 seconds produced brief hyperpolarizations in "true" pacemaker and transitional cells, and induced phasic changes in periodicity and conduction. These changes were out of phase with each other, and were dependent on the magnitude and duration of the vagal train, as well as on its position within the pacemaker period. When similar trains were applied repetitively at cycle lengths (200-1200 msec) that were independent of the pacemaker period, complex patterns of vagus-sinoatrial node interactions resulted. Hence, depending on the vagal stimulus cycle length, the sinoatrial pacemaker was forced to beat at stable and predictable harmonic (i.e., 1:1, 1:2, 2:1, etc.), subharmonic (3:2, 4:3, etc.), or more complex entrainment ratios. At some of these ratios, arrhythmic sinus patterns coexisted with intranodal conduction disturbances, including first- and second-degree block, Wenckebach phenomena, or combinations thereof. At other entrainment ratios, arrhythmias occurred in the absence of conduction changes. At still other ratios, conduction disturbances developed in the presence of apparently undisturbed sinus rhythm. These results provide insight into the mechanism of the dynamic vagal control of sinoatrial periodicity and conduction, and may have clinical implications as well.

Early afterdepolarizations (EADs) are one mechanism proposed to cause certain cardiac arrhythmias. We studied the effect of the Ca2+ channel agonist Bay K 8644 (1 x 10(-8) to 5 x 10(-5) M) on normally polarized sheep and canine cardiac Purkinje fiber short segments. EADs occurred with higher Bay K 8644 concentrations and had an average take-off potential of -34 mV. The initiation of EADs was preceded by lengthening of action potential duration and flattening of the plateau. Induction of EADs with Bay K 8644 was enhanced by low stimulation frequencies, lowering of [K]o, addition of tetraethylammonium chloride, or application of depolarizing constant current pulses during the plateau. EADs were abolished by increasing stimulation frequency, raising [K]o, the addition of tetrodotoxin, lidocaine, ethmozin, verapamil, and nitrendipine, or application of repolarizing constant current pulses. Using current pulses to modify the action potential plateau, a steep inverse relationship was found between the EAD peak voltage and its take-off potential, and EADs could be initiated over only a narrow range of take-off potentials. Thus, interventions that suppressed EADs shortened action potential duration or shifted the plateau away from the voltage range needed to initiate EADs. These observations suggest that mechanisms dependent on both time and voltage underlie EADs, and provide a unifying hypothesis for the induction of the EADs. We propose that induction of EADs requires 1) lengthening of action potential duration within a plateau voltage range where 2) recovery from inactivation and reactivation of an inward current possibly carried through Ca2+ channels can occur.