Significant Electrophysiologic Effects Research Articles

The Electrophysiological Effects of Alpha‐Chloralose Anesthesia in the Intact Dog: (1) Alone and (2) in Combination with Verapamil

The electrophysiological effects of alpha-chloralose anesthesia were determined in 13 chronically instrumented dogs and compared to baseline electrophysiological parameters in the conscious state. Alpha-chloralose anesthesia (75 mg/kg of a 4% solution in polyethylene glycol (PEG) delayed conduction and prolonged refractoriness of the AV node: (1) the P-R interval increased from 108 +/- 14 msec (mean +/- SD) in the conscious state to 125 +/- 23 msec (P less than 0.02); (2) the A-H from 98 +/- 12 msec to 108 +/- 16 msec (P less than 0.04); (3) the AV nodal effective refractory period from 136 +/- 16 to 153 +/- 29 msec (P = .05) and the AV nodal functional refractory period from 232 +/- 58 to 247 +/- 46 msec (P = 0.07); and (4) the AV block cycle length from 228 +/- 54 msec to 248 +/- 43 msec (P less than 0.04). Chloralose anesthesia also increased the ventricular refractory period from 139 +/- 13 msec to 161 +/- 22 msec (P less than .03) and the QTc interval from 273 +/- 22 to 306 +/- 32 msec (P less than 0.0002). To determine whether these effects on AV nodal conduction would influence experimental results, responses to verapamil were studied in the conscious state and during chloralose anesthesia. During chloralose anesthesia, (1) no relationship was detected between the sinus cycle length and verapamil concentrations; (2) a greater increment in AV conduction time was seen for a given verapamil concentration; and (3) AV block occurred at verapamil concentrations associated with 1:1 conduction in the conscious state. We conclude that chloralose anesthesia has significant electrophysiological effects and that these effects must be taken into consideration during the interpretation of experiments performed in animals during chloralose anesthesia.

Electrophysiologic effects of desethylamiodarone, an active metabolite of amiodarone: Comparison with amiodarone during chronic administration in rabbits

During acute superfusion studies by means of the standard microelectrode technique, we previously showed that both amiodarone and its major metabolite, desethylamiodarone, had a modest effect on the lengthening of the action potential duration (APD) at high drug concentrations and produced a rate-dependent block of the sodium channel in cardiac muscle. In this study the comparative electrophysiologic effects of the two compounds in rabbits treated chronically with these compounds were determined with particular reference to repolarization and sinus node automaticity. The changes were correlated with those in serum and tissue drug levels and in thyroid hormone indices. After 1 week neither compound had a significant effect on atrial or sinus nodal potentials; after 3 weeks, amiodarone increased the atrial APD at 90% repolarization time by 10.5% ( p < 0.05) and the effective refractory period (ERP) by 6.7% ( p < 0.05). The corresponding figures for desethylamiodarone were 13% (NS) and 18% (NS). The sinus cycle length was increased 12% (NS) by amiodarone and 27.9% ( p < 0.05) after the metabolite. In animals treated for 6 weeks, amiodarone increased the ventricular APD at 90% repolarization by 58.8% ( p < 0.001) and desethylamiodarone by 42.0% the corresponding figures for the ERP were 63.4% ( p < 0.01) and 47.4% ( p < 0.01), respectively. At the stimulation frequency used, neither compound exerted a significant effect on V max. Both amiodarone and desethylamiodarone significantly decreased serum triiodothyronine and increased reverse triiodothyronine levels but had no effect on thyroxine. Neither the electrophysiologic effects nor those in thyroid hormone indices could be related systematically to the serum or tissue levels of amiodarone or desethylamiodarone. The data indicate the after chronic drug administration, desethylamiodarone exerts electrophysiologic effects, the magnitude and latency of onset of which were comparable to those of the parent compound. The metabolite has significant electrophysiologic effects that are likely to be additive to those of the parent compound during chronic administration.

Electrophysiologic effects, clinical efficacy and safety of intravenous and oral nadolol in refractory supraventricular tachyarrhythmias

The electrocardiographic and electrophysiologic effects, clinical efficacy and safety of intravenous and oral nadolol therapy were examined in 34 patients with recurrent supraventricular tachyarrhythmias (SVT) undergoing electrophysiologic evaluation. Programmed electrical stimulation was performed in the control (drug-free) state, after infusion of intravenous nadolol (mean dose 0.09 ± 0.03 mg/kg) and after chronic oral nadolol therapy in patients who responded to intravenous nadolol (mean dose 83 ± 12 mg for 5 days). Intravenous nadolol administration prolonged mean sinus cycle length (p = 0.009), mean PR interval (p = 0.001) and mean AH interval (p = 0.001), with no significant electrophysiologic effects in the atrium, ventricle or accessory bypass tracts. Oral nadolol had similar electrocardiographic and electrophysiologic effects, but of lesser magnitude. Intravenous nadolol resulted in complete suppression of induced SVT in 78% of patients with sinus and atrioventricular nodal reentrant tachycardia and 11% of patients with atrioventricular (AV) reentrant tachycardia (p < 0.001). Partial responses were frequent in intraatrial or AV reentrant tachycardia (37%). Oral nadolol suppressed induction of SVT in patients who responded to intravenous nadolol. Adverse reactions to intravenous and oral nadolol were infrequent—6% and 8%, respectively—and usually did not require drug withdrawal. Intravenous nadolol is highly effective in sinus and AV nodal reentrant tachycardia, and a successful electrophysiologic response to it predicts efficacy of long-term oral nadolol therapy. It has limited efficacy alone in AV reentrant tachycardia and should be considered in combination with other antiarrhythmic therapy in this type of SVT.

Cardiac Electrophysiologic and Hemodynamic Effects Related to Plasma Levels of Bupivacaine in the Dog

To investigate electrophysiologic and hemodynamic responses to various plasma levels of bupivacaine, especially those in the range normally seen during regional anesthesia, bupivacaine was given intravenously as a bolus dose followed by continuous infusion in pentobarbital-anesthetized dogs. Cardiac electrophysiology was studied by His bundle electrography, programmed electrical stimulation, and monophasic action potential recordings. At plasma bupivacaine concentrations below 1000 ng/ml, no significant electrophysiologic or hernodynamic effects mere observed. This indicates that systemic responses to absorbed bupivacaine do not contribute to the cardiac electrophysiologic effects recently demonstrated during thoracic epidural analgesia. At a plasma level of about 2000 ng/ml, a level occasionally achieved during regional anesthesia, bupivacaine prolonged impulse conduction time in all parts of the heart, prolonged atrial and AV nodal refractoriness, decreased left ventricular inotropy, but had no effect on ventricular refractoriness or monophasic action potential duration. These electrophysiologic effects may enhance susceptibility to reentrant arrhythmias.

Cardiac Electrophysiologic and Hemodynamic Effects Related to Plasma Levels of Bupivacaine in the Dog

To investigate electrophysiologic and hemodynamic responses to various plasma levels of bupivacaine, especially those in the range normally seen during regional anesthesia, bupivacaine was given intravenously as a bolus dose followed by continuous infusion in pentobarbital-anesthetized dogs. Cardiac electrophysiology was studied by His bundle electrography, programmed electrical stimulation, and monophasic action potential recordings. At plasma bupivacaine concentrations below 1000 ng/ml, no significant electrophysiologic or hemodynamic effects were observed. This indicates that systemic responses to absorbed bupivacaine do not contribute to the cardiac electrophysiologic effects recently demonstrated during thoracic epidural analgesia. At a plasma level of about 2000 ng/ml, a level occasionally achieved during regional anesthesia, bupivacaine prolonged impulse conduction time in all parts of the heart, prolonged atrial and AV nodal refractoriness, decreased left ventricular inotropy, but had no effect on ventricular refractoriness or monophasic action potential duration. These electrophysiologic effects may enhance susceptibility to reentrant arrhythmias.

Electrophysiologic effects of chronic amiodarone therapy in patients with ventricular arrhythmias

Detailed electrophysiologic studies were performed in nine patients with chronic refractory ventricular arrhythmias before and after 7 to 20 weeks (mean 11 weeks) of amiodarone therapy. The amiodarone dose at the time of the repeat study ranged from 400 to 800 mg/day. The drug reduced the sinus rate ( p < 0.001) and prolonged the sinoatrial conduction time ( p < 0.05) with some prolongation of the corrected sinus node recovery time. Intra-atrial conduction was slightly prolonged both in sinus rhythm and during atrial pacing. Anterograde conduction through the AV node was significantly prolonged both in sinus rhythm ( p = 0.001) and during atrial pacing ( p < 0.005), and Wenckebach AV block was seen at significantly lower atrial pacing rates after the drug ( p < 0.005). The HV interval was prolonged both in sinus rhythm ( p < 0.05) and during atrial pacing ( p = 0.001), and so was the QRS width during atrial pacing ( p < 0.05) and the QT interval in sinus rhythm ( p < 0.005) and during atrial pacing ( p < 0.005). Significant prolongation of the refractory periods in the atrium, AV node, and ventricular muscle were also seen following the drug. We concluded that the significant electrophysiologic effects of this drug throughout the heart during chronic oral use attest to its clinical effectiveness in patients with atrial and ventricular arrhythmias. With due care and despite its effects on the HV interval and QRS width, it can be used in patients with intraventricular conduction defects complicating severe organic heart disease.

Comparative electrophysiologic effects of digoxin in the nonsedated chronically instrumented puppy

The electrophysiologic effects of acute but not chronic administration of cardiac glycosides have been studied. Nineteen chronically instrumented beagle puppies underwent 2-week courses of parenteral digoxin in three dosage regimens: six received digoxin, 0.04 mg/kg/day; seven received 0.03 mg/kg/day; and 11 received 0.02 mg/kg/day. Mean serum concentrations were 3.2 ng/ml, 1.3 ng/ml, and 1.0 ng/ml, respectively. Significant electrophysiologic effects on sinus node function were produced only by the highest dose. Atrioventricular node conduction was significantly delayed among animals receiving both high and middle dosages. All three regimens significantly effected atrioventricular specialized conduction system functional refractory periods. Atropine decreased digoxin-induced effects on all measured parameters but totally eliminated the digoxin effect on the corrected sinus node recovery time.

Effect of chronic ethanol exposure on the electric membrane properties of DRG neurons in cell culture.

Neural cell cultures of adult mouse dorsal root ganglia were utilized to investigate the effects of chronic ethanol exposure on neuronal electric membrane properties (EMP). After 12 days of exposure to various ethanol concentrations, the EMP of the neurons were determined in ethanol-free medium. Significant changes in a number of EMP were observed. Of particular physiological significance were decreased specific membrane resistance, increased specific membrane capacitance, relatively little change in membrane time constant, and increased electrical excitability. Various features of the action potential were also affected, e.g., reduced overshoot, afterhyperpolarization, and rate of rise. In preliminary experiments, EMP were determined at varying periods after the cultures had been withdrawn from ethanol medium and maintained in ethanol-free medium. These results indicated that the altered EMP persisted as long as one (Cm) to two (Rm) weeks after ethanol withdrawal. A possible mechanism for these ethanol-induced changes in EMP was suggested, utilizing the membrane expansion theory of anesthesia. Because of few previous reports demonstrating significant electrophysiological effects of ethanol at pharmacological concentrations, the neural cell culture system provides a useful new experimental model for studying the action of chronic ethanol exposure on neuronal EMP and the physical basis of the tolerance and withdrawal phenomena found in alcoholism and addiction in general. After being maintained for 12 days in culture media containing various concentrations of ethanol, non-neuronal cell survival was observed to have decreased in an approximately linear manner with increasing ethanol levels. By contrast, neuron survival was not affected until ethanol concentrations greater than 0.34 g % were used. This decreased cell survival due to chronic exposure to physiological levels of ethanol has not been reported previously. Neural cell cultures may therefore be useful for investigating the cellular pathology of chronic alcoholism and fetal alcohol syndrome.

Electrophysiologic and hemodynamic actions of diltiazem: Disparate temporal effects shown by experimental dose-response studies

Diltiazem (DT), a potent slow channel blocker, has been found to be clinically useful for treatment of coronary vasospasm, hypertension, and tachyarrhythmias. Nevertheless, only limited data are available on the hemodynamic and electrophysiologic effects of DT. Atrial, His, right ventricular apex, aortic, and Swan-Ganz thermodilution catheters were used in 10 anesthetized dogs, and recordings were made during control period and after each of four infusions of DT (0.01, 0.02, 0.04, and 0.08 mg/kg/min) each lasting 30 minutes. Results showed that heart rate, pulmonary capillary wedge pressure, stroke volume, and HV interval did not change significantly. However, two dogs had second-degree AV block and a third had escape junctional rhythm during DT 0.08 mg/kg/min. Mean aortic pressure (AP¯), corrected sinus node (SN) recovery time, and systemic vascular resistance (SVR) were significantly reduced, whereas AH interval, AV functional and effective refractory periods were prolonged by DT. AV nodal refractory periods and AH interval were the only parameters significantly affected at DT 0.02 mg/kg/min. SN recovery time was significantly shortened at DT 0.04 mg/kg/min, whereasAP¯ and SVR fell significantly at DT 0.08 mg/kg/min. DT had significant electrophysiologic effects at low doses, whereas hemodynamics were significantly altered only at high doses. Further, major electrophysiologic effects were on the AV node with lesser effects on SN function. Therefore, at a dose when antiarrhythmic effects are evident, the safety of diltiazem is corroborated by lack of adverse hemodynamic effects.

Electrophysiological and biochemical derangements in ischemic myocardium: interactions involving the cell membrane.

ABSTRACTSeveral lines of evidence indicate that metabolites accumulating in ischemic tissue may have a profound influence on membrane function and may thereby mediate many of the electrophysiological derangements characteristic of ischemic tissue in vivo. Recently, we have detected the accumulation of lysophosphoglycerides (LPG), intermediate metabolites of membrane phospholipids, in ischemic tissue in vivo, in effluents from ischemic isolated hearts and in venular effluents from ischemic regions in vivo. Furthermore, LPG, at comparable concentrations, induces reversible electrophysiological alterations in normoxic Purkinje fibers and ventricular muscle in vitro closely analogous to those changes characteristic of ischemic tissue in vivo. Concentration‐dependent changes seen include a reduction in resting potential, Vmax of phase 0, action potential duration and amplitude, with profound decreases in conduction velocity, heterogenous phase 0 depolarization, enhanced automaticity at reduced membrane potentials, and post‐repolarization refractoriness. Experiments utilizing 14C‐lysophosphatidyl choline (14C‐LPG) indicated that incorporation by LPC to a level of less than 1% of total cellular phospholipid is sufficient to induce electrophysiological derangements in isolated ventricular muscle. Based on the observations that venular effluents from ischemic regions in vivo exert deleterious electrophysiological effects in vitro, we have recently demonstrated a two‐fold increase in LPC in venular effluents from ischemic regions in vitro. at Although this two‐fold increase did not produce significant electrophysiological effects in vitro at normal pH, concomitant acidosis (pH = 6.7) comparable to that seen during ischemia in vivo, resulted in dramatic electrophysiological derangements after exposure to LPC. Subsequent experiments indicated that acidosis alone had modest electrophysiological effects but decreased the LPC concentrations three‐fold required to induce membrane effects but did not enhance the incorporation of 14C‐LPC into the cellular phospholipid fraction. Since long‐chain acyl carnitine also accumulate in ischemic myocardium and are also amphiphilic metabolites with many structural similarities to LPC, the effects of these compounds were also assessed in vitro. Palmitoyl carnitine at concentrations identical to LPC, induced electrophysiological derangements similar to LPC. In addition, the effects of the two compounds were additive and as with LPC, acidosis (pH = 6.7) decreased three‐fold the concentration of palmitoyl carnitine required to induce membrane derangements. The additive nature of the effects of these two different amphiphiles suggests that

Cardiovascular effects of phenothiazines

Phenothiazines have significant electrophysiologic and cardiocirculatory effects. The electrophysiologic effect of these drugs is similar to that reported for quinidine. Phenothiazines decrease the rate of rise of phase 0 of the action potential, decrease the duration and amplitude of phase 2, and prolong phase 3. The surface ECG changes produced by phenothiazines are lengthening of the QTC interval, ST-T wave changes, increased size of U waves, and prolongation of the PR interval. The degree of repolarization abnormalities secondary to phenothiazines seems to be dose-related. Various arrhythmias have been attributed to the effect of phenothiazine therapy and numerous cases of sudden death as a result of fatal arrhythmia have been described. Paradoxically, phenothiazines such as chlorpromazine and thioridazine also have been shown to have significant antiarrhythmic properties. Chlorpromazine shows a powerful vasodilatory effects which is caused by alpha-adrenergic receptor blockade, a central action, and a direct effect on the vascular wall. In addition, the drugs also have a direct depressant effect on the myocardium. As a result of peripheral vasodilatation and negative inotropic effects, hypotension is the most common adverse reaction of phenothiazines in patients with no evidence of congestive heart failure. Experimental studies have demonstrated significant reductions in systemic and pulmonary vascular resistance as well as systemic blood pressure following intravenous administration of chlorpromazine. These hemodynamic changes were accompanied by significant increase in cardiac output in one study and by no change in cardiac output in another study. The vasodilatory effect of chlorpromazine resulted in increased renal and mesenteric blood flow and prolongation of survival time in dogs following hemorrhagic hypotension. Chlorpromazine was found effective in relieving abnormal vascular tonus and improving the circulation in patients undergoing cardiopulmonary bypass surgery. In patients with myocardial infarction complicated by congestive heart failure, intravenous administration of chlorpromazine caused significant hemodynamic improvement and a considerable degree of sedation. The drug was found effective in reducing the vasoactive response in patients with cardiogenic shock which resulted in improved tissue perfusion and metabolism.