Isoproterenol specifically modulates reverse rate-dependent effects of d,l-sotalol, d-sotalol, and dofetilide.

The modulation of antiarrhythmic and proarrhythmic properties of antiarrhythmic compounds by increased sympathetic activity is of experimental and clinical interest. However, the interaction of adrenergic stimulation with the rate-response pattern of class III antiarrhythmic agents is not well established. Using standard microelectrode techniques, we evaluated the effects of isoproterenol (iso) on the action of d,l-sotalol (d,l-sot), d-sotalol (d-sot), and dofetilide (dof) on action-potential parameters recorded from isolated canine cardiomyocytes. The cell-isolation procedure was performed from the endocardial layers of left ventricular myocardium from healthy beagle dogs. The following electrophysiologic parameters were recorded: resting membrane potential (RMP), action-potential amplitude (APA), action-potential duration at 90% repolarization (APD 90), and effective refractory period (ERP). After exposure to iso, the class III activity of d,l-sot was well maintained over the entire range of frequencies studied. In contrast, iso differentially antagonized the action of d-sot and dof. In comparison to dof, the class III action of d-sot was particularly sensitive to iso, predominantly at faster stimulation rates. Our observations demonstrate specific rate regulation of the class III action of d,l-sot, d-sot, and dof in response to adrenergic stimulation. The unfavorable rate-response pattern of d-sot compared with d,l-sot and dof might prove disadvantageous in high-catecholamine states.

Is cyclic AMP involved in the defibrillating effect of sotalol?

Ventricular fibrillation induced in animals pretreated with sotalol, a class III antiarrhythmic agent, would spontaneously terminate and revert into a sinus rhythm. This phenomenon has been attributed to the class III action of this drug, i.e., prolongation of myocardial action potential duration and effective refractory period. Since various observations suggested that these alone cannot explain the defibrillating phenomenon, we hypothesised that sotalol affected ventricular intercellular synchronization by increasing intercellular coupling. Our recent experimental studies have shown that sotalol antagonized the cellular decoupling to guinea pig ventricular muscle strip caused by perfusion with either a hypoxic normal Tyrode's solution or an oxygenated high Ca2+ Tyrode's solution. We assumed that the most likely mechanism for the restoration of intercellular coupling would be increasing intracellular cAMP concentration. In order to test this hypothesis, we studied the modification of this sotalol-induced recoupling by a cAMP dependent protein kinase inhibitor. The results clearly supported our assumption since the addition of Arg-Gly-Tyr-Ala-Leu- Gly (pure A- kinase inhibitor) prevented the aforementioned cellular recoupling action of sotalol in a dose-dependent manner. It can thus be concluded that changes in intracellular cAMP level are involved in the synchronizing / defibrillating effect of sotalol.

Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes.

OBJECTIVES: The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias. BACKGROUND: The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration. METHODS: Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes. RESULTS: Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone. CONCLUSIONS: The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.

Isoproterenol antagonizes drug-induced prolongation of action potential duration in humans.

The effects of an isoproterenol infusion on the duration of the human right ventricular endocardial monophasic action potential at 90% repolarization were recorded in the absence and in the presence of an antiarrhythmic drug regimen containing class III effects in two similar groups of patients. The drugs used were amiodarone (N = 3, 300 +/- 50 mg), sotalol plus quinidine (N = 11, 156 +/- 13 mg sotalol, 1688 +/- 594 mg quinidine), and sotalol alone (N = 3, 300 +/- 20 mg). All patients had underlying coronary disease but no evidence of inducible ischemia. In the absence of antiarrhythmic drug, isoproterenol did not significantly change the relationship of action potential duration at 90% repolarization to cycle length; there was a linear decrease in action potential duration by 19.8% between a paced cycle length of 600 and 300 ms. Isoproterenol did not significantly shorten the action potential duration at any cycle length. However, isoproterenol decreased the ventricular effective refractory period at 400 ms drive from 240 +/- 5.0 to 225 +/- 6.0 ms (p < 0.05) accompanied by no change in the ratio of refractory period to steady-state action potential duration. In the presence of class III drug effects, the action potential duration was increased by an average of 9.2% at all paced cycle lengths longer than 300 ms (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.

Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.

Mechanism of the inotropic action of inosine on canine myocardium.

The positive inotropic effect of inosine in intact dog hearts was approximately halved by beta-adrenergic blockade with sotalol. The same result was obtained in dogs with chronic denervation of the heart, in which the sympathetic nerve terminals had degenerated. Therefore part of the positive inotropic action of inosine appears to be non-adrenergic. Inosine infusion caused supersensitivity of the positive inotropic effect over a wide range of doses of adrenaline. It is postulated that inosine may act by blocking the desensitising action of cyclic AMP on the reaction between calcium ions and the contractile proteins.