Pharmacodynamic, pharmacokinetic and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol.

In recent years, there has been a major shift from the use of antiarrhythmic drugs that act by slowing conduction to those that exert their beneficial actions by lengthening cardiac repolarisation. Such a shift is occurring because sodium channel blockers may increase mortality, especially in patients with structural heart disease, and because drugs such as sotalol and amiodarone are effective, with a potential for decreasing arrhythmic mortality. In this context, the electrophysiological and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol, are of major importance. d-Sotalol is essentially devoid of beta-blocking actions and may be considered a pure class III compound. It has been assumed that its clinical efficacy would approximate that of amiodarone and sotalol, but without the complex adverse effect profile of amiodarone and the adverse beta-blocker effects of racemic sotalol. d-Sotalol has pharmacokinetic properties that resemble those of the racemate. It lengthens the QT/QTc interval but does not affect other electrocardiographic (ECG) intervals. It increases the refractory period in the atria, ventricles, bypass tracts and the His-Purkinje system while minimally slowing the heart rate. In preliminary studies, it had a weak suppressant effect on premature ventricular contractions, prevented inducibility of ventricular tachycardia or fibrillation in about 40% of patients, and demonstrated the potential to terminate atrial flutter and fibrillation and maintain stability of sinus rhythm during prophylactic administration. The drug exhibits little or no negative inotropic actions. Thus, it is likely to be better tolerated in patients with congestive heart failure dependent on sympathetic stimulation for compensation. Because it produces less bradycardic effect than the racemate, it is believed that the drug might induce a lower rate of torsade de pointes. The role of d-sotalol in controlling cardiac arrhythmias is being addressed in a number controlled clinical trials. However, one such double-blind, placebo-controlled trial, Survival With Oral d-Sotalol (or SWORD), in survivors of myocardial infarction with depressed ventricular function was recently terminated prematurely because of a strikingly greater all-cause mortality compared with placebo (4.6 versus 2.6%). These preliminary findings, still to be fully analysed and interpreted for clinical significance, nevertheless raise valid concerns regarding the currently popular concept of controlling cardiac arrhythmias by the selective or isolated prolongation of repolarisation ('pure' class III action) as an antiarrhythmic principle.

Swimming causes myosin adaptations in the rat cardiac isograft.

To investigate the contributions of humoral and hemodynamic factors to cardiac adaptations associated with chronic exercise, female Fischer 344 rats were subjected to chronic swimming, infrarenal cardiac transplantation, or both. Swimming resulted in hypertrophy (11-12%) of the in situ hearts in both the unoperated and operated animals compared with the matched sedentary controls. The cardiac isograft exhibited atrophy (32-35%), which was not attenuated by swimming. The cardiac isograft was also associated with a decrease in the percent of V1 myosin isoenzyme, which was attenuated by swimming (45 +/- 5% versus 66 +/- 6%). Swimming also increased the percent of this isomyosin in the in situ hearts of operated rats. These data suggest that hemodynamic load and/or neural innervation are necessary for hypertrophy associated with chronic conditioning by swimming, whereas myosin isoenzyme control is significantly mediated by humoral factors.

Microsomal metabolism of carbon tetrachloride: participation of pyridine nucleotide synergism.

The role of pyridine nucleotide synergism in CCl4 metabolism was evaluated for its potential contribution to enhanced lipid peroxidation. Male Sprague-Dawley rats receiving either no treatment (control) or treatment with phenobarbital (PB) were used to prepare hepatic microsomes. Metabolism was evaluated in the presence and absence of an NADPH generator system and in the presence and absence of NADH. The generator system produced a greater extent of metabolism for both control and PB microsomes. NADH-catalyzed CCl4 metabolism occurred to a similar extent in control and PB microsomes, amounting to 9-10% and 5-6% of the NADPH rate in control and PB microsomes, respectively. Synergism by NADH occurred at the lowest concentrations of NADPH, apparently decreasing the Km for NADPH and having little effect on the Vmax. Addition of NAD+ produced synergism, as did the addition of 5' AMP, an inhibitor of nucleotide pyrophosphatase. Thus, the synergistic increase in CCl4 metabolism produced by NADH may occur in part from an increased availability of NADPH, as a result of decreased degradation, rather than by electron donation from NADH.