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A model of arrhythmias based on the application of sinusoidal alternating current (ac) to isolated heart preparations has been employed to determine the effects of hypoxia (30 vol % O2 in the perfusion medium) on the threshold of arrhythmia and asystole. With this method three representatives of different classes of antiarrhythmic drugs, flecainide, bepridil and amiodarone, have been investigated in isolated papillary muscles and left atria from guinea-pigs. Hypoxia reduces both the threshold for ac-arrhythmia and the threshold for ac-asystole. Flecainide (3 and 10 mumol/l) elevates both thresholds under normoxia and has a protective effect against the hypoxia-induced reduction of threshold. Bepridil (10 mumol/l) is without effect on the threshold of ac-arrhythmia in papillary muscle, prevents the hypoxia-induced decline of the threshold of ac-arrhythmia in left atria and depresses the threshold of ac-asystole both in normoxia and hypoxia. amiodarone (10 mumol/l) elevates the threshold of ac-arrhythmia both during normoxia and hypoxia in papillary muscle but only during the second hour of hypoxia in left atria. The results may be interpreted with respect to the inhibitory action on Na+-channels (flecainide), Ca2+-channels (bepridil) or protective effects against hypoxia-induced changes in action potential duration (amiodarone, but also flecainide and bepridil) as shown by additional electrophysiological experiments.

The method for inducing arrhythmias or asystole by the application of a 50 Hz alternating current (ac) has been applied to isolated guinea-pig left atria and papillary muscles in order to characterize arrhythmogenic and antiarrhythmic substances. Aconitine, BaCl2 (less than 2 mmol/l) and hypoxia decrease threshold of ac-arrhythmia and ac-asystole, in both tissues to a similar extent, whereas carbachol and BaCl2 (greater than 2 mmol/l) increase threshold. The calcium antagonists nifedipine and diltiazem lower threshold of ac-asystole but differ with respect to threshold of ac-arrhythmia, which is increased by 10(-6) mol/l diltiazem in left atria and papillary muscles by about 30% and remains nearly unaffected with nifedipine. The Na+-inhibitory substance flecainide reverses the decrease in threshold of ac-arrhythmia and ac-asystole brought about by aconitine. Threshold of ac-arrhythmia lowered by hypoxia is increased by diltiazem in a concentration-dependent manner, whereas decrease of threshold of ac-asystole is even augmented. Therefore, the method offers an opportunity of quantifying the action of arrhythmogenic agents at concentrations which are too low to induce arrhythmia, as well as to characterize the activity of antiarrhythmic drugs in the presence of arrhythmogenic substances.

The cardioselectivity and specificity of diacetolol, the major metabolite of the beta-adrenoceptor blocking drug acebutolol, was studied in the isolated right atrium of the guinea-pig and rat and the papillary muscle and trachea of the guinea-pig. The beta-adrenoceptor blocking potency of diacetolol is about ten times lower than that of acebutolol. Like acebutolol, diacetolol was a more effective isoprenaline antagonist in the heart than in the trachea, thus showing relative cardioselectivity. The high water solubility of diacetolol and acebutolol led to a much faster disappearance of the beta-blockade after washout than the blockade by the lipid soluble agents propranolol and penbutolol. Like acebutolol, diacetolol had a weak intrinsic sympathomimetic activity. Cardiac depressant effects, e.g. decrease of maximum upstroke velocity and duration of the action potential and reduction in force of contraction, occurred with concentrations 100-1000 times higher than those needed for beta-blockade, thus indicating relative specificity.