Effects of organic Ca2+ channel antagonists, Ni2+ and ryanodine on the electrophysiological and positive inotropic responses to histamine were examined in isolated guinea-pig left atria. Histamine increased force of contraction, prolonged action potential duration (APD) and hyperpolarized the membrane in a concentration-dependent manner. Histamine at a concentration of 1 mumol/l produced a dual-component positive inotropic response composed of an initial increasing phase (initial component) and a second and late developing, greater positive inotropic phase (second component), whereas causing monophasic changes in APD and resting potential. The electrophysiological and dual-component positive inotropic effects induced by histamine were antagonized by chlorpheniramine (1 mumol/l) but not by cimetidine (10 mumol/l), indicating that both effects are exclusively mediated by H1-receptors. The positive inotropic response to 1 mumol/l histamine was changed by the pretreatment with nifedipine (1 mumol/l) and nisoldipine (1 mumol/l). In the presence of these dihydropyridines, the second component was almost completely abolished, while the initial component was hardly affected. On the other hand, verapamil (3 mumol/l) and diltiazem (10 mumol/l) failed to modify the multiphasic inotropic response to histamine. None of the Ca2+ channel antagonists affected the histamine-induced APD prolongation. In the presence of Ni2+ at a concentration of 0.3 mmol/l, at which it produced no negative inotropic action, the second component of the positive inotropic effect of histamine was specifically suppressed whereas the histamine-induced APD prolongation was unaffected. Preferential attenuation of the second component was also observed in the presence of 30 nmol/l ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Since it has been reported that several class I drugs stereoselectively block sodium channels, potassium channels and muscarinic receptors in cardiac tissues, electrophysiologic and anticholinergic effects of enantiomers of pirmenol, a class I antiarrhythmic drug, were examined. Both (+) and (-) pirmenol depressed the maximum upstroke velocity (Vmax) of the action potential in a concentration-dependent manner in guinea-pig papillary muscles driven at 1.0 Hz, and there was no significant difference in the potency of the class I effect between the enantiomers. The onset rates of use-dependent block (UDB) of Vmax at 2.0 Hz for 10 mumol/l (+) and (-) pirmenol were 0.30 +/- 0.03 and 0.29 +/- 0.01 per action potential, and the recovery time constants from UDB for (+) and (-) pirmenol were 27.0 +/- 2.7 and 27.7 +/- 1.9 s, respectively, indicating no difference in the binding and unbinding kinetics to the sodium channel between the enantiomers. Both (+) pirmenol and (-) pirmenol prolonged action potential duration (APD) at low concentrations (1-10 mumol/l) and shortened it at high concentrations (30-100 mumol/l). Again, there was little difference with respect to the effects on APD between the enantiomers. However, in the isolated guinea-pig left atria (-) pirmenol more potently antagonized the negative inotropic effect of carbachol than (+) pirmenol, and the pA2 values for (+) and (-) pirmenol were 6.41 and 6.71, respectively. The functional study was supported by the radioligand binding experiments using [3H]N-methylscopolamine ([3H]NMS) in guinea-pig left atrial membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

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