Electrophysiologic and anticholinergic effects of pirmenol enantiomers in guinea-pig myocardium.

Abstract

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)