Cardiac effects of ketanserin, a serotonin antagonist--electrophysiological examinations as a part of toxicity studies.

Cardiac effects of ketanserin were examined mainly electrophysiologically with using rat and guinea pig heart muscle preparations. 10(-6)M ketanserin slightly antagonized the positive chronotropic but not inotropic action of serotonin in spontaneously beating guinea pig atria. Ketanserin, only at the concentration as high as 10(-4)M, produced slight rightward shift of the positive chronotropic but not inotropic dose-response curves for norepinephrine in guinea pig atria. In both rat and guinea pig atria, ketanserin per se produced negative chronotropic effect and slight prolongation of action potential duration (APD) at high concentrations, 0.1 or 0.3 mg/ml. In guinea pig ventricular preparation, 1 mg/ml of ketanserin did not affect the rate of rise of the action potential (+Vmax), action potential amplitude and APD. In rat ventricular free wall preparations, 1 mg/ml of ketanserin produced slight increase in APD without affecting the other action potential parameters. In rat ventricular papillary muscle and septum preparations, 0.3 mg/ml of ketanserin tended to produce a decrease in +Vmax and an increase in APD. However, since these changes were produced only at extremely high concentrations and slight in degree, it was concluded that ketanserin does not produce electrophysiological side effects of clinical relevance.

Lack of parallelism between the positive inotropic effects of various cardiac stimulants and their activities to produce the slow channels in the depolarized myocardium.

Positive inotropic actions in the normal guinea pig cardiac muscle and the activities required to produce electrical and mechanical responses in the depolarized muscle were examined using epinephrine, dopamine, metanephrine, aminophylline, histamine, serotonin, tyramine, tetraethylammonium (TEA), tetramethylammonium (TMA), and X-537A, a calcium ionophore. In the normal cardiac muscle, histamine produced the greatest positive inotropic action, followed by epinephrine, dopamine and TEA. In the cardiac muscle made inexcitable by the elevated potassium (30 mM), all of the agents tested produced electrical and mechanical responses. Aminophylline was the most potent in the activity to produce the mechanical response in the depolarized muscle; the potencies of histamine, dopamine, X-537A, epinephrine and TEA were much the same. From these results, it was concluded that the positive inotropic effects of the cardiac stimulants are not produced solely through the mechanisms related to the slow channels, but that other mechanisms must be involved in the normal condition where the fast sodium channels are functioning.