DIRECT AND BETA ADRENERGIC RECEPTOR BLOCKING ACTIONS OF NETHALIDE ON ISOLATED HEART MUSCLE

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

The direct and beta adrenergic receptor blocking actions of methalide were studied in papillary muscles of kittens and in isolated atria of kittens and guinea pigs. On cat papillary muscles nethalide has very weak positive inotropic effects in 3 x 10^-7 to 3 x 10^-6 M concentrations, and marked depressant effects in concentrations above 10^-5 M. Both effects are the result of changes in the degree of activation of the contractile element, and both are influenced by the frequency of stimulation. Low concentrations of nethalide show very weak positive chronotropic effects on cat atrium and no effect on the guineapig S-A node. Concentrations above 10^-5 M greatly depress the rate of impulse formation in the atrial pacemaker of both species.

Nethalide shifts the inotropic and chronotropic log concentration-effect curves of levarterenol to the right in parallel fashion. The highest concentration of nethahide which has no significant direct cardiac effects shifts both curves by approximately 1.5 logarithmic units. The maximum inotropic response to levarterenol is not decreased by nethalide concentrations up to 10^-5 M. The antagonism of nethahide and levarterenol appears to be a simple, competitive one, the pA₂ is 6.8 Nethahlide effectively antagonizes the positive inotropic actions of tyramine. Increasing concentrations of nethalide progressively increase the slope of the concentration-effect curve for tyramine and depress the maximum response to tyramine. This results in part from the negative inotropic effects of high tyramine concentrations.