alpha-Adrenoceptors mediating positive inotropic effects on the ventricular myocardium: some aspects of structure-activity relationship of sympathomimetic amines.

Experiments were carried out on the isolated papillary muscle of the rabbit in order to further characterize the alpha-adrenoceptors mediating the positive inotropic effect. For this purpose dose-response relations of seven sympathomimetic amines were compared under the influence of alpha- and/or beta-adrenolytic drugs. Phentolamine (10(-6) M) shifted the lower part of the dose-response curves for norfenephrine, synephrine and epinine as for phenylephrine and adrenaline to the right, while prindolol (10(-8) M) affected only the upper part of the curves. In the presence of both alpha- and beta-adrenoceptor blocking agents the entire dose-response curves for sympathomimetic amines were shifted in a parallel manner. Noradrenaline affected preferentially beta-adrenoceptors, whereas its effect on alpha-adrenoceptors was so weak that it could be detected only when the neuronal and extraneuronal uptake mechanism of amines were blocked by cocaine (3 X 10(-5) M) and corticosterone (4 X 10(-5) M), respectively. The effect of dopamine was not affected either by phentolamine or by prindolol, but was antagonized by the simultaneous application of both alpha- and beta-adrenoceptor blocking agents. From the present results, it appears that the following relationships are present between the structure of amines and the alpha-adrenoceptor stimulating activity in the heart: (1) N-methylation increases the potency: (2) Absence of the hydroxyl group either in 3 or in 4 position decreases the intrinsic and beta-adrenoceptor stimulating activities, but increases the alpha-adrenoceptor stimulating activity.