α-ADRENOCEPTORS MEDIATING POSITIVE INOTROPIC EFFECTS ON THE VENTRICULAR MYOCARDIUM: SOME ASPECTS OF STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES

Abstract

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