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

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Abstract
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 7 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 .times. 10-5 M) and corticosterone (4 .times. 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. It appears that the following relationships are present between the structure of amines and the .alpha.-adrenoceptor stimulating activity in the heart: N-methylation increases the potency; 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.

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