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Alpha 1 but not alpha 2-adrenoceptors mediate contractions of the cat nictitating membrane. The contractions of this tissue evoked by alpha 1-adrenoceptor agonists, but not those evoked by angiotensin II, are potentiated by pre-dosing with alpha 2-adrenoceptor agonists. This potentiation is reversed by the alpha 2-adrenoceptor antagonist, WY 26392. Pressor responses evoked by alpha 1-adrenoceptor agonists or angiotensin II were not affected by alpha 2-adrenoceptor agonists. Contractions of the nictitating membrane evoked by noradrenaline were reduced by pretreatment with WY 26392. These results suggest that in some tissues the role of alpha 2-adrenoceptors may be to modulate responses to alpha 1-adrenoceptors, rather than to evoke a discrete response themselves.

M7 was originally reported to be a selective presynaptic alpha 2-adrenoceptor agonist in the pithed rat preparation. Subsequent work showed that M7 also stimulated postsynaptic alpha 2-adrenoceptors in this preparation, producing a pressor response. We have now investigated the selectivity of M7 for alpha 1-and alpha 2-adrenoceptors in vitro. Our results demonstrate that M7 is very potent stimulating presynaptic alpha 2-adrenoceptors in the rat vas deferens and postsynaptic alpha 2-adrenoceptors in the dog saphenous vein. However, at higher doses M7 is also an alpha 1-adrenoceptor agonist, its ED50 at alpha 1-adrenoceptors being approximately 60 fold greater than that at postsynaptic alpha 2-adrenoceptors. It is clear that the postsynaptic effects of M7 will depend upon the relative proportions of alpha 1-and alpha 2-adrenoceptors contained in the tissue under study.

The decrease in mesenteric blood flow produced by dopamine administered intra-arterially in the anaesthetised dog was investigated by means of drugs selective for alpha 1- and alpha 2-adrenoceptors. The selective alpha 1-adrenoceptor agonist phenylephrine (0.3-100 microgram) given by intra-arterial injection (i.a.) into the superior mesenteric artery of the anaesthetized dog produced a decrease in mesenteric blood flow which was preferentially blocked by the alpha 1-adrenoceptor antagonist prazosin (30-300 microgram/kg i.v.). On the other hand, i.a. injections of the selective alpha 2-adrenoceptor agonist M7 (1-100 microgram) or of dopamine (1-300 microgram) produced a decrease in mesenteric blood flow which was blocked by the alpha 2-adrenoceptor antagonist yohimbine (100-300 microgram/kg i.v.) but was not significantly reduced by prazosin (300 microgram/kg i.v.). These results demonstrate that the mesenteric vascular bed of the dog contains both alpha 1- and alpha 2-adrenoceptors located postsynaptically and mediating vasoconstriction. The decrease in mesenteric blood flow produced by i.a. injections of dopamine is mediated predominantly via postsynaptic alpha 2-adrenoceptors.

The selective alpha 2-adrenoceptor antagonist, RX781094, evoked a dose-related pressor response in the pithed rat preparation when administered in bolus doses by the intravenous route. This response was enhanced following depletion of endogenous amines by reserpine, and inhibited by the selective alpha 1-adrenoceptor antagonist, prazosin. Two other selective alpha 2-adrenoceptor antagonists, Wy26703 and Wy26392, had no marked effect on the blood pressure of this preparation. Pretreatment of the preparation with Wy26703 had no significant effect on the pressor response evoked by RX781094. It is concluded that RX781094 is an alpha 1-adrenoceptor agonist at similar doses to those at which it exhibits alpha 2-adrenoceptor antagonist properties. The agonist activity exhibited by RX781094 is not a general property of all alpha 2-adrenoceptor antagonists and should be considered when this compound is employed as an alpha 2-adrenoceptor antagonist.

This work was undertaken to investigate whether diltiazem and verapamil, two blockers of the voltage-activated calcium channel, interfered with vascular smooth muscle responses mediated by stimulation of alpha 1- or alpha 2-adrenoceptors. In pithed rats (and in isolated canine saphenous vein strips) cirazoline behaved as a preferential alpha 1-adrenoceptor agonist, since its pressor (and contractile) effects were blocked selectively by the alpha 1-adrenoceptor antagonist prazosin and were relatively unaffected by the alpha 2-adrenoceptor antagonist yohimbine. In the same preparations, M-7 (2,N,N-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene) exhibited preferential alpha 2-adrenoceptor agonist properties. The pressor response to M-7 developed much more slowly than that to cirazoline, M-7 requiring approximately twice as long as cirazoline to reach the same peak effect. Pithed rats received a 30-minute intravenous infusion of either diltiazem (12.5-25.0 micrograms/kg per min) or verapamil (6.2-12.5 micrograms/kg per min) that was continued while dose-response curves to M-7 and cirazoline were generated. These compounds depressed the maxima and the slopes of arterial pressure dose-response curves to M-7 but not cirazoline. In canine saphenous vein strips, diltiazem did not change the contractile response to cirazoline but inhibited those to M-7. Verapamil however did antagonize the responses to cirazoline although significantly less than those to M-7. These results indicate that diltiazem and verapamil preferentially inhibit alpha 2-adrenoceptor-mediated responses. The hypothesis is advanced that the pharmacomechanical coupling for alpha 2-adrenoceptors involves a receptor-operated calcium channel that is sensitive to diltiazem and verapamil and, thus, might become activated when the potential across the cellular membrane attains critical values.