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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.

1 The effects of endogenous noradrenaline released by tyramine and the influence of depletion of the tissue noradrenaline with reserpine and/or alpha-methyl-p-tyrosine on the twitch responses of the field-stimulated mouse vas deferens have been studied.2 Tyramine (10-40 muM) inhibited the twitch responses to field stimulation and failed to produce a contraction. The inhibition decreased as the rate of stimulation increased.3 The inhibition produced by tyramine was antagonized by cocaine (10 muM) and by yohimbine (10 nM), which indicated that it was produced by released noradrenaline acting on presynaptic alpha-adrenoceptors.4 Depletion of the tissue noradrenaline by 39% by blockade of the synthesis of noradrenaline with alpha-methyl-p-tyrosine, was without effect on the twitch response but it reduced the inhibitory effect of tyramine.5 Depletion of the tissue noradrenaline by 96.5% with reserpine alone and by 99.4%, with a combination of reserpine and alpha-methyl-p-tyrosine, reduced the twitch responses by approximately 66% and virtually abolished the inhibition produced by tyramine. It also increased the rate of decline of the responses when the tissue was continuously stimulated. The remaining twitch was not antagonized by phenoxybenzamine (15 muM).6 Residual twitches were bigger in tissues depleted by 99.4% than in those depleted by only 96.5%. This difference was eliminated in the presence of yohimbine (128 nM).7 It is concluded that inhibition of the twitch responses by tyramine is produced by stimulation of presynaptic alpha-adrenoceptors and that the twitch response is associated with stimulation of the sympathetic neurone, but that it is not mediated by postsynaptic alpha-adrenoceptors.

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.

The modulation of noradrenaline release from sympathetic nerves by presynaptic alpha 2-adrenoceptors has now been demonstrated in a variety of tissues. The heart is a particularly useful organ in which to study the modulation of noradrenaline release both in vivo and in vitro for two reasons: (a) the postsynaptic adrenoceptors are of the beta-subtype; and (b) the ease with which the sympathetic nerve supply can be isolated and stimulated electrically. Blood vessels however have been difficult to study directly due to the fact that they possess postsynaptic alpha-adrenoceptors and to the lack of a good in vivo model of a discrete vascular bed. Using both in vivo and in vitro preparations, it was demonstrated that the sympathetic innervation of the heart and blood vessels possesses a functional negative feedback system modulating noradrenaline release mediated via alpha 2-adrenoceptors. The effect of this system depends upon the frequency of nerve stimulation and the total number of stimuli. This article covers some of the more recent contributions to the understanding of the presynaptic modulation of noradrenaline release that have been made by the study of the peripheral cardiovascular system.

Postsynaptic alpha 2-adrenoceptors have been reported to mediate pressor responses in vivo in several species. It has been suggested that it is the presence of these receptors that renders the pressor response to injected noradrenaline resistant to the alpha 1-adrenoceptor antagonist prazosin in these species. We have now investigated this phenomenon in the perfused cat spleen preparation in vitro. We find that the pressor responses to nerve stimulation and phenylephrine are blocked to a greater extent by prazosin than the responses to either noradrenaline or the selective alpha 2-agonist M7. In the presence of cocaine the increases in spleen perfusion pressure induced by noradrenaline, phenylephrine, and nerve stimulation are equally blocked by prazosin. We conclude from these results that the responses of the perfused spleen to exogenous noradrenaline are resistant to prazosin because the access of noradrenaline to alpha 1-adrenoceptors is limited by the neuronal uptake mechanism. The difference in the sensitivity of neuronally released and exogenously administrated noradrenaline to blockade by prazosin may be due to the preferential noradrenergic innervation of alpha 1-adrenoceptors, and the predominant extrasynaptic location of alpha 2-adrenoceptors in vascular smooth muscle.

1 Noradrenaline (ID50, 0.75 micrometer) and clonidine (ID50, 2.8 nM) produced a dose-related inhibition of the twitch response of the isolated vas deferens of the mouse to electrical stimulation, their effectiveness decreasing as frequency of stimulation increased from 0.2 to 16 hertz. 2 Phenylephrine (1.0--2.0 micrometer) produced a dose-related contraction of the mouse isolated vas deferens and potentiated the responses to field stimulation. 3 Yohimbine (10 nM) antagonized the inhibitory effects of noradrenaline and clonidine, but had no effect on the motor activity of phenylephrine. At a concentration of 128 nM yohimbine potentiated the twitch response by 110% at 1 Hz, but its effectiveness decreased with increasing frequency of stimulation up to 16 hertz. 4 Thymoxamine (0.3 micrometer) antagonized the effects of phenylephrine, but not those of clonidine. 5 From a consideration of the known characteristics of pre- and postsynaptic alpha-adrenoceptors, it is concluded that the inhibitory effect of noradrenaline is produced by stimulation of the former and the effects of phenylephrine by stimulation of the latter.

In the anaesthetised rat, human and rat CGRP (calcitonin gene-related peptide) which differ by 4 out of 37 amino acids, when given intravenously, lowered blood pressure and increased heart rate. The effects of human CGRP were unaltered by either propranolol or by mepyramine plus cimetidine. In the rat isolated perfused heart the peptides decreased coronary perfusion pressure and evoked a tachycardia. The latter effect was not seen in the rabbit isolated heart, although human CGRP increased coronary flow. The two peptides were equipotent at increasing the rate and force of contraction in the rat isolated right atrium, effects unaltered by propranolol. In the guinea-pig isolated atrium, rat CGRP was 10 times as potent as a chronotropic agent than as an inotrope, unlike human CGRP which was equipotent. In conclusion, human and rat CGRP probably acted directly on the cardiovascular system to produce their qualitatively similar effects.