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1. In the autoperfused hind limb of the dog prazosin (10µg/kg intravenously) markedly antagonized responses to lumbar sympathetic stimulation, whereas responses to injected nor-adrenaline were largely unaffected. 2. In ß-adrenoreceptor- and ganglion-blocked animals, the hind limb pressor responses to phenylephrine were antagonized to a greater degree by prazosin than responses to injected noradrenaline. 3. Rauwolscine, a selective a2-adrenoreceptor-blocking agent, antagonized responses to the a2-adrenoreceptor agonist guanabenz, but not those to phenylephrine. 4. Hind limb pressor responses to noradrenaline were significantly inhibited by rauwolscine and further reduced by prazosin. 5. These results demonstrate that in this vascular bed a1- and a2-adrenoreceptors are located postsynaptically. Furthermore the results suggest that neuronally released noradrenaline acts mainly upon a1-adrenoreceptors, whereas exogenous noradrenaline acts upon a1- and a2-adrenoreceptors. 6. It is suggested that this selectivity of prazosin in blocking the vasoconstriction to neuronally-released noradrenaline may in part explain the effectiveness of this drug as an antihypertensive agent.

Substituted 1,4-benzoxazines bearing an amino side chain at the 2-position were prepared and were found to have a moderate activity on intracellular calcium. Of the compounds studied it was found that those which possess a homoveratrylamino moiety exhibited superior potency. The chain length and the nature of the amine (4-fluorophenylpiperazine, 4-fluorobenzhydryloxyethylamine, N-substituted homoveratrylamine) is discussed. The 4-benzyl-3,4-dihydro-2-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]propyl]-2H-1,4-benzoxazine (3c) is the most potent derivative of the series with a ratio of IC50 values against PE (phenylephrine) and K⁺ of 2.1. Under these test conditions a ratio near 1 indicates potential intracellular calcium activity while a ratio greater than 100 an action on extracellular calcium influx.

The selectivity of yohimbine and its two diastereoisomers rauwolscine and corynanthine for pre- and postsynaptic alpha adrenoceptors has been investigated in the anesthetized dog. Antagonism of the inhibitory effect of clonidine on the tachycardia produced by electrical stimulation of the ansa subclavia was used as a measure of presynaptic alpha-2 adrenoceptor blockade. Inhibition of the diastolic pressor response to phenylephrine in ganglion and beta blocked dogs was used as a measure of postsynaptic alpha-1 adrenoceptor blockade. All three of the isomers reduced, and at higher doses reversed, the inhibitory effect of clonidine Yohimbine and rauwolscine were equipotent in this respect and were approximately 100-fold more potent than corynanthine. However, all the isomers were equipotent as antagonists of the diastolic pressure response to phenylephrine. Yohimbine and rauwolscine were approximately 30 times more potent as alpha-2 adrenoceptor than alpha-1 adrenoceptor antagonists, whereas corynanthine was 10-fold more potent at alpha-1 adrenoceptors than at alpha-2 adrenoceptors. These results are in broad agreement with those previously reported from in vitro experiments showing yohimbine and rauwolscine to be preferential alpha-2 adrenoceptor antagonists and corynanthine to be a preferential alpha-1 adrenoceptor antagonist. It is concluded that the high affinity of the antagonists yohimbine and rauwolscine for alpha-2 adrenoceptors is responsible for their selectivity because at the level of blockade of postsynaptic alpha-1 adrenoceptors both isomers were equipotent with corynanthine.

Prazosin causes relaxation of vascular smooth muscle and produces a non‐classical functional blockade of α‐adrenoceptors quite unlike the occupancy block caused by conventional α‐adrenoceptor blocking drugs. The antihypertensive effect of prazosin in dogs with renal hypertension is not accompanied by tachycardia or renin release and the development of tolerance is not a problem. It has been shown by measuring impulse traffic in the carotid sinus nerve in cats that prazosin considerably increases baroreceptor sensitivity, presumably as a consequence of smooth muscle relaxation and enhanced distensibility in the carotid sinus region. This probably contributes to the overall antihypertensive response. The recent realization, principally through the work of Langer et alii, Starke and Rand et aliiof the existence of an important local control mechanism at the terminal ramifications of adrenergic nerves in which noradrenaline regulates its own release through a negative feedback mechanism, mediated by prejunctional α‐receptors, prompted the determination of prazosin's affinity for the latter sites. Prazosin was found to be completely devoid of affinity for prejunctional α‐receptors, which not only explains the absence of tachycardia and renin release after prazosin administration, but affords support to the important suggestion of Rand et aliias to why the original clinical expectations of α‐adrenoreceptor antagonists in hypertension were not fulfilled. This was hypothesized as due to the loss of the feedback inhibitory loop and consequent enhancement of release of noradrenergic transmitter that resulted from their blocking prejunctional in addition to postjunctional α‐adrenoceptors. In preliminary experiments employing 2‐14C‐prazosin, inconclusive evidence was obtained of the release of prazosin from neuronal storage sites in response to nerve stimulation.