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The modulation of noradrenaline release from sympathetic nerves by presynaptic a2-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 vivoand in vitrofor two reasons: (a) the postsynaptic adrenoceptors are of the ß-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 a-adrenoceptors and to the lack of a good in vivomodel of a discrete vascular bed. Using both in vivoand in vitropreparations, it was demonstrated that the sympathetic innervation of the heart and blood vessels possesses a functional negative feedback system modulating noradrenaline release mediated via a2-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 a2-adrenoceptors have been reported to mediate pressor responses in vivoin 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 a1-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 a2-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 a1-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 a1-adrenoceptors, and the predominant extrasynaptic location of a2-adrenoceptors in vascular smooth muscle.

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.

1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (±)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (±)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (±)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (±)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.

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.

M7 was originally reported to be a selective presynaptic a2-adrenoceptor agonist in the pithed rat preparation. Subsequent work showed that M7 also stimulated postsynaptic a2-adrenoceptors in this preparation, producing a pressor response. We have now investigated the selectivity of M7 for a2- and a1-adrenoceptors in vitro. Our results demonstrate that M7 is very potent in stimulating presynaptic a2-adrenoceptors in the rat vas deferens and postsynaptic a2-adrenoceptors in the dog saphenous vein. However, at higher doses M7 is also an a1-adrenoceptor agonist, its ED50 at a1-adrenoceptors being approximately 60 fold greater than that at postsynaptic a2-adrenoceptors. It is clear that the postsynaptic effects of M7 will depend upon the relative proportions of a1- and a2-adrenoceptors contained in the tissue under study.

Summary A comparison of the effects of noradrenaline and 6-fluoronoradrenaline has been made at several peripheral sympathetic neuroeffector junctions. In the rat vas deferens preparation in the presence of 1 μM cocaine, 6-fluoronor-adrenaline was found to be about 9 times more potent than noradrenaline as an agonist at presynaptic inhibitory α2-adrenoceptors. In the rabbit aorta, 6-fluoronoradrenaline had approximately one tenth of the potency of noradrenaline in stimulating the postsynaptic α1-adrenoceptors. Furthermore 6-fluoronoradrenaline, in contrast to previous reports, appears to be a substrate for the neuronal uptake process since exposure to cocaine potentiated the inhibition of the twitch response of the vas deferens by 6-fluoronoradrenaline. In addition, 6-fluoronoradrenaline increased the spontaneous outflow of radioactivity from rabbit pulmonary artery strips prelabelled with 3H-noradrenaline and this increase was blocked by cocaine (30μM).

The dihydropyridines mentioned in the title, e.g. (IV), (VIII), and (XIV), are prepared on different synthetic routes partly outlined in the reaction scheme.