The vascular receptors activated following sympatho-adrenal stimulation were determined by analysing the effects of 'selective' antagonists on the vasopressor response to spinal sympathetic nerve activation in the pithed rat. The net vascular response to adrenal stimulation was a balance between alpha-adrenoceptor-mediated vasoconstriction and beta-adrenoceptor-mediated vasodepression. Part of the alpha-adrenoceptor-mediated response was 'prazosin-sensitive' (alpha 1) and the remainder was abolished by rauwolscine (alpha 2). As with adrenal stimulation, direct sympathetic nerve stimulation of the vasculature evoked pressor responses which were partly resistant to prazosin. Rauwolscine only partly blocked the prazosin-sensitive component. Reserpine pretreatment led to smaller responses than prazosin plus rauwolscine. Thus, the response resistant to alpha-adrenoceptor antagonists could be mediated, in part, by adrenoceptors distinct from alpha-adrenoceptors, as currently defined. alpha, beta-Methylene ATP reduced the nerve-mediated pressor response after alpha-adrenoceptor blockade or reserpine pretreatment but not in drug-free controls. The results suggest that stimulation of the adrenal medulla can produce a vasopressor response which consists of summating alpha 1- and alpha 2-adrenoceptor-mediated components, and is identical to the effect of injected adrenaline. In contrast, the response to vasopressor nerve stimulation appears to be essentially mediated by alpha 1-adrenoceptors, with a facilitatory influence from alpha 2-adrenoceptors. A further response obtained after alpha-adrenoceptor blockade may contain a purinergic component and another which is adrenergic but not mediated by stimulation of alpha-adrenoceptors.

1 The influence of angiotensin II (All) on resting blood pressure and on sympathetic nervemediated pressor responses in the pithed rat was investigated either by inhibiting the reninangiotensin system or by infusing All. 2 Plasma All levels in the pithed rat were approximately 20 fold higher than in normotensive rats. 3 Infusion of a subpressor dose of All (50ngkg-'min-1) had no effect on sympathetic nerve mediated pressor responses but a pressor dose of All, (200 ng kg1min-1) facilitated nervemediated pressor responses. 4 The angiotensin converting enzyme inhibitor, teprotide, and the AII-receptor antagonist, saralasin, lowered the diastolic blood pressure and attenuated sympathetic nerve-mediated pressor responses. There was no difference in the effects of teprotide at 1 mg kg-1 and 10 mg kg-'. Infusion of sodium nitroprusside at concentrations producing a fall in diastolic blood pressure of similar magnitude to that produced by teprotide and saralasin significantly attenuated nerve-mediated pressor responses.5 After teprotide, Al 50mg kg-1 min-1 increased diastolic blood pressure. The inhibitory effect of teprotide on nerve-mediated pressor responses was antagonized by this infusion of All only if the rats were pretreated with the cyclo-oxygenase inhibitor, flurbiprofen. 6 It is concluded that All is a major determinant of vascular tone in the pithed rat and that inhibition of the renin-angiotensin system attenuates sympathetic nerve-mediated pressor responses at least in part through the fall in blood pressure per se. The demonstration of this is complicated by an excessive release of vasodilator prostaglandins possibly due to the infused All. Since plasma All levels are high, the effects of blockade of the renin-angiotensin system will be exaggerated and so the importance of All as a modulator of sympathetic responses will be overestimated in this model.

1The actions of the potassium channel openers, cromakalim and minoxidil sulphate, were compared in a range of isolated blood vessel preparations. 2 Cromakalim and minoxidil sulphate inhibited spontaneous mechanical activity of the guinea-pig portal vein and relaxed the noradrenaline precontracted rat aorta with similar potency. In contrast, minoxidil sulphate was less potent than cromakalim in inhibiting spontaneous activity in the rat portal vein and was essentially inactive in the noradrenaline precontracted rat mesenteric artery and rabbit aorta. 3 Minoxidil sulphate did not antagonize the effects of cromakalim in the rabbit aorta indicating it was not acting as a partial 'agonist'. 4 Charybdotoxin, noxiustoxin and rubidium failed to discriminate between cromakalim and minoxidil sulphate indicating that the apparently selective effects of minoxidil sulphate were not mediated by either Ca2 +-activated potassium channels, delayed rectifiers or rubidium impermeable potassium channels. 5 Glibenclamide antagonized the effects of cromakalim in an apparently competitive manner whereas the effects of minoxidil sulphate were antagonized in a non-competitive manner. The involvement of subtypes of ATP-sensitive potassium channels is discussed.

A subset of antiandrogen compounds, the N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropanamides 1, were found to activate ATP sensitive potassium channels (KATP) and represent a new class of potassium channel openers (PCOs). A structure-activity relationship was carried out on the western region of this series with the goal of obtaining an activator of the ATP sensitive potassium channel suitable for use in the treatment of urge urinary incontinence. In particular three large 4-(N-aryl) substituents, the (N-phenyl-N-methylamino)sulfonyl, benzoyl, and 4-pyridylsulfonyl moieties, yielded non-antiandrogen, KATP potassium channel openers (39, 41, and 64, respectively) that are bladder selective in an in vivo rat model that simultaneously measures bladder contractions, heart rate, and blood pressure. Substitutions of the aryl rings of 41 and 64 gave several derivatives that also display selectivity in the in vivo rat model; however, none appear to offer a substantial advantage over 41 and 64. The PCO activity of 41 and 64 resides in the (S)-(-) enantiomers. ZD6169, 41(S), has been selected into development for the treatment of urge urinary incontinence.

1The influence of blood gases on a-and a2-adrenoceptor-mediated pressor responses was studied in the pithed rat by varying the inspired gas mixture or the ventilation stroke volume. 2 Acidosis favoured the peak responses to the m2-adrenoceptor agonist, xylazine, while alkalosis favoured the peak responses to the a,-adrenoceptor agonist, phenylephrine. A combination of hypoxia and hypercapnia greatly depressed the ml response to phenylephrine whereas the M2 response to xylazine remained relatively unaffected. 3 When Pao2 was varied in either acidotic or alkalotic conditions the response to the phenylephrine increased as Pao2 increased. 4 To prevent hypoxia in air ventilated rats, large stroke volumes were required. This caused alkalosis and hence decreased responsiveness to xylazine. Consequently, air ventilated pithed rats gave poorer responses to xylazine than did those ventilated on 100% 02. 5 The results show that ml-and a2-adrenoceptor-mediated pressor responses can be differentially affected by blood gases. The relative contribution of al-and M2-adrenoceptors to vascular tone may be either under-or over-estimated depending on the arterial blood gases.

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SUMMARY1. The influence of arterial blood gas tensions on angiotensin II-mediated pressor responses in the pithed rat was studied by altering the inspired gas mixture at a fixed tidal volume.2. When rats were ventilated to produce physiological Pa co2 levels (35)(36)(37)(38)(39)(40) responses to boluses of angiotensin II were greater with increasing Pa 02 over the Pa, 02 range of 65-460 mmHg.3. There was no difference in response to angiotensin II over the Pa, co, range studied (18-50 mmHg). All variations in response to angiotensin II were attributable to changes in Pa, 02.