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The cardioprotective effect of N‐[(1S, trans)‐2‐hydroxycyclopentyl]adenosine (GR79236), an adenosine A1receptor agonist, was compared with that produced by ischaemic preconditioning in an anaesthetized rabbit model of myocardial ischaemia and reperfusion. In addition, we examined the effect of different body core temperatures on GR79236‐ or ischaemic preconditioning‐induced cardioprotection when administered prior to ischaemia, and on cardioprotection induced by GR79236 administered 10 min prior to the onset of reperfusion.When rabbits were subjected to 30 min occlusion of the left coronary artery, followed by 2 h reperfusion, GR79236 (3×10−8mol kg−1i.v. (10.5 μg kg−1i.v.)) or ischaemic preconditioning (5 min ischaemia followed by 5 min reperfusion), administered or applied 10 min prior to the occlusion, significantly limited the development of infarction. The cardioprotective effect of ischaemic preconditioning was significantly greater than that seen after administration of GR79236. Pre‐treatment with the selective adenosine A1receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 3.3×10−6mol kg−1(1 mg kg−1i.v.)), prevented the cardioprotective effect of GR79236, but not that of ischaemic preconditioning.Maintaining body core temperature at 38.5°C rather than at 37.0°C did not influence infarct size in control groups of rabbits, but reduced the cardioprotective effect of GR79236 when administered 10 min prior to occlusion or 10 min prior to the onset of reperfusion. The cardioprotective effect of ischaemic preconditioning was not temperature‐dependent.In conclusion, myocardial protection conferred by GR79236 in anaesthetized rabbits is mediated viaadenosine A1receptors. Myocardial protection can be conferred when GR79236 is administered before the onset of ischaemia orreperfusion, and is reduced when body core temperature is maintained at 38.5°C rather than at 37.0°C. In contrast, myocardial protection conferred by ischaemic preconditioning is not reduced by adenosine A1receptor blockade, or by maintaining body core temperature at 38.5°C rather than at 37.0°C. These findings point to distinct differences in the mechanisms of induction of myocardial protection by adenosine A1receptor agonist and ischaemic preconditioning. They also highlight the need for careful control of body core temperature when investigating the phenomenon of cardioprotection.

The interactions between clonidine and the selective α1- and α2-adrenoceptor antagonists, prazosin and yohimbine, on the angiotensin-induced reflex vagal bradycardia have been investigated in propranolol-treated chloralose-anaesthetized cats. Clonidine (1–10 μg intracisternally) had little effect on the pressor responses to angiotensin, only slightly increased the peak but markedly increased the duration of the reflex bradycardia. Neither prazosin nor yohimbine (200 μg intracisternally of either antagonist) had any effect on the reflex bradycardia to angiotensin. Yohimbine greatly diminished the clonidine-induced potentiation of the response, but prazosin was without effect. Clonidine appears to potentiate the vagal reflex bradycardia by stimulating central α2-adrenoceptors.

The antagonist activity of GR138950 (1-[[3-bromo-2-[2-[[(trifluoromethyl)sulphonyl]amino]phenyl]-5- benzofuranyl]methyl]-4-cyclopropyl-2-ethyl-1H-imidazole-5-carboxamide) was investigated at angiotensin AT1 receptors and AT2 receptors in vitro and on blood pressure in conscious rats. GR138950 suppressed and displaced angiotensin II (AII) concentration-effect curves in the rabbit isolated aorta (pKb approximately 9.0-9.7) but had no effect against phenylephrine or serotonin induced-contractions. GR138950 competed with [3H]-AII for angiotensin AT1 receptors in rat liver membranes (pKi = 9.09). GR138950 had no apparent affinity for angiotensin AT2 receptors (bovine cerebellum; pKi < 6.0). GR138950 (1 mg/kg i.a. and p.o.) inhibited pressor responses to AII, but not phenylephrine, in conscious normotensive rats. Parallel displacements in AII dose-response curves occurred without any reduction in the maximum response to AII. The antagonist activity of GR138950 lasted for up to 24 h. GR138950 (> 0.03 mg/kg i.a., > 0.3 mg/kg p.o.) significantly reduced diastolic blood pressure (DBP) in renal artery ligated hypertensive rats. DBP was reduced maximally, 5 to 7 h after administration and the antihypertensive effect of GR138950 lasted for up to 48 h. Daily administration (5 days) of GR138950 to renal artery ligated hypertensive rats produced a sustained reduction in DBP. Acute administration of GR138950 (1 mg/kg i.a.) also significantly reduced DBP in spontaneously hypertensive rats but not in normotensive rats. Heart rate was little changed in renal artery ligated hypertensive rats, normotensive rats and spontaneously hypertensive rats. These experiments demonstrate that GR138950 is a potent, selective and specific angiotensin AT1 receptor antagonist that is orally active and reduces DBP in conscious hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The early proposals that pre- and post-junctional a-adrenoceptors might be different stemmed largely from two separate observations. Firstly, the orders of potency of a series of agonists at inhibiting the response to sympathetic nerve stimulation and in increasing inotropic activity in the rabbit isolated heart were different [1, 2]. Secondly, phenoxybenzamine was more potent in inhibiting vasoconstrictor responses to sympathetic nerve stimulation than in increasing transmitter overflow from the cat spleen [3]. These experiments illustrate the most fundamental, pharmacological ways of distinguishing between receptors: namely, by comparing the relative potencies of agonists and/or antagonists in producing, or preventing, pharmacological effects. There are, however, difficulties in using agonists to classify receptors because their ability to generate a response depends not only upon their intrinsic properties of affinity for, and efficacy at, the receptors but also upon the capacity of the tissue to translate the stimulus into a response. Thus agonists with a relatively low intrinsic efficacy may produce a small response, or no response at all, in a tissue in which the efficiency of the stimulus-response coupling mechanism is low. The importance of this phenomenon in influencing tissue responses to agonists with low efficacy has been demonstrated for the a-adrenoceptor agonist prenalterol [4] and for the a-adrenoceptor agonist oxymetazoline [5].

The aim of this study was to investigate whether the pentobarbitone anesthetized cat is a suitable preparation in which to characterize renal tubular dopamine receptors. Intravenous infusion of dopamine (10–100 μg/kg/min) resulted in a dose-related increase in mean blood pressure (MBP). urine output, sodium excretion (UNaV), and fractional sodium excretion (FENa). This diuretic effect occurred despite little change in glomerular filtration rate, suggesting that it is a consequence of decreased tubular reabsorption. Dopamine (10–100 μg/kg/min, i.v.) also induced marked dose-renal blood flow was not significantly reduced. The increases in MBP, urine output, UNaV, and FENainduced by dopamine (10–100 μg/kg/min, i.v.), were unaffected by pretreatment of cats with either the selective dopamine DA1or DA2receptor antagonists, SCH 23390 (30 μg/kg, i.v.), or domperidone (100 μg/kg, i.v.), respectively. In contrast, pretreatment of cats with the nonselective α-adrenoceptor antagonist, phentolamine (1 mg/kg, i.v.) prevented dopamine-induced increases in urine output and MBP. Infusion of the selective dopamine DA1receptor agonist fenoldopam (0.01–10 μg/kg/min) into the left renal artery failed to increase left renal vascular conductance, or left kidney urine output, UNaV, or FENa. In conclusion, this study provides no evidence for the involvement of renal tubular dopamine receptors in dopamine-induced diuresis in anesthetized cats. Rather, the diuretic effect appears to be linked to stimulation of α-andrenoceptors.

Summary:

The a-adrenoceptor blocking potency of WB 4101 at a1- and a2-adrenoceptors has been investigated in pithed rats.

The quantitative contribution of the adrenal medulla to the pressor response resulting from stimulation of the entire preganglionic sympathetic spinal outflow of the rat, has been estimated. Adrenalectomy reduced the pressor responses not only to preganglionic nerve stimulation but also to injected noradrenaline. This reduction in cardiovascular sensitivity occurred within about 10 min of adrenalectomy and continued throughout the course of each experiment. Intramuscular injection of cortisone (20 mg/kg) restored cardiovascular sensitivity to injected noradrenaline thus allowing analysis of the adrenal medullary component of the overall response to spinal nerve stimulation.