The effects of alpha,beta-,methylene-adenosine triphosphate, (alpha,beta-methylene ATP, a P2-receptor desensitising agent) have been evaluated on vasoconstrictor responses elicited by exogenous agonists or electrical field stimulation in isolated perfused SHR or WKY tail arteries and on tritium release elicited by electrical field stimulation in SHR-tail arteries pre-labeled with 3H-noradrenaline. Exposure to alpha,beta-methylene ATP (0.1 mumol/l) significantly inhibited vasoconstrictor responses to electrical field stimulation in SHR tail arteries. These inhibitory effects were not further increased at a higher concentration of alpha,beta-methylene ATP (1 mumol/l). In WKY tail arteries, alpha,beta-methylene ATP (1 mumol/l) failed to significantly inhibit vasoconstrictor responses to electrical stimulation. In SHR tail arteries prelabelled with 3H-noradrenaline, alpha,beta-methylene ATP (1 mumol/l) did not inhibit the stimulation evoked release of tritium. However, at this concentration, alpha,beta-methylene ATP significantly antagonized the vasoconstrictor responses of SHR tail arteries induced by exogenous ATP (1 mumol/l), beta,gamma-methylene ATP (30 mumol/l), a stable agonist at P2-receptors, or 60 mmol/l KCl. These effects of alpha,beta-methylene ATP on contractile responses to KCl were not observed in WKY-tail arteries. In tail arteries obtained from reserpine pretreated SHR, despite a 85-95% decrease in endogenous noradrenaline tissue content, the vasoconstrictor responses induced by periarterial field stimulation were greatly diminished, but not abolished. These residual responses to periarterial field stimulation were not antagonized by prazosin (0.1 mumol/l), but were practically abolished by the addition of alpha,beta-methylene ATP (1 mumol/l). In tail arteries from WKY rats pretreated with reserpine, exposure to prazosin (0.1 mumol/l) further reduced the residual responses elicited by electrical field stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

1 Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin.2 The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated.[3H]-prazosin was potently displaced by al-adrenoceptor specific agents including alfuzosin, its (+ )-and (-)-enantiomers and prazosin (IC5o 0.035, 0.023, 0.019 and 0.00411M, respectively), but only weakly by M2-adrenoceptor selective agents, for example, yohimbine (IC50= 6.0 IM). produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular al-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-' alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure. 5 Alfuzosin is a potent selective a,-adrenoceptor antagonist in tissues of the lower urinary tract including the human prostate. This provides a pharmacological basis for its use in the treatment of benign prostatic hypertrophy.

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In urethane-anaestetised rats intraventricular (i.c.v.) injections of histamine (0.1-10.0mug) elicited dose-related rises in both the resting blood pressure and heart rate. These cardiovascular effects of histamine were antagonised in a dose-dependent manner by i.c.v. pretreatments with the histamine H1-receptor antagonists mepyramine (10, 50 and 100 mug) and diphenylpyraline (100 and 200mug). Pretreatment with the histamine H2-receptor antagonist metiamide (100 and 200 mug i.c.v.) failed to modify either of the responses. A dose-related antagonism of the hypertensive response to histamine i.c.v. was elicited by phentolamine (100 and 200 mug i.c.v.) but the positive chronotropic effect was not modified by this pretreatment. The cardiovascular responses to histamine i.c.v. were abolished by mecamylamine (5.0 mg/kg i.v.) and greatly reduced by 6-hydroxydopamine (3 X 250 mug i.c.v.), but only the tachycardia was significantly modified by atropine (100 mug i.c.v.) and propranolol (1 mg/kg i.v.). Propranolol (100 mug i.c.v.), bilateral vagotomy, or acute bilateral adrenal demedullation failed to modify the cardiovascular responses to histamine i.c.v. The results suggest that histamine is able to modify the resting blood pressure and heart rate by independent central modes of action, which involve central adrenergic and cholinergic mechanisms.

In isolated perfused tail arteries of spontaneously hypertensive rats (SHR), the selective alpha 2-adrenergic receptor antagonist idazoxan ( RX781094 ) at low concentrations antagonized vasoconstrictor responses induced by norepinephrine (NE) and low frequency periarterial field stimulation. The vasoconstrictor responses to the selective alpha 2-adrenergic receptor agonist TL99 or to phenylephrine were also antagonized by low concentrations of idazoxan . In contrast, idazoxan did not antagonize responses induced by the alpha 1-adrenergic receptor agonists amidephrine or methoxamine in perfused tail arteries of SHR. The alpha 1-adrenergic receptor antagonist prazosin was very potent against methoxamine or phenylephrine and responses to periarterial field stimulation in SHR and Wistar-Kyoto (WKY) rat tail arteries, but only showed a modest selectivity for TL99 -induced responses in SHR arteries. The results support the contention that postjunctional alpha 2-adrenergic receptors can be demonstrated in arterial smooth muscle in vitro and are particularly evident in arteries from hypertensive animals. In SHR tail arteries, postsynaptic alpha 2-adrenergic receptors contribute to the vasoconstrictor responses to exogenous NE and may be activated by endogenously released NE.