The present experiments were designed to elucidate what mechanism(s) would be responsible for beta-adrenoceptor blocking drugs (beta-blockers)-induced pressor responses in rats. In urethane-anaesthetized rats, 6 beta-blockers at i.v. doses ranging from 0.3 to 300 micrograms/kg evoked the pressor response in a dose-dependent manner. The relative potency in causing the pressor action was correlated not to their beta 1-blocking activities (r = 0.374, P greater than 0.05) but to their beta 2-blocking ones (r = 0.856, P less than 0.05). In pithed or adrenalectomized rats with low levels of plasma catecholamines, however, propranolol failed to exert its sustained pressor action. Propranolol (300 micrograms/kg i.v.) distinctly potentiated the pressor responses not to noradrenaline but to adrenaline and to electrical stimulation of the sympathetic outflow (E.S.) in pithed rats. On the contrary, there was not any potentiation of pressor response to E.S. in pithed, adrenalectomized rats treated with propranolol (300 micrograms/kg i.v.). In rats treated with phenoxybenzamine (5 mg/kg i.v.), adrenaline was shown to have much more potent vasodilating action resulting from beta 2-stimulation than noradrenaline, the dose difference for causing the diastolic blood pressure decrease by a 25 mm Hg being almost 80 times. In pithed rats, infusion of adrenaline at the rate of 0.02 micrograms/min caused a significant increase in plasma adrenaline level from 0.02 +/- 0.01 to 0.45 +/- 0.048 ng/ml, being close to basal level obtained in urethane-anaesthetized rats. Under this situation, propranolol (1-100 micrograms/kg i.v.) showed a distinct pressor response in a dose-dependent fashion as observed in adrenal intact rats anaesthetized with urethane.(ABSTRACT TRUNCATED AT 250 WORDS)

I.v. propranolol (Prop) produced sustained pressor responses in rats but not in dogs under urethane anesthesia. In the dogs there was a progressive reduction

A series of novel pyridazinone derivatives (II) having a phenoxypropanolamine moiety was synthesized. Their hypotensive and beta-blocking activities were evaluated after intravenous administration of the compounds to anesthetized rats. Among them, the 5-chloro-2-cyanophenoxy derivative (29) showed the promising dual activities and was selected for further studies.

Types of beta-adrenoceptors mediating renin release induced by isoproterenol were investigated in conscious dogs. The nonselective beta-adrenoceptor blocking drugs propranolol, D-32, and pindolol significantly inhibited increases in heart rate and plasma renin activity and a fall of blood pressure produced by intravenous infusion of isoproterenol (10 microgram . kg-1 . 20 min-1). d-Propranolol and d-D-32 did not inhibit these three responses to isoproterenol. The selective beta 1-adrenoceptor blocking drug atenolol, at the oral dose of 6 mg/kg, which selectively suppressed isoproterenol-induced tachycardia, significantly inhibited the renin release caused by isoproterenol. By contrast, the renin release induced by isoproterenol was not modified by the selective beta 2-adrenoceptor blocking drug IPS-339 at an oral dose of 3 mg/kg, which fully and selectively antagonized the fall of blood pressure in response to isoproterenol. There was good correlation between suppression of isoproterenol-induced renin release and that of isoproterenol-induced tachycardia after various beta-adrenoceptor blocking drugs. These results lead to the conclusion that in conscious dogs the beta-adrenoceptors mediating release are mainly of the beta 1 type.

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