Studies on the Autonomic Nervous System with SK&F 92657, a New Antihypertensive Agent Causing Direct Arterial Vasodilatation and β-Adrenoceptor Blockade
1981; Lippincott Williams & Wilkins; Volume: 3; Issue: 2 Linguagem: Inglês
10.1097/00005344-198103000-00013
ISSN1533-4023
AutoresE. M. Taylor, Roger J. Eden, R. Fielden, David Owen,
Tópico(s)Pharmacological Receptor Mechanisms and Effects
ResumoSummary The β-adrenoceptor-blocking properties of SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, were studied both in vivo and in vitro. The pA2 against isoprenaline tachycardia (β1 effect) in isolated guinea pig right atria was 7.16 (6.14–7.87). In contrast, histamine-induced tachycardia was unaffected by SK&F 92657. The pA2 against isoprenaline relaxation of guinea pig tracheal muscle (β2 effect) was 7.03 (6.28–7.61). In vivo ED50‘s against isoprenaline tachycardia (β1) and vasodilation (β2) in anesthetized cats were 5.7 × 10−8 and 6.2 × 10−8 mol/kg, i.v., respectively. Increases in heart rate caused either by activation of autonomic reflexes or by stimulation of efferent cardiac sympathetic nerves were also antagonized by SK&F 92657. The β-adrenoceptor blockade caused by SK&F 92657 was shown to be competitive both in vivo and in vitro and to be equally effective on β1- and β2-receptor populations. SK&F 92657 was a weak partial agonist in vivo and had only minimal local anesthetic activity. The compound had no direct effect on the functioning of the autonomic nervous system, apart from β-blockade, but reflexes maintaining homeostasis were reduced because (1) SK&F 92657 is a β-adrenoceptor antagonist preventing reflex increases in heart rate and cardiac output, and (2) it is a potent vasodilator counteracting reflex vasoconstriction. Postural reflexes were unaffected because SK&F 92657 selectively dilates arterial blood vessels.
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