Studies on the autonomic nervous system with SK&F 92657, a new antihypertensive agent causing direct arterial vasodilatation and beta-adrenoceptor blockade.
The beta-adrenoceptor-blocking properties of SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, were studied in both in vivo and in vitro. The pA2 against isoprenaline tachycardia (beta 1 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 (beta 2 effect) was 7.03 (6.28-7.61). In vivo ED50's against isoprenaline tachycardia (beta 1) and vasodilation (beta 2) in anesthetized cats were 5.7 x 10(-8) and 6.2 x 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 beta-adrenoceptor blockade caused by SK&F 92657 was shown to be competitive both in vivo an vitro and to be equally effective on beta 1- and beta 2-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 beta-blockade, but reflexes maintaining homeostasis were reduced because (1) SK&F 92657 is a beta-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.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002346:Carotid Sinus / Q000187:drug effects; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D011187:Posture; D011724:Pyridazines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D011724:Pyridazines; D011943:Receptors, Adrenergic, beta; D014665:Vasodilator Agents; C024293:prizidilol