SK & F 95018, a vasodilator/beta-adrenoceptor antagonist

The pharmacological properties of a novel vasodilator/beta-adrenoceptor antagonist, SK & F 95018 6-[4-[3-(3-[4-(2-Cyclopropylmethoxyethyl)phenoxy]-2- hydroxypropylamino)propionamido]phenyl]-4,5-dihydro-5-met hylpyridazin- 3(2H)-one methanesulphonate] are described. SK & F 95018 lowered blood pressure and increased hindquarters blood flow in anaesthetised rats over the same dose range 1-5 mumol kg-1. Over a similar dose range SK & F 95018 inhibited isoprenaline-induced tachycardia in ganglion-blocked, anaesthetized cats. SK & F 95018 had minimal effect on bronchial beta 2-adrenoceptors, while simultaneously antagonizing cardiac beta 1-adrenoceptors in anaesthetized guinea-pigs. SK & F 95018 was demonstrated to be a potent antihypertensive agent in conscious spontaneously hypertensive rats over the dose range of 1.6-13 mumol kg-1 i.v. and 13-103 mumol kg-1 p.o. A marked and persistent hypotension was observed in conscious cats at a dose of 7.5 mumol kg-1 i.v. and 19 mumol kg-1 p.o., without reflex tachycardia. In anaesthetized cats, the hypotensive response to the compound was found to be via a reduction in total peripheral resistance with a maintained cardiac output. Vasodilatation and beta-adrenoceptor antagonism have been demonstrated in the same molecule (SK & F 95018) in a combination which would be suitable for effective treatment of hypertension.