Abstract

Carbuterol—[5-[2-(tert.-butylamino)-1-hydroxyethyl]-2-hydroxyphenyl] urea hydrochloride, SK&F 40383-A—was evaluated for its bronchodilator and cardiovascular actions, mechanism of action and acute toxicity by various routes of administration in several animal species. Comparisons were made with isoproterenol and salbutamol. Carbuterol exhibited potent bronchodilator activity in vitro and in vivo in the cat, dog and guinea pig and, compared with isoproterenol, was much more selective for tracheobronchial smooth muscle than for cardiac muscle. Both the bronchodilator and cardiac activities of carbuterol are apparently mediated through beta adrenergic receptor stimulation. Thus, carbuterol discriminates between the cardiac (beta-1) and tracheobronchial smooth musde (beta-2) receptors proposed by Lands and co-workers (Lands, A. M. and Brown, T. G., Jr. Proc. Soc. Exp. Biol. Med. 116: 331-333, 1964; Lands, A. M., et al. Nature (London) 214: 596-598, 1967, Life Sci. 6: 2241-2249, 1967). Although carbuterol was similar in bronchodilator potency to isoproterenol, its relative vasodepressor potency was much less, thereby demonstrating a further selectivity of action. At equiactive aerosol bronchodilator doses, the duration of action of carbuterol was at least 10 times that of isoproterenol, and its oral bronchodilator activity was also more prolonged. In general, carbuterol was approximately equivalent to salbutamol in bronchodilator potency, duration of action and degree of separation between bronchodilator and cardiovascular-stimulant activity, except that carbuterol exhibited a somewhat greater separation than salbutamol in doses producing bronchodilation and cardiac stimulation after oral administration in conscious guinea pigs. Acute toxicity studies in mice, rats and guinea pigs indicated a wide safety margin for carbuterol. The results demonstrate that carbuterol, administered either orally or by aerosol, is a selective bronchodilator in animals and suggest it to be a potentially useful agent in man.