CHARACTERIZATION OF ARBUTAMINE - A NOVEL CATECHOLAMINE STRESS AGENT FOR DIAGNOSIS OF CORONARY-ARTERY DISEASE

Arbutamine, -hydroxy-2-[[4-(4-hydroxyphenyl)butyl[amino]ethyl] hydroch loride, (R), is a new catecholamine being developed as a pharmacologic stress agent for the diagnosis of coronary artery disease and myocard ial ischemia. The pharmacology of arbutamine was studied in vitro usin g receptor binding assays and functional bioassays of alpha- and beta- adrenoceptor activity, and in vivo using the hemodynamic responses to intravenous infusion in anesthetized and conscious dogs. In isolated m embranes, receptor binding studies demonstrated K-i values of 196 +/- 12 nM and 147 +/- 11 nM for beta(1)- and beta(2)-adrenoceptors, and 26 5 +/- 4 nM and 867 +/- 40 nM for alpha(1)- and alpha(2)-adrenoceptors, suggesting that arbutamine is a mixed beta(1+2)-adrenoceptor agonist with significant affinity for alpha(1)-adrenoceptors. This was support ed by in vitro bioassay data, where arbutamine increased spontaneous a trial rate beta(1)-activity, ED(50) = 16 +/- 6 nM), relaxed isolated t racheal rings beta(2)-activity, ED(50) = 13 +/- 5 nM), and contracted aortic rings alpha-activity, ED(50) = 430 +/- 80 nM), indicating 25-30 -fold selectivity for beta adrenoceptor activation. In conscious or an ethetized dogs, arbutamine elicited dose-dependent increases in heart rate and LV dP/dt with little fall in mean arterial pressure. The data demonstrate that arbutamine exhibits similar degrees of inotropic and chronotropic activity, while eliciting less peripheral vasodilation t han isoproterenol and less inotropic activity than dobutamine. Moreove r, there was rapid termination of the tachycardia, as heart rate resol ved to 50% of the maximal effect within 7.2 +/- 1.1 min following arbu tamine, compared to 5.5 +/- 1.0 min following isoproterenol and 5.9 +/ - 1.4 min following dobutamine. This hemodynamic profile and rapid pha rmacodynamic offset makes arbutamine ideally suited for use as a pharm acologic stress agent (C) 1994 Wiley-Liss, Inc.