Antisympathomimetic effects of Kö 1313 and Kö 1366 in guinea-pig atria.

The antagonistic effects of two new ƒÀ-receptors blocking agents, Ko 1313 and Ko 1366 against the chronotropic and inotropic responses to noradrenaline and tyramine were studied on the isolated right and left atria of guinea-pigs. From the KB values estimated by means of three different methods, it was found that the potencies of KO 1366 were 5 to 10 times and 5 to 7 times those of Ko 1313 in the antagonism against chronotropic and inotropic effects of noradrenaline respectively. From the depression of maximum chronotropic and inotropic effects of tyramine in the presence of these agents, Ko 1366 was demonstrated to be approx. three times more potent than Ko 1313 in the antagonism against both effects of tyramine. Ko 1313 (dl-o-(2-hydroxy-3-(isopropylamino)-propoxy) benzonitrile hydrochloride) and Ko 1366 (dl-o-(2-hydroxy-2-(tert-butylamino)-propoxy) benzonitrile hydrochloride) have been found to be effective and potent ƒÀ-receptor blocking agents (1-3) as well as antiarrhythmic agents (4) with a slightly intrinsic ƒÀ-receptor stimulant component in their profile of the activity (2, 3). It was concluded that the ƒÀ-receptor blocking activity of Ko 1366 was more potent than that of Ko 1313 in antagonism of the cardiac action of isoproterenol and sympathetic nerve stimulation (1-3). In the present study the antagonism of Ko 1313 and Ko 1366 against the sympathomietic action of noradrenaline and tyramine was investigated in the isolated guinea-pig atrium. It is to be expected that the study of the interaction of the ƒÀ-receptor blocking agents with these sympathomimetic amines may provide information, not only on the ƒÀ-receptor blocking activity but also on other properties of the agents which may directly and indirectly influence the manifestation of the former activity. METHODS Guinea-pigs weighing 230 to 350g were sacrificed by a blow on the head. The right or left atrium was isolated and suspended at 30•Ž in a 20 ml organ bath containing Tyrode solution (NaCl, 137; KCl, 4; MgCl2, 1.2; CaCl2, 2.4; NaHCO3, 12; NaH2PO4, 0.4 and glucose, 5.5 in mM). The solution was aerated with a mixture of 95% O2 and 5% CO2. * Present address: Dr. Karl Thomae GmbH, Abt. Pharmakologie, 795 Biberachander Riss, West Germany.