European Journal of Pharmacology, 84 (1982) 177-187 177 Elsevier Biomedical Press EFFECTS OF ALINIDINE (ST 567) ON BARORECEPTOR-HEART RATE REFLEXES AND ITS INTERACTIONS WITH CLONIDINE ON THE BAROREFLEX AND ON THE SYMPATHETIC TERMINALS OF THE ISOLATED ATRIUM BIRGER G.J. HEINZOW, JAMES A. ANGUS and PAUL I. KORNER * Baker Medical Research Institute, Melbourne, Australia Received 7 April 1982, revised MS received 2 July 1982, accepted 21 July 1982 B.G.J. HEINZOW, J.A. ANGUS and P.I. KORNER, Effects of alinidine (ST 567) on baroreceptor-heart rate reflexes and its interactions with clonidine on the baroreflex and on the sympathetic terminals of the isolated atrium, European J. Pharmacol. 84 (1982) 177-187. Alinidine (ST 567), an N-allyl derivative of clonidine, slowed the heart rate of conscious rabbits by 41 ± 2.3 (S.E.D.) b//min and reduced mean arterial pressure (MAP) by 6.4- + 1.4 mmHg (P<0.001). The cardiac slowing was considered to be a direct effect in agreement with previous findings by others, since it was present in rabbits without functioning autonomic nerves, but the fall in blood pressure did not occur in these animals. Alinidine produced no significant changes in the reflex tachycardia response evoked by infusing nitroprusside, or in the pressure-related parameters of the MAP-heart period (HP) curve of the baroreceptor-heart rate reflex (i.e. HP range, gain, or median blood pressure BP50). Intravenous (i.v.) clonidine produced characteristic rises in baroreflex HP range and gain, which were due to vagal facilitation, and also produced falls in BPs0 and resting MAP. I.v. alinidine suppressed the clonidine-induced vagal facilitation, but had no effect on the blood pressure changes. Intracisternal alinidine could be given in only relatively low dose, but reduced the clonidine-induced rise in vagal component of HP range. The main site of antagonism between i.v. alinidine and clonidine was probably in the CNS. We studied the nature of the antagonism at the sympathetic nerve terminal of the isolated left guinea pig atrium. Clonidine depressed the inotropic response to field stimulation of the sympathetic nerves and this was competitively antagonised by phentolamine>yohimbine> alinidine at potencies of about 1200 : 80 : 1. Alinidine was considered to be a weak but specific a2-antagonist; it has no a~-antagonist properties since it was without effect on the contractile response to noradrenaline of the guinea pig aorta. The a2-antagonist property explains the suppression by alinidine of the clonidine-induced facilitation of the vagal component of the baroreceptor-heart rate reflex. Baroreceptor-heart rate reflex Alinidine al-Adrenoceptor Guinea pig aorta fl-Adrenoceptor Clonidine az-Adrenoceptor Nitroprusside Rabbit Guinea pig left atrium 1. Introduction Alinidine (ST 567) is an N-allyl derivative of clonidine, that slows the heart but has relatively little effect on blood pressure in anaesthetised animals and in man (Kobinger et al., 1979a, b; Harron et al., 1981). The cardiac slowing does not depend on /3-adrenoceptor blocking properties of * To whom all correspondence should be addressed: Baker Medical Research Institute, Commercial Road, Prahran, Victoria, Australia 3181. 0014-2999/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press the drug (Kaspar et al., 1981) but is due to its direct effect on the sino-atrial node (Little et al., 1979). In man alinidine diminishes the exercise tachycardia (Harron et al., 1982). There has been little analysis of its involvement in other heart rate reflexes. The purpose of the present investigation was (i) to determine the direct effects of alinidine on blood pressure, and heart rate under 'open loop' conditions in the conscious rabbits treated with guanethidine + methscopolamine (Anderson et al., 1977); (ii) to examine quantitatively whether the