A COMPARISON OF THE CARDIOVASCULAR AND SEDATIVE ACTIONS OF THE α‐ADRENOCEPTOR AGONISTS, FLA‐136 AND CLONIDINE, IN THE RAT

1 The cardiovascular and sedative effects of FLA‐136 have been compared with those of clonidine after intracerebroventricular (i.c.v.) administration in the rat. The effects of both drugs on pre‐ and postsynaptic α‐adrenoceptors in the periphery have been investigated after intravenous (i.v.) administration in the pithed rat. 2 In the anaesthetized rat, i.c.v. FLA‐136 and clonidine produced dose‐related hypotension, FLA‐136 having three to 30 times less activity than clonidine; both drugs caused concomitant bradycardia. In the conscious rat i.c.v. FLA‐136 had less sedative potential than clonidine, in terms of overt sedation assessed visually. 3 Yohimbine reduced the hypotension and bradycardia produced by i.c.v. FLA‐136 and clonidine; prazosin and mianserin also antagonized the cardiovascular responses to clonidine, but not those to FLA‐136. 4 Chemical sympathectomy by 6‐hydroxydopamine (6‐OHDA) markedly reduced the cardiovascular effects of FLA‐136 but only slightly reduced those of clonidine. 5 Naloxone antagonized the cardiovascular responses to clonidine, but not FLA‐136, suggesting a direct or indirect involvement of central opiate receptors in the responses induced by clonidine. 6 Metiamide attenuated the cardiovascular responses to FLA‐136 and clonidine, implying a direct or indirect involvement of central histamine (H 2 )‐receptors in such responses. 7 FLA‐136, unlike clonidine, did not stimulate peripheral pre‐ or postsynaptic α‐adrenoceptors in the pithed rat. 8 FLA‐136 is a novel centrally‐acting hypotensive compound which, unlike clonidine, selectively stimulates central α‐autoreceptors (yohimbine‐sensitive) in the rat; these autoreceptors may be different from peripheral pre‐ and postsynaptic α‐adrenoceptors. The results suggest that clonidine lowers blood pressure by stimulation of two types of central postsynaptic α‐adrenoceptors in the rat, ‐one type being sensitive to yohimbine and the other to prazosin.