A comparison of the cardiovascular and sedative actions of the alpha-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 alpha-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 alpha-adrenoceptors in the pithed rat.8 FLA-136 is a novel centrally-acting hypotensive compound which, unlike clonidine, selectively stimulates central alpha-autoreceptors (yohimbine-sensitive) in the rat; these autoreceptors may be different from peripheral pre- and postsynaptic alpha-adrenoceptors. The results suggest that clonidine lowers blood pressure by stimulation of two types of central postsynaptic alpha-adrenoceptors in the rat, one type being sensitive to yohimbine and the other to prazosin.