Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats

1 Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2 ( 5-250 mug kg(-1) i.v.) were assessed in conscious, normotensive, Hannover, Sprague-Dawley (HSD) rats, and in hypertensive, transgenic ((mRen-2)27) (ab breviated to TG) rats. 2 In HSD rats, WIN 55212-2 caused presser, and renal and mesenteric vasocon strictor effects, with a hindquarters vasodilator effect occurring only at the highest dose. In TG rats, the effects of the cannabinoid agonist were q ualitatively similar to those seen in HSD rats, except there was no hindqua rters vasodilatation. 3 In both strains of rat, in the presence of losartan, pentolinium and a va sopressin (VI-receptor) antagonist, the presser and vasoconstrictor effects of WIN 55212-2 were abolished, but the hindquarters vasodilator response w as enhanced (HSD rats) or was seen only in that circumstance (TG rats). Und er these conditions, both strains of rat showed a modest fall in blood pres sure, together with mesenteric vasodilatation. 4 In additional experiments in normotensive SD rats from Charles River (CRS D), it was shown that, in the presence of the VI-receptor antagonist alone, or losartan alone, or the two antagonists together, the cardiovascular eff ects of WIN 55212-2 (50 or 150 mug kg(-1)) were not attenuated. Hence, the effects described above were likely due to pentolinium. 5 There were no consistent differences between HSD and TG rats in their hae modynamic responses to methoxamine or noradrenaline, indicating the two str ains were not likely to differ markedly in their responsiveness to any puta tive sympathetic activation induced by WIN 55212-2. 6 Collectively, the results indicate that the predominant cardiovascular ef fects of WIN 55212-2 in conscious HSD and TG rats (i.e., presser and vasoco nstrictor actions) can be attributed largely to indirect, pentolinium-sensi tive mechanisms, which appear to differ little in the normotensive and hype rtensive state, at least in conscious animals. Under the conditions of our experiments, signs of cannabinoid-induced vasodilatation were modest.