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

Abstract

1 Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2 (5 ± 250 mg kg 71 i.v.) were assessed in conscious, normotensive, Hannover, Sprague-Dawley (HSD) rats, and in hypertensive, transgenic ((mRen-2)27) (abbreviated to TG) rats. 2 In HSD rats, WIN 55212-2 caused pressor, and renal and mesenteric vasoconstrictor eects, with a hindquarters vasodilator eect occurring only at the highest dose. In TG rats, the eects of the cannabinoid agonist were qualitatively similar to those seen in HSD rats, except there was no hindquarters vasodilatation. 3 In both strains of rat, in the presence of losartan, pentolinium and a vasopressin (V 1 -receptor) antagonist, the pressor and vasoconstrictor eects of WIN 55212-2 were abolished, but the hindquarters vasodilator response was enhanced (HSD rats) or was seen only in that circumstance (TG rats). Under these conditions, both strains of rat showed a modest fall in blood pressure, together with mesenteric vasodilatation. 4 In additional experiments in normotensive SD rats from Charles River (CRSD), it was shown that, in the presence of the V 1 -receptor antagonist alone, or losartan alone, or the two antagonists together, the cardiovascular eects of WIN 55212-2 (50 or 150 mg kg 71 ) were not attenuated. Hence, the eects described above were likely due to pentolinium. 5 There were no consistent dierences between HSD and TG rats in their haemodynamic responses to methoxamine or noradrenaline, indicating the two strains were not likely to dier markedly in their responsiveness to any putative sympathetic activation induced by WIN 55212-2. 6 Collectively, the results indicate that the predominant cardiovascular eects of WIN 55212-2 in conscious HSD and TG rats (i.e., pressor and vasoconstrictor actions) can be attributed largely to indirect, pentolinium-sensitive mechanisms, which appear to dier little in the normotensive and hypertensive state, at least in conscious animals. Under the conditions of our experiments, signs of cannabinoid-induced vasodilatation were modest.

Complex regional haemodynamic effects of anandamide in conscious rats

“…Indeed, the pro®le of cardiovascular eects of anandamide resembled, in several respects, those of 5-HT, which triggers the von Bezold-Jarisch re¯ex through stimulating 5-HT 3 -receptors on vagal aerent ®bres, with subsequent vagal eerent activation (Veelken et al, 1998). The only vascular bed to show vasodilatation in response to anandamide was the hindquarters, which is consistent with the eects of the synthetic cannabinoid, WIN 55212-2, in our model (Gardiner et al, 2001;2002a, b). We have shown that the hindquarters vasodilator responses to WIN 55212-2 are sensitive to CB 1 -receptor antagonism, and involve b 2 -adrenoceptors (Gardiner et al, 2002a, b).…”

“…However, in those cases, the hindquarters vasodilator eects were also inhibited by AM 251. Furthermore, at least with WIN 55212-2, the hindquarters vasodilatation was insensitive to ganglion blockade (Gardiner et al, 2001), leading us to speculate on the possibility of involvement of CB 1 -receptor-mediated release of adrenaline from chroman cells (Gardiner et al, 2002b). In contrast, in the case of anandamide, it appears that CB 1 -receptors are not involved.…”

The complexities of the cardiovascular actions of cannabinoids

“…In contrast to the actions of anandamide, these cardiovascular effects were sensitive to the cannabinoid CB 1 receptor antagonist, AM251, but the hindquarters vasodilatation was also inhibited by a b 2 -adrenoceptor antagonist. Studies on conscious normotensive and hypertensive rats have also demonstrated pressor effects with WIN 55,212-2, which were sensitive to ganglion blockade (Gardiner et al, 2001). From these findings it was concluded that the effects of synthetic cannabinoids were mediated via CB 1 -receptors linked to increases in sympathetic activity.…”

“…This is mirrored by studies on anaesthetised animals that report hypotensive effects (Varga et al, 1995). However, findings in conscious animals are more complex and do not support the notion that cannabinoids are hypotensive agents (Stein et al, 1996;Lake et al, 1997;Gardiner et al, 2001;Gardiner et al, 2002a;Gardiner et al, 2002b). Similarly, there is no general consensus regarding the molecular target(s) for cannabinoids.…”

In Vitro Metabolism ofR(+)-[2,3-Dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist

“…Whereas the physiological effects of WIN55212-2 via CB1 receptor mediation have been studied extensively (Aceto et al, 2001;Bridges et al, 2001;Gardiner et al, 2001;Simoneau et al, 2001), to our knowledge, there has been very little research on the metabolism of WIN55212-2 and other aminoalkylindole analogs, either in vitro or in vivo. Because of the remarkable structural difference between aminoalkylindoles and other cannabinoid ligands, it is hypothesized that AAIs could undergo biotransformations that also differ significantly from the metabolic patterns of the classical and nonclassical cannabinoids.…”