title: Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats.
abstract: Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2 (5 - 250 microg kg(-1) i.v.) were assessed in conscious, normotensive, Hannover, Sprague-Dawley (HSD) rats, and in hypertensive, transgenic ((mRen-2)27) (abbreviated to TG) rats. In HSD rats, WIN 55212-2 caused pressor, and renal and mesenteric vasoconstrictor effects, with a hindquarters vasodilator effect occurring only at the highest dose. In TG rats, the effects of the cannabinoid agonist were qualitatively similar to those seen in HSD rats, except there was no hindquarters vasodilatation. In both strains of rat, in the presence of losartan, pentolinium and a vasopressin (V1-receptor) antagonist, the pressor and vasoconstrictor effects 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. In additional experiments in normotensive SD rats from Charles River (CRSD), it was shown that, in the presence of the V1-receptor antagonist alone, or losartan alone, or the two antagonists together, the cardiovascular effects of WIN 55212-2 (50 or 150 microg kg(-1)) were not attenuated. Hence, the effects described above were likely due to pentolinium. There were no consistent differences between HSD and TG rats in their haemodynamic responses to methoxamine or noradrenaline, indicating the two strains were not likely to differ markedly in their responsiveness to any putative sympathetic activation induced by WIN 55212-2. Collectively, the results indicate that the predominant cardiovascular effects 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 differ 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.
authors.affiliation: School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Gardiner
authors.forename: J E
authors.initials: JE
authors.lastname: March
authors.forename: P A
authors.initials: PA
authors.lastname: Kemp
authors.forename: T
authors.initials: T
authors.lastname: Bennett
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D048588:Benzoxazines; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D003243:Consciousness; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000097:blood*; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D014662:Vasoconstrictor Agents; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D008729:Methoxamine; D009638:Norepinephrine