Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats.
OBJECTIVE
The cardiovascular effects of cannabinoids can be influenced by anaesthesia and can differ in chronic hypertension, but the extent to which they are influenced by acute hypertension in conscious animals has not been determined.


METHODS
We examined cardiovascular responses to intravenous administration of anandamide and the synthetic cannabinoid, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), in conscious male Wistar rats made acutely hypertensive by infusion of angiotensin II (AII) and arginine vasopressin (AVP). Rats were chronically instrumented for measurement of arterial blood pressure and vascular conductances in the renal, mesenteric and hindquarters beds.


RESULTS
Anandamide dose-dependently decreased the mean arterial blood pressure of rats made hypertensive by AII-AVP infusion, but not normotensive rats. Interestingly, acute hypertension also revealed a hypotensive response to WIN55212-2, which caused hypertension in normotensive animals. The enhanced depressor effects of the cannabinoids in acute hypertension were associated with increased vasodilatation in hindquarters, renal and mesenteric vascular beds. Treatment with URB597, which inhibits anandamide degradation by fatty acid amide hydrolase, potentiated the depressor and mesenteric vasodilator responses to anandamide. Furthermore, haemodynamic responses to WIN55212-2, but not to anandamide, were attenuated by the CB(1) receptor antagonist, AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide].


CONCLUSIONS
These results broadly support the literature showing that the cardiovascular effects of cannabinoids can be exaggerated in hypertension, but highlight the involvement of non-CB(1) receptor-mediated mechanisms in the actions of anandamide.
Ho
W-S Vanessa
WS
School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK. vho@sgul.ac.uk
Gardiner
Sheila M
SM
D000208:Acute Disease; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D003243:Consciousness; D063388:Endocannabinoids; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D048588:Benzoxazines; D002186:Cannabinoids; D002219:Carbamates; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C078814:anandamide