Effects of chronic nitric oxide synthase inhibition on the cardiovascular responses to cannabinoids in vivo and in vitro.
OBJECTIVE
Since the vasorelaxant potency of the endocannabinoid anandamide is enhanced in perfused mesenteric vascular beds from rats made hypertensive by chronic inhibition of NO synthase (L-NAME in drinking water), we hypothesized that in vivo, anandamide-induced vasodilatation would be similarly enhanced in L-NAME-treated animals.


METHODS
Male Sprague-Dawley rats were given L-NAME in drinking water (7.5 mg kg(-1) day(-1)) for 4 weeks. Relaxant effects of anandamide were measured in perfused mesenteric vascular beds and in isolated small mesenteric arteries. Renal, mesenteric and hindquarters haemodynamic responses to anandamide, methanandamide, the synthetic cannabinoid agonist WIN-55212-2 and the cannabinoid receptor antagonist AM251 were assessed in conscious, chronically-instrumented rats.


RESULTS
Vasorelaxant responses to anandamide were enhanced in the perfused mesentery but not in isolated mesenteric resistance vessels. In vivo, anandamide caused vasodilatation only in the hindquarters vascular bed and only in control rats. Methanandamide caused a late-onset (40 min after administration) tachycardia, mesenteric and hindquarters vasoconstriction, and renal vasodilatation, which did not differ between control and L-NAME-treated rats. AM251 had no effect on resting blood pressure in control or L-NAME-treated rats and WIN55212-2 caused pressor and renal and mesenteric vasoconstrictor responses, with hindquarters vasodilatation in both groups of animals.


CONCLUSIONS
The results provide no in vivo evidence for enhanced vasodilator responses to cannabinoids, or up-regulation of endocannabinoids or their receptor activity, following chronic NO synthase inhibition.
Wheal
A J
AJ
Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
Bennett
T
T
Randall
M D
MD
Gardiner
S M
SM
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009025:Morpholines / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000098:blood supply; D019331:NG-Nitroarginine Methyl Ester; D009281:Naphthalenes / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000187:drug effects; D012079:Renal Circulation; D013152:Splanchnic Circulation; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D014665:Vasodilator Agents; C088155:methanandamide; 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; D019001:Nitric Oxide Synthase; C078814:anandamide; D019331:NG-Nitroarginine Methyl Ester