Chronic treatment with the cannabinoid 1 antagonist rimonabant altered vasoactive cyclo-oxygenase-derived products on arteries from obese Zucker rats.
To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, obese Zucker rats were treated with rimonabant (10 mg/kg per day) during 20 weeks and then vascular and endothelial reactivity were assessed in aortic rings by analyzing response to phenylephrine and acetylcholine. The presence of cyclo-oxygenase-1 and cyclo-oxygenase-2 selective inhibitors (SC-560 and NS-398, respectively) and the enzyme immunoassay revealed lower PGI2 production by aortic rings from obese rats with rimonabant able to restore such response toward levels found in the lean animals. The treatment also reduced TXB2 but did not alter its participation on acetylcholine-induced relaxation as the TP receptor antagonist ICI-192,605 revealed. Those effects were associated with an enhancement of cyclo-oxygenase-2 expression without affecting p38MAPK phosphorylation. Obese rats also exhibited higher nitric oxide plasma concentrations and greater inducible nitric oxide synthase participation on vascular phenylephrine-induced response without changes in inducible nitric oxide synthase protein expression. Although rimonabant reduced such alteration, the values were still higher than those found in lean rats. Finally, rimonabant was also able to reduce tumor necrosis factor-α produced by adipose tissue of obese Zucker rats. These results highlight a crosstalk among cannabinoids and cyclo-oxygenase-derived products in the vasculature of obese animals.
Mingorance
Carmen
C
Department of Pharmacology, School of Pharmacy, University of Seville, Seville, Spain.
de Sotomayor
Maria Alvarez
MA
Marhuenda
Elisa
E
Herrera
Maria Dolores
MD
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D009765:Obesity / Q000503:physiopathology*; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D009578:Nitrobenzenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C115461:SC 560; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D010656:Phenylephrine; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine; D000077285:Rimonabant