Effects of chronic treatment with the CB1 antagonist, rimonabant on the blood pressure, and vascular reactivity of obese Zucker rats

Abstract

Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity associated cardiovascular risk factors. Since cannabinoids are vasoactive compounds, the aim of this study is to evaluate the effect of chronic treatment with RM on systolic blood pressure (SBP), and endothelial and vascular reactivity. Obese Zucker rats (OZRs) and their lean counterparts were orally treated during 20 weeks with either RM (10 mg/kg/day). Endothelial and vascular function was assessed in aorta and small mesenteric arteries (SMAs) by concentration response curves to acetylcholine (ACh) and phenylephrine (Phe), respectively. Participation of nitric oxide (NO) was evaluated by incubation with the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) and cyclooxygenase (COX)-derived products involvement was analyzed by incubation with indomethacin (INDO). Plasma lipid profile, insulin and adiponectin were also analyzed. Sympathetic activity was evaluated by urinary excretion of noradrenaline. As expected, RM decreased body weight gain and enhanced adiponectin concentration. Insulin resistance and sympathetic activity were also decreased. The increase in SBP observed in OZRs was reduced by treatment with RM. Aortae and SMAs from OZRs exhibited lower contractile response to Phe, being this effect prevented by RM administration. Although ACh-induced response and NO participation remained unaltered with obesity, enhanced COX-derived constrictor products were found in OZRs. RM treatment neither altered endothelium-dependent relaxation nor L-NAME-sensitive component of the response. Nevertheless, it was able to regulate COX-derived vasoactive products participation. Those effects may contribute to explain some of the cardiovascular protective actions elicited by this drug.