Abstract 183: Chronic Systemic CB1 Cannabinoid Receptor Blockade Reduces Blood Pressure and Weight Gain and Improves Baroreflex Function and Heart Rate Variability in Hypertensive (mRen2)27 Rats

Abstract

The effect of the endocannabinoid system (ECS) on weight and energy metabolism is well accepted, but long term contributions of the ECS to cardiovascular regulation are not established. Evidence for receptor and signaling interactions between the ECS and the renin-angiotensin system (RAS) in brain and vasculature is emerging. In transgenic (mRen2)27 rats, a monogenetic angiotensin (Ang) II-dependent model of hypertension with increased body mass, acute blockade of CB1 receptors in the solitary tract nucleus (NTS) restores the impaired baroreflex sensitivity (BRS) for control of heart rate to normal levels. We interpret these data as evidence for upregulation of the ECS in brain of this RAS-dependent model of hypertension. Data from the acute studies prompted us to study the effects of chronic systemic CB1 receptor blockade in (mRen2)27 rats using rimonabant (SR141716A), an orally active antagonist with central and peripheral actions. Beginning at 16 weeks of age animals were given daily oral injections of SR141716A (10 mg/kg/day; n = 6) for 28 days. In comparison to rats receiving vehicle (0.1% Tween-80 in dH2O; n = 6), daily dosing of SR141716A significantly reduced systolic blood pressure within 1 wk and by day 25 values were 172 ± 1 in control vs. 151 ± 5 mmHg in treated rats (P < 0.01). This was accompanied by decreased cumulative weight gain (44 ± 3 vs. 26 ± 2 grams, P < 0.01) and adiposity index (2.8 ± 0.2 vs. 1.9 ± 0.2% of body weight, P < 0.05) without long-term changes in food or water consumption. At the end of the study, conscious pressure recordings were obtained via arterial catheter for spectral and sequence analysis of autonomic tone. Two-fold increases occurred in Sequence ALL (P < 0.05) and indices of vagal and sympathetic BRS, as well as in heart rate variability (SDRR, P < 0.01), a measure of vagus nerve tone. The chronic beneficial actions of SR141716A in (mRen2)27 animals are consistent with the interpretation that an upregulated ECS contributes to maintenance of hypertension and impaired BRS in this RAS-dependent model. We conclude that systemic blockade of CB1 receptors, perhaps in part via actions within the NTS, is an effective therapy for lowering blood pressure and body weight, with a concomitant positive influence cardiovagal reflexes in hypertension.