Acute and chronic systemic CB 1 cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats

We investigated acute and chronic effects of CB 1 cannabinoid receptor blockade in renin‐angiotensin system‐dependent hypertension using rimonabant (SR141716A), an orally active antagonist with central and peripheral actions. In transgenic ( mR en2)27 rats, a model of angiotensin II‐dependent hypertension with increased body mass and insulin resistance, acute systemic blockade of CB 1 receptors significantly reduced blood pressure within 90 min but had no effect in Sprague‐Dawley rats. No changes in metabolic hormones occurred with the acute treatment. During chronic CB 1 receptor blockade, ( mR en2)27 rats received daily oral administration of SR141716A (10 mg/kg/day) for 28 days. Systolic blood pressure was significantly reduced within 24 h, and at Day 21 of treatment values were 173 mmHg in vehicle versus 149 mmHg in drug‐treated rats ( P  < 0.01). This accompanied lower cumulative weight gain (22 vs. 42 g vehicle; P  < 0.001), fat mass (2.0 vs. 2.9% of body weight; P  < 0.05), and serum leptin (2.8 vs. 6.0 ng/mL; P  < 0.05) and insulin (1.0 vs. 1.9 ng/mL; P  < 0.01), following an initial transient decrease in food consumption. Conscious hemodynamic recordings indicate twofold increases occurred in spontaneous baroreflex sensitivity ( P  < 0.05) and heart rate variability ( P  < 0.01), measures of cardiac vagal tone. The beneficial actions of CB 1 receptor blockade in (mRen2)27 rats support the interpretation that an upregulated endocannabinoid system contributes to hypertension and impaired autonomic function in this angiotensin II‐dependent model. We conclude that systemic CB 1 receptor blockade may be an effective therapy for angiotensin II‐dependent hypertension and associated metabolic syndrome.