Abstract
We investigated acute and chronic effects of CB1 cannabinoid receptor blockade in renin‐angiotensin system‐dependent hypertension using rimonabant (SR141716A), an orally active antagonist with central and peripheral actions. In transgenic (mRen2)27 rats, a model of angiotensin II‐dependent hypertension with increased body mass and insulin resistance, acute systemic blockade of CB1 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 CB1 receptor blockade, (mRen2)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 CB1 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 CB1 receptor blockade may be an effective therapy for angiotensin II‐dependent hypertension and associated metabolic syndrome.
Highlights
Hypertension, diagnosed when arterial pressure (AP) exceeds 140/90 mmHg, is the single most important risk factor for the development of cardiovascular disease and currently affects one in three U.S adults (Go et al 2014)
SR141716A in27 rats caused a transient reduction in heart rate (HR), which fell from 409 Æ 17 bpm at baseline to 363 Æ 15 bpm after 90 min (P < 0.05), but fully recovered within 24 h (Fig. 1B)
We report for the first time effects of acute and chronic systemic blockade of CB1 cannabinoid receptors on blood pressure, body weight, fat mass, feeding, serum leptin and insulin content, and conscious baroreflex function in transgenic hypertensive rats with upregulated renin-angiotensin system (RAS) activity
Summary
Hypertension, diagnosed when arterial pressure (AP) exceeds 140/90 mmHg, is the single most important risk factor for the development of cardiovascular disease and currently affects one in three U.S adults (Go et al 2014). The mechanisms involved in the development of hypertension are still not fully understood, the widespread use of medications that inhibit the formation of the peptide hormone angiotensin (Ang) II or its actions at the ubiquitously expressed Ang II type 1 (AT1) receptor as first-line treatments implicates disturbances in the renin-angiotensin system (RAS) in the maintenance of the disease (Herichova and Szantoova 2013). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. There is need for further research into the mechanisms linking the RAS with the metabolic syndrome in hypertension
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