Acute and chronic systemic CB₁cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats

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.

A 4-week Pilot Study With the Cannabinoid Receptor Agonist Dronabinol and Its Effect on Metabolic Parameters in a Randomized Trial

“…14,17,32 However, in our study, leptin levels were also constant throughout the study period. Although leptin levels are intimately connected to adiponectin levels and visceral fat deposits, our study did not examine adiponectin levels.…”

“…14,16,17,27 At 3 weeks of twice-daily dosing, both AM251 and tetrahydrocannabivarin improved insulin sensitivity and reduced insulin levels. 27 On the other hand, in an early studying that involved the use of marijuana on hunger in humans, glucose measurements were taken and did not significantly increase with the administration of marijuana.…”

“…16 Another recent study reported that rimonabant at 10 mg/kg daily for 28 days decreased leptin and insulin levels with no change in glucose concentration. 17 Dronabinol may be used for nausea and vomiting in patients with cancer and in patients with anorexia due to AIDS. 18 Recently, dronabinol was found to decrease visceral sensitivity in patients with noncardiac chest pain.…”

Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA–salt hypertensive rats

“…The CB 1 receptor antagonists rimonabant and AM251 [2] further increase and the FAAH inhibitors URB597 [2] and AM3506 [11] decrease the elevated BP and cardiac contractility in hypertensive anaesthetised animals without affecting any hemodynamic parameters in normotensive controls. On the other hand, rimonabant reduces BP in conscious angiotensin IIdependent hypertensive (mRen2)27 rats but not in their normotensive controls [39]; although the results of the latter study cannot be easily reconciled with the data of the other studies, they nonetheless point to a role of the endocannabinoid system in hypertension.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…The supersensitivity of hypertensive rats to CB1 receptor-mediated cardiovascular depression was related to increased G protein coupling of CB1 (296). These studies were carried out with acute administration of a single dose of the FAAH inhibitor, whereas more recent studies highlighted how chronic CB1 inhibition in transgenic hypertensive rats with upregulated renin-angiotensin system activity improves blood pressure regulation and metabolic profile (777). The indirect and sustained activation of CB1 needs to be carefully addressed in the context of the cardiovascular system, since genetic deletion of FAAH in a doxorubicin-induced cardiomyopathy model promotes myocardial injury (600).…”