Published online before print September 27, 2004, doi: 10.1161/01.CIR.0000143230.23252.D2
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(Circulation. 2004;110:1996-2002.)
© 2004 American Heart Association, Inc.
Hypertension |
Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension
From the Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Md (S.B., P.P., D.O-H., S.R., J.L., J.H.-W., L.O., G.K.); the Department of Physiology, University of Washington, Seattle, Wash (K.M.); and the Cardiovascular Disease Research Program, North Carolina Central University, Durham, NC (M.A.R., R.D.B).
Correspondence to George Kunos, MD, PhD, NIAAA/NIH, MSC-8115, Bethesda, MD 20892-8115. E-mail gkunos{at}mail.nih.gov
Received November 18, 2003; de novo received May 6, 2004; accepted June 17, 2004.
Background— Endocannabinoids are novel lipid mediators with hypotensive and cardiodepressor activity. Here, we examined the possible role of the endocannabinergic system in cardiovascular regulation in hypertension.
Methods and Results— In spontaneously hypertensive rats (SHR), cannabinoid-1 receptor (CB1) antagonists increase blood pressure and left ventricular contractile performance. Conversely, preventing the degradation of the endocannabinoid anandamide by an inhibitor of fatty acid amidohydrolase reduces blood pressure, cardiac contractility, and vascular resistance to levels in normotensive rats, and these effects are prevented by CB1 antagonists. Similar changes are observed in 2 additional models of hypertension, whereas in normotensive control rats, the same parameters remain unaffected by any of these treatments. CB1 agonists lower blood pressure much more in SHR than in normotensive Wistar-Kyoto rats, and the expression of CB1 is increased in heart and aortic endothelium of SHR compared with Wistar-Kyoto rats.
Conclusions— We conclude that endocannabinoids tonically suppress cardiac contractility in hypertension and that enhancing the CB1-mediated cardiodepressor and vasodilator effects of endogenous anandamide by blocking its hydrolysis can normalize blood pressure. Targeting the endocannabinoid system offers novel therapeutic strategies in the treatment of hypertension.
Key Words: hypertension • blood pressure • contractility • endocannabinoids • pharmacology
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