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1 Laboratory of Physiologic Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: gkunos{at}mail.nih.gov.
Endocannabinoids and CB1 receptors (CB1) have been implicated in endotoxin (lipopolysaccharide [LPS])-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 which are inhibited by SR141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, i.v. injection of 10 mg/kg LPS elicits hypotension associated with profound decreases in cardiac contractility, moderate tachycardia and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR141716 were similar in pentobarbital-anesthetized wild-type, CB1-/- and CB1 -/-/CB2-/- mice. We conclude that SR141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2, which mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.
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