Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors.
Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 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 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 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. SR-141716 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 SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1(-/-), and CB1(-/-)/CB2(-/-) mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.
Bátkai
Sándor
S
National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-8115, USA.
Pacher
Pál
P
Járai
Zoltán
Z
Wagner
Jens A
JA
Kunos
George
G
D000818:Animals; D002186:Cannabinoids / Q000037:antagonists & inhibitors*; D004731:Endotoxins; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000378:metabolism; D000077285:Rimonabant; D014655:Vascular Resistance / Q000187:drug effects
D002186:Cannabinoids; D004731:Endotoxins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C103505:AM 251; D000077285:Rimonabant