Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors

Abstract

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.

Fig. 1

Hemodynamic effects of LPS in anesthetized rats in the absence and presence of the CB1 antagonist SR-141716. LPS (10 mg/kg iv) was injected at 0 min, 10 min after the injection of vehicle (●) or SR-141716 (3 mg/kg iv; ○). Mean arterial pressure (MAP; A), heart rate (HR; B), left ventricular systolic pressure (LVSP; C), maximal slope of systolic pressure increment (+dP/dt; D), mean aortic blood flow (MAF; E), and change (Δ) in peripheral resistance index (PRI; F) were monitored or computed as described in materials and methods. Values are means ± SE from experiments in 4–5 separate animals. Significant difference (P < 0.05): *from corresponding baseline value in the vehicle + LPS group; #between corresponding values in the 2 treatment groups.

Fig. 2

SR-141716 reverses the hemodynamic effects of LPS. SR-141716 (3 mg/kg) or vehicle was injected intravenously 15 min after the intravenous injection of 10 mg/kg LPS, as indicated by arrows. Values are means ± SE from 5 rats treated with SR-141716 (○) or 5 other animals treated with vehicle (●). MAP (A), LVSP (B), and +dP/dt (C) were continuously monitored and calculated at the indicated time points.

Fig. 3

LPS-induced hypotension is inhibited by SR-141716 but not by AM251. A: representative tracings of the effects of LPS on MAP in a rat pretreated with vehicle (left), SR-141716 (3 mg/kg iv; center), and AM251 (3 mg/kg iv; right). B: mean ± SE ΔMAP from similar experiments from 4–5 animals. *Significant difference from values in vehicle + LPS-treated rats (P < 0.05).

Fig. 4

Effect of LPS on MAP in wild-type (A), CB1^−/− (B), and CB1^−/−/CB2^−/− (C) mice pretreated with vehicle (●) or SR-141716 (3 mg/kg iv; ○). The numbers of animals in the 3 groups were 5 (A), 5 (B), and 4 (C). *Significant difference from corresponding value in the vehicle + LPS group.