Effects of AM281, a cannabinoid antagonist, on circulatory deterioration and cytokine production in an endotoxin shock model: comparison with norepinephrine.

PURPOSE

The purpose of this study was to examine the comparative effects of AM281, a cannabinoid antagonist, and norepinephrine (NE) on systemic hemodynamics, and renal and mesenteric artery blood flow in an endotoxin shock model.

METHODS

The study was designed to include two sets of experiments: (1) measurements of changes in systemic hemodynamics and organ artery blood flows (n = 20), and (2) measurements of biochemical variables (n = 20). For each set of experiments, male 7-week-old Wistar rats were randomly divided into four groups: group 1, controls (n = 5); group 2, receiving lipopolysaccharide (LPS: Escherichia coli endotoxin, 10.0 mg.kg(-1) intravenous bolus) (n = 5); group 3, receiving intravenous LPS and NE (continuous infusion at 0.2 microg.kg.min(-1)) (n = 5); group 4, receiving LPS and AM281 (0.1 mg.kg.min(-1)) (n = 5). Systemic hemodynamics, regional artery blood flow changes, and biochemical variables were assessed before treatment and 1 and 3 h after treatment.

RESULTS

Infusion of NE or AM281 prevented endotoxin-induced decreases in systemic arterial pressure, aortic blood flow, carotid artery blood flow, and renal artery blood flow. Both AM281 and NE inhibited endotoxin-induced increases in cytokine production, with significant differences observed among the three groups at 1 and 3 h after treatment. Endotoxin-induced decreases in mesenteric arterial blood flow were restored by AM281 but not by NE. AM281 improved arterial oxygenation and reduced lactate overproduction and body temperature elevation induced by endotoxin.

CONCLUSIONS

Although NE and AM281 both prevented endotoxin-induced deterioration of systemic hemodynamics, AM281 yielded better preservation of mesenteric blood flow and attenuation of cytokine production than NE.