Effects of AM281, a cannabinoid antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality in septic shock in rats

Abstract

The purpose of this study was to examine the effects of AM281, a cannabinoid receptor antagonist, on systemic haemodynamics, internal carotid artery blood flow and mortality during septic shock in rats. The study included three sets of experiments: measurements of changes in systemic haemodynamics and left internal carotid artery flow (30 animals divided into three groups of 10); measurements of biochemical variables (n=30); assessment of mortality (n=30). Male Wistar rats (7 weeks old) were randomly divided into three groups: group 1, control; group 2, lipopolysaccharide (LPS) i.v., Escherichia coli endotoxin 10.0 mg kg(-1) i.v., bolus; group 3, LPS 10.0 mg kg(-1) i.v.+AM281 1 mg kg(-1) i.v. Systemic haemodynamics, carotid artery flow changes and biochemical variables were assessed at pretreatment and 1, 2 and 3 h after the treatment was performed. Administration of AM281 could prevent the haemodynamic changes induced by sepsis. Tumour necrosis factor-alpha and interleukin 1-beta increased in the LPS i.v. and LPS i.v.+AM281 groups at 1, 2 and 3 h after treatment; significant differences were observed in these levels in the two groups at these times. Internal carotid artery blood flow remained fairly constant in the control and LPS i.v.+AM281 groups compared with baseline values. In the LPS i.v. group, it decreased at 2 and 3 h after the treatment compared with baseline values [at 2 h: control 12.7 (SD 0.9) ml min(-1), LPS i.v. 8.7 (1.4) ml min(-1) (P<0.05), LPS i.v.+AM281 11.5 (0.9) ml min(-1); at 3 h: control 12.7 (0.4) ml min(-1), LPS i.v. 7.7 (1.3) ml min(-1) (P<0.05), LPS i.v.+AM281 11.6 (1.0) ml min(-1)]. Significant differences in mortality within 6 and 12 h were found between the LPS i.v. and LPS i.v.+AM281 groups [6 h mortality: LPS i.v. 5/10 (50%), LPS i.v.+AM281 2/10 (20%), P<0.05; 12 h mortality: LPS i.v. group 10/10 (100%), LPS i.v.+AM281 5/10 (50%), P<0.05]. Administration of AM281 prevented changes in systemic haemodynamic and internal carotid artery blood flow and could improve mortality in experimentally induced septic shock in rats. These findings may have significant therapeutic implications in the treatment of septic shock.