am-281 and Shock--Septic

On the basis of previous findings that the anandamide antagonist AM281, an endogenous cannabinoid receptor antagonist, could restore the hemodynamic and cerebral blood flow changes and improve the mortality rate in non-diabetic rats during sepsis, this study was conducted to examine whether AM281 could restore the hemodynamic variables and improve the mortality rate in streptozotocin-induced diabetic rats during sepsis.. The study was designed to include three sets of experiments, each set of experiment being conducted in both diabetic and non-diabetic animals: (1) measurement of changes in systemic hemodynamics and carotid artery blood flow, (2) measurement of biochemical variables and (3) assessment of mortality rate. Systemic hemodynamics, carotid artery blood flow changes and biochemical variables were assessed at pre-treatment and 1, 2 and 3 h after the treatment was performed.. In both non-diabetic and diabetic rats, administration of lipopolysaccharide (LPS) induced a reduction in hemodynamic variables, these reductions being greater in diabetic than in non-diabetic rats. In diabetic rats, administration of AM281 could only partially prevent these hemodynamic changes, these changes being insufficient to elevate these variables to control values. Significant differences were observed in mortality rates at 6 and 12 h between non-diabetic and diabetic groups with the same treatment. At 12 h, only non-diabetic AM281 group rats were still alive (mortality rate 50%).. Administration of AM281 only partially prevented the hemodynamic, biochemical and carotid artery blood flow changes associated with LPS-induced septicemia in diabetic rats, as compared with non-diabetic rats in whom these changes were prevented to a greater extent.

Topics: Analysis of Variance; Animals; Blood Glucose; Blood Pressure; Cannabinoid Receptor Antagonists; Carotid Artery, Internal; Diabetes Mellitus, Experimental; Heart Rate; Hemodynamics; Interleukin-1beta; Male; Morpholines; Pyrazoles; Random Allocation; Rats; Rats, Wistar; Regional Blood Flow; Shock, Septic; Sodium Nitrite; Survival Analysis; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

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.. 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.. 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.. 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.

Topics: Adrenergic alpha-Agonists; Animals; Cannabinoids; Cytokines; Lipopolysaccharides; Male; Monitoring, Physiologic; Morpholines; Norepinephrine; Pyrazoles; Random Allocation; Rats; Regional Blood Flow; Renal Circulation; Shock, Septic; Splanchnic Circulation

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.

Topics: Animals; Cannabinoid Receptor Antagonists; Carotid Artery, Internal; Hemodynamics; Ligands; Male; Morpholines; Pyrazoles; Rats; Rats, Wistar; Regional Blood Flow; Shock, Septic; Survival Analysis; Treatment Outcome