Beneficial effects of combined thromboxane and leukotriene receptor antagonism in hemorrhagic shock.

OBJECTIVE: Both thromboxane A2 and peptide leukotrienes D4/E4 have been implicated in the pathophysiology of circulatory shock. In the present study, we evaluated the effect of thromboxane A2 and leukotriene D4/E4 receptor antagonism in circulatory shock. DESIGN: Prospective, randomized, controlled trial. SETTING: Research laboratory. SUBJECTS: Male Sprague-Dawley rats (325 to 375 g). INTERVENTIONS: The effect of selective receptor antagonists of thromboxane A2 (i.e., SQ-29,548) and leukotrienes D4/E4 (i.e., LY-171883) was investigated, either alone or in combination, in a model of hemorrhagic circulatory shock. Animals were randomly assigned to one of eight experimental groups: a) sham plus vehicle; b) sham plus LY-171883 (4 mg/kg); c) sham plus SQ-29,548 (2 mg/kg); d) sham plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg); e) hemorrhage plus vehicle; f) hemorrhage plus LY-171883 (4 mg/kg); g) hemorrhage plus SQ-29,548 (2 mg/kg); and h) hemorrhage plus SQ-29,548 (2 mg/kg) plus LY-171883 (4 mg/kg). Circulatory shock was induced by acute hemorrhage to a mean arterial pressure (MAP) of 45 mm Hg. We investigated the effect of SQ-29,548 and LY-171883 on the progression of circulatory shock. MEASUREMENTS AND MAIN RESULTS: Neither pharmacologic agent, alone or in combination, had any significant effect on MAP or heart rate in nonhemorrhaged rats. Both thromboxane receptor antagonism (p < .01) and combined thromboxane/leukotriene receptor antagonism (p < .001) significantly improved survival time after hemorrhage. However, leukotriene receptor antagonism alone did not significantly improve survival time after hemorrhage. After acute blood loss and 20% decompensation, the shed blood was returned to the animal; maximal postreinfusion blood pressures were not significantly different between experimental groups. The postreinfusion MAP was maintained at higher values in hemorrhaged rats given the thromboxane receptor antagonist or the combination of thromboxane and leukotriene receptor antagonists. Only the combined therapy significantly altered all of the measured indices of cardiovascular compensation (i.e., maximum bleed-out volume, time to maximum blood loss, and 20% decompensation time). Furthermore, only combined receptor antagonism resulted in a significant (p < .02) attenuation of plasma cathepsin D activity. CONCLUSIONS: The present findings support a role for thromboxane A2 and peptide leukotrienes D4/E4 as important mediators in circulatory shock and suggest that combined thromboxane/leukotriene receptor antagonism may have superior therapeutic efficacy to leukotriene receptor antagonism.

Peptide leukotriene receptor antagonism in myocardial ischaemia and reperfusion.

OBJECTIVE: The aim was to investigate the role of peptide leukotrienes in the pathophysiology of myocardial injury during reperfusion of previously ischaemic myocardium. METHODS: Adult male cats (2.9-5.4 kg) were subjected to left anterior descending coronary artery occlusion for 3 h followed by 3 h of reperfusion. The peptide leukotriene receptor antagonist, LY-171883, was given intravenously only during the reperfusion period (3 mg.kg-1 bolus; 3 mg.kg-1 x h-1 infusion). Ischaemic injury was assessed by nitroblue tetrazolium staining and tissue creatine kinase activity; neutrophil infiltration was determined by myeloperoxidase activity of myocardial homogenates. RESULTS: There was no significant difference at any time point in the experimental protocol between mean arterial blood pressure or pressure-rate index in cats given LY-171883 (3 mg.kg-1) and cats given vehicle. The area at risk of infarction (AAR) was 24(SEM 2)% for vehicle treated cats and 22(2)% for the drug treated cats. The necrotic area was 48(5)% of the AAR for the vehicle group but only 29(5)% of the AAR for the group given LY-171883 (p < 0.02). Left ventricular maximum +dP/dt tended to be higher with drug treatment compared to vehicle at the end of the reperfusion period. Tissue from the area at risk was assayed for creatine kinase activity and neutrophil specific myeloperoxidase activity as an index of the accumulation of neutrophils in this region. Creatine kinase activity was significantly higher (p < 0.05) in the AAR for drug nu vehicle treated cats following reperfusion, confirming the histochemical analysis. Myeloperoxidase activity increased approximately 12-fold in the AAR of cats receiving vehicle. LY-171883 did not reduce the myeloperoxidase activity significantly in the area at risk. CONCLUSIONS: LY-171883 has a protective effect in ischaemia-reperfusion injury to the myocardium. These findings suggest a role for peptide leukotrienes both in the extension of ischaemic damage and in post-ischaemic ventricular dysfunction during reperfusion.

Influence of dietary n-3 fatty acids on myocardial ischemia and reperfusion.

We have investigated the effect of elevated n-3 (omega-3) fatty acid content in the diet on arrhythmias, ischemic damage, and inflammatory cell infiltration into the reperfused left ventricular free wall (LVFW). Weanling rats were fed purified diets in which the lipid was replaced with either corn oil (CO) or menhaden oil (MO). After 4 wk, MO feeding resulted in significant elevations in both the ratio of n-3 to n-6 fatty acids and the unsaturation index in myocardial phospholipids. Rats were subjected to 15 min of ischemia followed by reperfusion. After 6 h of reperfusion of the left coronary artery there was significantly less creatine kinase (CK) lost from the LVFW of rats fed MO. Leukocyte infiltration into the LVFW, as measured by myeloperoxidase (MPO) activity, was also significantly reduced with MO feeding at 6 h. Arrhythmias were studied in a separate group of 17 rats; both the incidence and severity of ventricular tachycardia and ventricular fibrillation were significantly reduced during the ischemic and reperfusion periods with MO feeding. After 24 h of reperfusion there was also significantly less CK lost from the LVFW of MO-fed rats; however, there was no significant difference in tissue MPO activity in ventricular homogenates. Survival after 24 h of reperfusion was 76% (16/21) for MO- and 41% (9/22) for CO-fed rats. The data suggest a protective effect for dietary MO in myocardial ischemia-reperfusion, which may involve both an early reduction in leukocyte infiltration and a reduction in the incidence of fatal arrhythmias.