Lipoxygenase inhibitor nafazatrom fails to attenuate postischaemic ventricular dysfunction.
The role of lipoxygenase activation in the genesis of postischaemic myocardial dysfunction was investigated in open chest dogs undergoing a 15 min occlusion of the left anterior descending artery followed by 4 h of reperfusion. Treated animals (n = 9) received nafazatrom, a potent lipoxygenase inhibitor, 10 mg.kg-1 orally 4 h before occlusion followed by intravenous boluses of 1.5 mg.kg-1 and 0.5 mg.kg-1 5 min before occlusion and 1 min before reperfusion respectively. Control animals (n = 10) received saline. No discernible haemodynamic effects were produced by the drug. Collateral flow to the ischaemic zone (radioactive microspheres) was 0.14(0.02) ml.min-1.g-1 in the control group and 0.16(0.05) ml.min-1.g-1 in the treated group. The size of the occluded bed as determined by postmortem perfusion was 25.5(0.8)% of the left ventricle in the control and 24.3(1.3)% in the treated group. Histological examination showed a decrease in neutrophil infiltration of the non-ischaemic myocardium and, to a lesser extent, of the reperfused myocardium in nafazatrom treated animals, suggesting lipoxygenase inhibition. Systolic wall thickening (an index of regional function) was assessed using an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions. Though treated animals showed less dyskinesis during coronary occlusion (p less than 0.05), recovery of function was not enhanced over controls and in both groups the reperfused myocardium was still dyskinetic at 4 h. Thus nafazatrom failed to improve postischaemic ventricular dysfunction, suggesting that leukotrienes do not contribute importantly to this phenomenon.
D000818:Animals; D003327:Coronary Disease / Q000201:enzymology / Q000503:physiopathology*; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008084:Lipoxygenase / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones
D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D047069:Pyrazolones; D008084:Lipoxygenase; C018845:nafazatrom