Mithat Mardin

Effects of nafazatrom and indomethacin on experimental myocardial ischemia in the anesthetized dog

Summary: The anti-ischemic effects of nafazatrom (10 mg/kg intraduodenally) have been studied in a canine model of myocardial infarction. Nafazatrom was given 30 min before and 2 h after occlusion of the left anterior descending coronary artery (LAD). Effects were compared with those after intravenous indomethacin (10 mg/kg) treatment. Infarct size was measured at 6 h of coronary occlusion by postmortem tetrazolium staining. Myocardial ischemia was reduced after nafazatrom administration, whether related to total left ventricle (18 ± 3.3 vs. 30.7 ± 4.8%; p < 0.05) or to the LAD vessel area at risk for infarction (51.4 ± 4.0 vs. 82.5 ± 4.5%; p < 0.01). Salvage with nafazatrom occurred in the subepicardial and endomural tissues without lateral protection. Indomethacin had no effects on infarction. The LAD occlusion-induced hemodynamic consequences were reduced at 15 min by nafazatrom and remained unchanged by indomethacin. During the following experimental course, no differences were noted between the groups. At 6 h, blood flow in the nonoccluded circumflex artery increased by 12.6 ± 3.2 ml/min (p < 0.05) following nafazatrom treatment. Thus, nafazatrom reduced ischemia by a mechanism unrelated to changes in hemodynamics. Most likely, this was due to 5-lipoxygenase inhibition. This may shift arachidonic acid metabolism to cyclooxygenase products and prevent release of deleterious lipoxygenase products by neutrophils during ischemic injury.

The effects of nafazatrom in an acute occlusion-reperfusion model of canine myocardial injury

SummaryThe effects of the lipoxygenase enzyme inhibitor nafazatrom on infarct size, haemodynamics, and prostanoid release was studied in a canine occlusion-reperfusion model of ischaemic myocardial injury. Treatment was with 10 mg/kg nafazatrom i.d., starting before coronary occlusion, 2 h and 6 h thereafter, and was repeated in 6 h intervals. The left anterior descending (LAD) coronary artery was occluded for 6 h and reperfused for 42 h. Infarct size and anatomic area dependent on the occluded LAD were determined post mortem by the tetrazolium staining technique. Nafazatrom significantly reduced the extent of irreversible myocardial ischaemic damage whether it was expressed as g/100 g left ventricle (24 ± 4 vs. 46 ± 6 in controls;p<0.01; mean ± SEM) or as percentage of LAD risk region for infarcting (38 ± 8 vs. 65 ± 7% in controls;p<0.05). Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure anddP/dtmax decreased while filling pressure, heart rate, and the S-T segments of the ECG increased. The incidence of ventricular fibrillation was 8% during drug treatment and coronary ligature vs. 25% in controls (n.s.). During reperfusion, nafazatrom reduced the incidence of ventricular premature contractions and tachycardia. Ex vivo platelet aggregation in response to collagen was not inhibited by nafazatrom. Prostanoid release (thromboxane B2 and 6-keto-prostaglandin F1α as breakdown products of thromboxane A2 and prostacyclin, respectively) remained unaltered in vehicle controls but nafazatrom treatment elevated prostacyclin release significantly at 4 and 5 h during LAD occlusion. We conclude, that inhibition of 5-lipoxygenase by nafazatrom may promote endogenous prostacyclin release and reduce infiltration of reparatory white blood cells with deleterious release of arachidonic acid products contributing to extension of infarction. This mechanism may reduce ultimate ischaemic damage to the heart.

Leukotrienes on porcine hemodynamics and prostanoid release

We studied the effect of intracoronary leukotriene B4, C4, D4 and E4 (0.1-3 micrograms) on coronary artery blood flow and resistance in anesthetized pigs. Conventional hemodynamics were measured, and the peripheral electrocardiogram was obtained in lead II. Thromboxane B2 and 6-keto-prostaglandin F1 alpha (as breakdown products of thromboxane and prostacyclin, respectively) were measured during the influence of leukotrienes on the heart. All leukotrienes except B4 reduced coronary flow. Peak reduction was produced by 3 micrograms of each eicosanoid: C4 = 96 +/- 4%+; D4 = 98 +/- 2%+; E4 = 82 +/- 8%+. Coronary resistance increased after the same dose B4 = 65 +/- 18%; C4 = 225 +/- 94% (P less than 0.01); D4 = 442 +/- 118%+; E4 = 110 +/- 43% (+ = P less than 0.001). Increase in filling pressure and heart rate but blood pressure reduction and diminution in left ventricular d P/dtmax were observed with leukotriene C4, D4 and E4. The S-T segments of the electrocardiogram were elevated, thus indicating myocardial ischemia during the blood flow reduction. Indomethacin (5 mg/kg i.v.) had no effects on the leukotriene-induced hemodynamic sequelae. Thromboxane B2 concentration in coronary sinus blood plasma increased by 132-176% (P less than 0.05) at peak leukotriene effects on blood flow. Thus, leukotriene C4, D4, and E4 are vasoconstrictors in the situ porcine heart. Leukotriene B4, however, exerts no hemodynamic effects. The electrocardiographic ischemia and changes in hemodynamics indicate actions on coronary resistance and myocardial depression. These eicosanoids may contribute to cardiac dysfunction and vasospasm in coronary artery disease.

Nifedipine on cardiovascular leukotriene D4 actions in the anaesthetized dog

Open-chest dogs were used to study the effects of intracoronary leukotriene (LTD4; 0.5 microgram/kg) on haemodynamics, coronary blood flow in the left circumflex artery and coronary resistance in the absence or presence of nifedipine (10 micrograms/kg, i.v.). LTD4 increased ventricular filling pressure by 133% (P less than 0.001), the S-T segments and coronary resistance by 490% (P less than 0.001) and abolished coronary flow for 3 min. Nifedipine pretreatment inhibited the cessation of coronary flow. No change in filling pressure and no ischemia signs in the peripheral ECG were noted. However, nifedipine did not inhibit the LTD4-induced decrease in left ventricular dP/dtmax. Haemodynamic LTD4 actions thus could be partially reversed by i.v. nifedipine, suggesting that leukotriene effects on the coronary and peripheral circulation are mediated by calcium release.

Enhancement of canine coronary collateral flow by nafazatrom

The ability of oral nafazatrom treatment (10 mg/kg) 2 h preceding occlusion of the left anterior descending coronary artery for 6 h to limit expansion of myocardial injury was studied in anaesthetized canine hearts. Collateral blood flow was obtained with a load line analysis, employing aortic pressure, post-stenotic coronary pressure, and retrograde coronary flow from the occluded vessel. Contractile changes in the subendocardial ischemic perfused muscles were measured with ultrasonic techniques. Infarct size was determined post-mortem by a biochemical staining method and excision of necrosis. Post-stenotic coronary pressure was slightly below aortic pressure in both groups before coronary occlusion, and fell to 29 and 27% of aortic pressure in vehicle- and drug-treated hearts, respectively, after the insult. Retrograde flow was 2.4 +/- 0.6 vs. 4.1 +/- 0.7 ml/min in tylose- or nafazatrom-treated hearts. Collateral flow amounted to 1.5 +/- 0.06 vs. 2.5 +/- 0.04 ml/min in controls and drug-protected hearts. Contractility (dP/dtmax) and the %-segment shortening were greater in the ischaemic myocardium after nafazatrom treatment. Infarct size was 38 +/- 5.2 vs. 17 +/- 3.4 g/100 g left ventricle in the vehicle controls and nafazatrom group, respectively. Nafazatrom reduced infarct size by 46%. Besides other mechanisms, this was due to improved %-segment shortening and increased periinfarction collateral blood supply to jeopardized but viable myocardium. The drug may be of value in ischaemic heart disease as shown by the enhanced regional myocardial perfusion and improved contractility.