Volker B. Fiedler

Reduction of myocardial infarction and dysrhythmic activity by nafazatrom in the conscious rat

The effects of nafazatrom (30 and 100 mg/kg b.i.d.) on myocardial lesions caused by coronary artery ligation were determined in rats. The treatment lasted ten days preceding and twenty days following the cardiac insult, and its effects were compared with the effects of oral 1% Tylose suspension as drug vehicle. Nafazatrom reduced the number of extrasystoles and the duration of ventricular tachycardia and fibrillation occurring in the early (0-10 min) and late phases (2-4 h) of cardiac arrhythmias observed in the controls. Pretreatment with nafazatrom reduced the size of the ultimate infarct by 36 and 48 percent (P less than 0.05), and by 28 and 39% (P less than 0.05) with post-ligature nafazatrom treatment.

Molsidomine: alternative approaches to treat myocardial ischemia.

The long‐acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions.

Reduction of acute myocardial ischemia in rabbit hearts by nafazatrom.

The effects of oral nafazatrom pretreatment (10 mg/kg, twice a day, for 10 days) on myocardial ischemia were studied in the rabbit heart during 6-h occlusion of the left anterior descending coronary artery (LAD). The tension-time index (TTI), hemodynamics, and ischemia size were determined (Evans blue-triphenyltetrazolium chloride staining with planimetry). In drug-vehicle controls, left ventricular (LV) and peripheral pressures and LV dP/dtmax decreased, while heart rate, end-diastolic pressure, the TTI, and electrocardiographic ST segments increased. Hemodynamics were nearly unaltered in the nafazatrom-pretreated animals, except for a heart rate elevation during the initial phase of LAD occlusion. In drug-treated hearts, 45 ± 6% of the LAD perfusion region at risk was ischemic, showing a patchy distribution. In vehicle controls, 82 ± 4% (p < 0.02 vs. nafazatrom pretreatment) of the LAD-perfused myocardial regions was transmurally ischemic, showing a uniform pattern. Thus, nafazatrom pretreatment prevented most hemodynamic changes following LAD occlusion in the rabbit heart. Significant amounts of the muscle remained normoxic within the nonperfused arterial regions. These results indicate that the inhibition of lipoxygenase enzymes by nafazatrom may delay the development of ischemic damage to the heart following acute coronary artery occlusion.

Effects of nifedipine and indomethacin on leukotriene C4- and D4-induced coronary constriction at normal and reduced coronary perfusion in dogs

Summary: The effects of intracoronary leukotriene C4 (LTC4) and D4 (LTD4) (both 0.1 μg/kg) were studied in 23 anesthetized open-chest dogs at normal (= mean aortic pressure) and reduced (51 ± 2 and 32 ± 2 mm Hg) coronary perfusion pressures. The left anterior descending coronary artery was cannulated and blood flow measured. Subendocardial fiber segment length was obtained with ultrasonic crystals. At normal coronary perfusion pressure, LTC4 and LTD4 reduced coronary blood flow from 81 ± 6 and 78 ± 7 ml/min per 100 g by 41 ± 4% and 41 ± 4% (both p < 0.0005), respectively. However, segment length shortening was not depressed by LTC4 or LTD4. At reduced coronary perfusion pressure, LTC4 and LTD4 diminished coronary blood flow from 35 ± 5 and 32 ± 3 ml/min per 100 g, by 28 ± 5% (p < 0.0025) and 30 ± 5% (p < 0.005). Thus, reduction of coronary blood flow was less by both LTC4 (p < 0.01) and LTD4 (p < 0.05) at reduced rather than at normal coronary perfusion pressure. Segment length shortening was depressed by LTC4 from 6.5 ± 1.2% to 2.4 ± 1.6% (p < 0.05) and by LTD4 from 5.6 ± 1.4% to 3.1 ± 0.9% (p < 0.05), respectively. Indomethacin (5 mg/kg, i.v.) and nifedipine (10 μg/kg, i.v.) did not abolish the LT-induced coronary artery constriction. However, in animals pretreated with indomethacin or nifedipine, reduction of coronary blood flow by LTs was not attenuated at reduced coronary perfusion. We conclude that negative inotropic effects of LTs were due to myocardial ischemia. Myocardial ischemia attenuates coronary constriction evoked by LTs by a mechanism that is inhibited by indomethacin and nifedipine.

Role of Arachidonic Acid Metabolites in Cardiac Ischemia and Reperfusion Injury

Myocaradial reperfusion after prolonged periods of ischemia may result in the acceleration and exacerbation of ventricular injury. This is associated with intramitochondrial calcium overload and gross alterations in ultrastructure. Prostaglandins (PGs) (e.g., PGE2, PGE2α, thromboxane A2, PGI2) are synthesized by the heart during myocardial infarction, and cardiotoxic influences of arachidonate on contractile recovery with enhanced efflux of enzymes occur after reperfusion. Accumulation of arachidonic acid in early ischemia indicates degradation of phospholipids as structural components of myocyte membranes. One major cause for reperfusion‐induced exacerbation of ischemic damage is a free radical‐induced peroxidation of lipids with cellular disruption. On reperfusion, both vasoconstrictive and dilator PGs are released from platelets, myocytes, and endothelium, and flushed downstream. This may cause additional vasoconstriction in the microcirculation of normally and/or hypoperfused cardiac regions. Locally released vasodilating PGs can improve cardiac perfusion and prevent plugging of blood elements, thereby antagonizing cell destruction during flow restoration. Several drugs are available that modify blood cell and myocyte arachidonate metabolism, and may favor synthesis of dilating and antiaggregatory PGs.

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.

Effects of carbocromene on ventricular fibrillation during acute myocardial ischemia in anesthetized dogs.

The effects of carbocromene, 4 mg/kg intravenously, prior to coronary artery occlusion plus 40 microgram/kg/min during coronary artery occlusion and reperfusion on ventricular fibrillation threshold (VFT) were studied in pentobarbital-anesthetized open-chest dogs and compared to controls receiving saline. Coronary artery occlusion decreased VFT by 46 +/- 4% (mean +/- SEM, p less than 0.02) in controls and by 22+/-3% in drug-treated animals. Reperfusion of the occluded artery decreased VFT by 83+/-7% (p less than 0.01) in controls and by 47+/-5% in carbocromene-treated hearts (p less than 0.02). Hemodynamics did not change in the drug group during coronary artery occlusion. In controls, blood pressure and dP/dtmax decreased while heart rate, end-diastolic pressure and ST-T segments increased significantly during both coronary artery occlusion and reperfusion. The underperfused, ischemic region was assessed by staining with Evans blue and involved 34+/-3% of the left ventricular mass in controls but only 27+/-3% in carbocromene-treated hearts (p less than 0.05). These results indicate protective effects of carbocromene on ventricular vulnerability in canine hearts during coronary artery occlusion and subsequent reperfusion.

Effects of molsidomine, nitroglycerin, and isosorbide dinitrate on the coronary circulation, myocardial oxygen consumption, and haemodynamics in anaesthetized dogs.

SummaryThe effects of i.v. molsidomine administration on the coronary circulation, myocardial oxygen consumption, and haemodynamics were studied in open-chest dogs with non-constricted coronary arteries, and compared to those of nitroglycerin and isosorbide dinitrate. Molsidomine (50, 100, 250 μg/kg) reduced coronary flow while nitroglycerin (5, 10, 20 μg/kg) and isosorbide dinitrate (50, 100, 250 μg/kg) augmented coronary flow indicating coronary dilatation. Coronary resistance remained unaffected by molsidomine but fell after both nitrates. Molsidomine decreased myocardial oxygen consumption whereas nitroglycerin and isosorbide dinitrate initially increased oxygen consumption followed by a reduction. A decrease in stroke work was calculated after all three drugs. Minute work fell after molsidomine and nitroglycerin but not after isosorbide dinitrate.Heart rate and contractility remained unchanged by molsidomine but were both significantly enhanced by both nitrates. Stroke volume and cardiac output fell after molsidomine but increased immediately after both nitrates when administered with a subsequent decrease. Peripheral resistance was unchanged by the low dose of molsidomine but significantly decreased by the two nitrates immediately after administration indicating precapillary vasodilatation. The fall in blood pressure after molsidomine followed the reduction in cardiac output as sequel of lowered preload and venous return to the heart. The same mechanism decreased heart work after both nitrates but in addition vasodilatation of the coronary arteries and arterial vessel occurred.The effects of the three compounds are mainly the consequence of extracardiac effects, i.e. increased capacity of postcapillary vessels (molsidomine) plus arteriolar vasodilatation of short (nitroglycerin) and long duration (isosorbide dinitrate), respectively. Whereas molsidomine exerts no effects on the heart and coronary circulation both nitrates dilate coronary arteries and change heart performance thus indicating direct effects on the entire heart.