Biomedical subjects
Publications and source records attributed to R E Nitz.
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The effect of molsidomine on platelet function has been studied in various experimental models. Molsidomine prevented mortality induced by arachidonic acid as well as thrombocytopenia induced by collagenase, the combination of collagen plus adrenaline, or PAF-acether. Arterial bleeding time was prolonged. Carotid or coronary artery thrombosis and jugular venous thrombosis were inhibited. These effects were obtained in various animal species and were dose-dependent. They suggest the administration of molsidomine for the prevention of thrombotic disorders.
This study was designed to analyze the effects of carbocromene on circulatory and electrophysiologic failure in rats anesthetized with urethane. Amitriptyline was infused at 0.4 mg/kg/min (n = 12) until death of the animals at 30 +/- 6.7 min due to vascular collapse. Following initial heart rate increase and QRS prolongation, this was characterized by progressive hypotension, bradycardia, intraventricular conduction delay, S-T segment elevation and A-V block. In the initial 31 rats, carbocromene was administered i.v. with 4 mg/kg followed in two groups by 40 (n = 13) and 80 micrograms/kg/min (n = 18) i.v., respectively. The drug was effective in protecting the animals against the acute cardiovascular failure induced by amitriptyline. The preservation was associated with a diminution of the hypotension, negative chronotropic actions, S-T segment elevation and the incidence of A-V block produced by amitriptyline. Survival time of the rats increased to 46 +/- 5.3 min (p less than 0.05 vs. amitriptyline controls) and 63 +/- 6.5 min (p less than 0.01) with infusion of 40 and 80 micrograms/kg/min carbocromene, respectively. These results suggest that carbocromene is an effective treatment of amitriptyline-induced cardiotoxicity by massive overdose with beneficial effects largely due to hemodynamic and metabolic oxygen-sparing impact on the heart. Membrane stabilizing antiarrhythmic carbocromene effects may be contributory factors in its protective value in the treatment of acute amitriptyline poisoning.
This study was designed to analyze the effects of carbocromene and dipyridamole on the haemodynamic and electrocardiographic side-effects resulting from imipramine infusion in anaesthetised rats and dogs. Imipramine was infused at 1 mg/kg/min until cardiac failure and vascular collapse terminated the experiment at 21 +/- 2.3 min in rats and at 29.5 +/- 2.1 min in dogs. This was characterized by hypotension, bradycardia, intraventricular conduction delay, cardiac tachyarrhythmia and A-V block. Carbocromene (4 mg/kg i.v., followed by 80 micrograms/kg/min) protected the animals against heart failure. This was associated with delayed hypotension and negative inotropy, and lower incidence of heart block. Survival time increased to 37 +/- 1.5 min (P less than 0.05), and 54.2 +/- 2.6 min (P less than 0.02) in rats and dogs, respectively. Dipyridamole (0.5 mg/kg i.v., followed by 80 micrograms/kg/min) failed to decrease imipramine toxicity as judged by the haemodynamic and electrocardiographic parameters and did not alter survival time of imipramine controls. These results suggest that carbocromene is an effective treatment for imipramine-induced cardiovascular collapse and cardiac arrhythmias, the beneficial effects being largely due to metabolic and membrane stabilizing effects. Carbocromene has both therapeutic and prophylactic value and appears to be superior to dipyridamole therapy.
The cardioprotective and antithrombotic activity of molsidomine, a novel therapeutic agent for the treatment of coronary heart disease, was investigated in a series of animal models of myocardial ischemia. Molsidomine given to dogs with marked ST segment elevation (epicardial electrogram), induced by a reduction of left descending coronary artery (LAD) flow to 20% to 30% of the original value, resulted within 40 minutes in complete normalization of ECG changes. In another animal model molsidomine given either before or after occlusion of the LAD significantly reduced infarct size. All these molsidomine effects were accompanied by a marked lowering of preload, resulting in a reduction of extravascular coronary artery resistance and in increased blood flow toward the ischemic zones. In a model of myocardial ischemia and reperfusion in the anesthetized dog, molsidomine had a marked protective effect against the incidence of spontaneous ventricular fibrillation. This effect could also be attributed to the anti-ischemic activity of molsidomine, which would reduce the disparity between the refractory periods in normal and ischemic areas and thus increase ventricular stability. The antithrombotic activity of molsidomine was investigated in dogs in which the left circumflex coronary artery was electrically stimulated, a procedure that leads to thrombotic occlusion. Molsidomine in a dose-dependent manner prevented coronary thrombotic occlusion and reduced thrombus wet weight and the size of the resulting infarction. These effects of molsidomine were not related to its hemodynamic activity, since nitroglycerin and isosorbide dinitrate had similar hemodynamic effects but did not prevent coronary thrombosis. The antithrombotic activity of molsidomine is probably related to its ability to lower coronary venous blood thromboxane levels.
In pentobarbital-anesthetized mongrel dogs the intravenous actions of 0.50 mg/kg molsidomine on pulmonary artery and left ventricular (LV) end-diastolic pressures and internal heart dimensions (preload), left ventricular systolic and peripheral blood pressures, and total peripheral resistance (afterload), as well as on heart rate, dP/dt, stroke volume, and cardiac output (heart performance) were studied for 2 h. Hemodynamic molsidomine effects were influenced by increasing amounts of intravenously infused dihydroergotamine solution (DHE, 1-64 micrograms X kg-1 X min-1). Molsidomine decreased preload, stroke volume, and cardiac output for over 2 h but decreased ventricular and peripheral pressures for 45 min. Systemic vascular resistance showed a tendency to decrease while heart rate and LV dP/dtmax were not altered. DHE infusion reversed molsidomine effects on the preload and afterload of the heart. The diminished stroke volume was elevated so that cardiac output also increased. Total peripheral resistance increased while heart rate fell in a dose-dependent fashion. The LV dP/dtmax remained unchanged until the highest dose of 64 micrograms X kg-1 X min-1 DHE elevated the isovolumic myocardial contractility. These experiments indicate that DHE can reverse the intravenous molsidomine effects on hemodynamics. Most likely, this is mediated through peripheral vasoconstriction of venous capacitance vessels, thereby affecting molsidomine's action on postcapillary beds of the circulation.
High doses of vitamin D3 induce myocardial lesions, necrotic alterations, and calcification of the vascular smooth muscle, (Mönckeberg arteriosclerosis) (6). These effects are accompanied by an increased calcium influx into the wall of the aorta and mesenterial vessels (1). Prophylactic application of MgCl2 nearly prevents this calcium overload, whereas KCl or calcium antagonists are less active. In our studies, the uptake of calcium-45 4 days after a single dose of vitamin D3 (90,000 IU/200 g) was increased in rat heart and aorta by a factor of 3 to 7, and up to 30-fold in mesenterial vessels. Application of carbocromen (10 mg/kg b.i.d.) for 4 days decreases the vitamin D3-induced radiocalcium uptake by 44 (aorta) to 67% (mesenterial vein), MgCl2 (15 mmol/kg b.i.d.) by 46 (mesenterial vein) to 92% (mesenterial artery), and verapamil (5 mg/kg b.i.d.) by 15 (aorta) to 44% (mesenterial vein).
The effect of molsidomine, a novel antianginal agent, on the epicardial electrographic changes induced by reduced perfusion of the left anterior descending coronary artery (LAD) was investigated in the anesthetized dog. The LAD was cannulated and perfused at a constant volume with blood taken from a carotid artery. The perfusion volume was than reduced by approximately 75%. The sum of the ST-segment changes obtained from six unipolar epicardial leads was taken as a measure of myocardial hypoxia. Simultaneously, heart rate, blood pressure, left ventricular end-diastolic pressure, pulmonary arterial pressure, and heart contractility were also recorded. In control animals, reduction of the perfusion volume of the LAD resulted in a dramatic elevation of the ST segments lasting more than 4 hr. Molsidomine administered after the induction of the ischemia at a dose of 0.05 mg/kg i.v. resulted within 40 min in a complete normalization of the electrographic changes. This effect was evident for over 4 hr in spite of the continuous reduced perfusion of the LAD. The beneficial effect of molsidomine on the electrical changes paralleled the reduction of the left ventricular end-diastolic pressure. It is suggested that the effect of molsidomine on the ischemic electrographic changes is brought about by a reduction of the preload, resulting in a better perfusion of the ischemic zones.
The effect of the novel antianginal agent molsidomine on the incidence of spontaneous ventricular fibrillation during myocardial ischemia and reperfusion was investigated in the anesthetized dog. Molsidomine was administered as an intravenous bolus at the dose of 0.05 mg/kg. Twenty minutes later, the left anterior descending coronary artery was occluded for 90 min. During the occlusion period, molsidomine was given as a continuous intravenous infusion at the dose of 0.5 micrograms/kg per ml per min. After release of the occlusion, the animals that survived were monitored for another 30 min. Control animals received saline. In the control animals, coronary occlusion was accompanied by an increase in heart rate, heart contractility, left ventricular end-diastolic pressure, and blood pressure as well as by ventricular arrhythmias. Molsidomine either abolished or reduced both hemodynamic and electrical changes. During the reperfusion period, 10 out of 12 control animals died, and the deaths were from ventricular fibrillation; one out of eight molsidomine-treated animals also died of ventricular fibrillation. It is postulated that the protective effect of molsidomine rests on its hemodynamic effects resulting in a shift in blood flow toward the ischemic zones and, consequently, in an increase in ventricular electrical stability.
The effects of oral administration of molsidomine (50, 100 and 250 micrograms/kg) on left ventricular function, dimensions and hemodynamics were studied in chronically equipped, resting conscious dogs and compared to those of orally administered nitroglycerin (5, 10 and 20 micrograms/kg), as well as isosorbide dinitrate (50, 100 and 250 micrograms/kg). Enteral absorption of molsidomine was similar to that following intravenous administration of the compound, but was delayed in the case of both nitrates, so that restraint hemodynamic effects were noted. Molsidomine significantly decreased ventricular preload and internal heart dimensions. These effects were longer-lasting and more pronounced than those induced by either nitrate compound. Heart rate and LV dP/dtmax remained unaffected by molsidomine but increased in a dose-dependent fashion after administration of the nitrates. Left ventricular ejection phase contractility decreased with all three compounds. This effect was probably due to the reduced ventricular volumes and dimensions caused by molsidomine and isosorbide dinitrate, and to the additional tachycardia with concomitant reduction in ejection phase induced by nitroglycerin. Ejection time and stroke volume fell with all three agents but the effect occurred with a greater delay of onset and was more persistent after molsidomine. Nitroglycerin was found to increase cardiac output, initially, as a sequel of positive inotropy and chronotropy, with a subsequent decrease of cardiac output. In contrast, cardiac output fell by 28% and 30% (p less than 0.02) after administration of 250 micrograms/kg molsidomine or isosorbide dinitrate, respectively. These results suggest that molsidomine has no direct effects on myocardial hemodynamics and function in the resting, awake dog. The drug exerts its beneficial effects on heart performance by a long-lasting diminution of cardiac preload caused preferentially by dilatation of postcapillary venous vessels.
Cardiovascular dynamic, inotropic and electrophysiologic effects of the new tetracyclic antidepressant 2,3,3a,4,5,6-hexahydro-8-methyl-1H-pyrazino[3,2,1-j,k]-carbazole hydrochloride (pirlindole) (0.5, 1, 2.5, 5 and 10 mg/kg, i.v.) were investigated in anaesthetized dogs and compared with those of i.v. imipramine (0.5, 1, 2.5 and 5 mg/kg) administration. Noradrenaline (norepinephrine)-induced systemic blood pressure increase was significantly potentiated by imipramine but not by pirlindole. Severe hypotension was caused by most imipramine doses, whereas the initial blood pressure fall after pirlindole was followed by an increase. Heart rate did not alter with lower prilindole doses but increased after 2.5 mg/kg. Imipramine caused severe tachycardia. Pirlindole had no effects on contractility but imipramine was negative-inotropic. Left ventricular end-diastolic pressure fell after pirlindole; imipramine caused transient decrease in filling pressure between 0.5 and 2.5 mg/kg, whereas 5 mg/kg significantly elevated this variable. Myocardial oxygen consumption increased with 5 and 10 mg/kg pirlindole but was reduced by imipramine. Pirlindole did not induce changes in the electrophysiology of the heart. Imipramine decreased PQ-time and elevated ST-T segments indicating myocardial ischaemia. Imipramine effects on electrical conduction were deleterious so that no dog survived 10 mg/kg. These results suggest that pirlindole may be a possible therapeutic regimen for treatment of depressed human patients with a previous history of cardiovascular disease.
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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 high doses of vitamin D on rat hearts were investigated 72 h after the administration of 500 000 U/kg. Histological examination showed disseminated focal necrosis with reactive round cell and granulocytic infiltration in the heart. The calcium content was increased by about 70%. These findings indicate vitamin D-induced myocardial lesions. Heart mitochondrial calcium binding and uptake activities were lower than in control animals. Na+-K+-ATPase activity of heart washed particles was reduced by the treatment with vitamin D whereas neither calcium binding and uptake activities of cardiac sarcoplasmic reticulum nor myofibrillar ATPase activity were affected. Carbocromen (20 and 100 mg/kg/d) treatment reduced vitamin D-induced decreases in mitochondrial calcium accumulating ability and Na+-K+-ATPase activity of heart washed particle, suggesting a beneficial effect of carbocromen against vitamin D-induced cardiac injury.
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The effects of the antianginal drug carbocromene on hemodynamics, infarct size, and arrhythmias after 90 min of coronary artery occlusion and following 30 min reperfusion were investigated in anesthetized, open-chest dogs. Carbocromene led to only slight pressure and rate alterations after ligation and reperfusion whereas untreated animals gave evidence of significant changes in these parameters. Furthermore, contractility remained unaffected by carbocromene but was significantly augmented in the control group after both experimental procedures. Preload (end-diastolic pressure) increased after occlusion and reperfusion in both groups, and this augmentation was permanently higher in the controls than in the carbocromene group. Increases in oxygen consumption and in ST-segment elevation were small after drug treatment but significant in control animals. Infarcted areas were significantly smaller in the carbocromene group than in the controls. Hemorrhage occurred in both groups but the amount was significantly smaller in the drug group. The onset of arrhythmias was delayed in the carbocromene group after ligation and reperfusion so that the mortality was significantly lower as compared to that in the non-treated control animals. Carbocromene possibly exerts metabolic effects on the heart, in addition to its coronary dilating properties, which confer the cardioprotective effects observed in acute canine experiments.
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