[Inhibition by Intensain of phosphodiesterease from rat hearts].
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Adenine Nucleotides↗
Biomedical subjects
R E Nitz
Publications and source records attributed to R E Nitz.
[Biochemical pharmacological studies of the coronary dilator 3-(beta-diethylamino-ethyl)-4-methyl-7-carbethoxy-methoxy-2-oxo-(1,2-chromene)-hydrochloride. 1. Methods for determination of the substance and its metabolites in plasma, tissues and urine].
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Animals↗
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. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
Cardiovascular System↗
Electron microscopic autoradiographic localization of carbocromene in the coronary vessel walls and myocardium.
The ultrastructural distribution of 14-C- and the 3-H-carbocromene in monkeys and rats showed a characteristic pattern in the coronary artery wall and the heart muscle. The radioactivity was found to be located on the coronary vessel wall mainly in the tunica media over the smooth muscle cells and in the myocardium over the contractile elements and the mitochondria.
Administration, Oral↗
Effects of molsidomine on the coronary circulation in anesthetized dogs.
The intravenous effects of molsidomine on the coronary circulation, myocardial oxygen consumption, and hemodynamics were investigated in anesthetized, open-chest dogs. Left coronary artery flow was reduced after drug administration, while coronary resistance remained unaffected. The coronary arteriovenous oxygen difference did not change after molsidomine. Myocardial oxygen consumption was significantly reduced. Stroke work of the heart was diminished. Molsidomine caused a dose-dependent decrease in aortic and left ventricular pressures (after-load) as well as a sustained fall in left ventricular end-diastolic and mean pulmonary artery pressures (preload). Heart rate and contractility were only moderately affected. Stroke volume and cardiac output decreased significantly for the experimentation time, while total peripheral resistance increased after 0.25 mg/kg molsidomine. All observed effects of the drug can be explained by extracardiac effects: an increase in venous capacity. No direct effects of molsidomine on myocardial function could be noted. The fall in blood pressure was not induced by vasodilatation of peripheral arteriolar vessels but occurred as sequel of the reduced cardiac output following decreased ventricular filling. Molsidomine improved the oxygen supply-demand balance by decreasing external work of the heart and hence myocardial oxygen demand.
Anesthesia↗
Comparison of various methods for assessing infarct-size in the dog.
Various methods used for the assessment of infarct-size were compared in a canine model of coronary artery occlusion. The ability of molsidomine (an antianginal agent) to reduce infarct-size was also investigated. Open-chest dogs underwent occlusion of the left anterior descending coronary artery and starting 30 min after the occlusion received either molsidomine (n=8) as an infusion at the rate of 1 microgram/kg/min for 30 min and at a rate of 0.75 microgram/kg/min for 2 h, or saline (controls, n=8). Three hours after the occlusion methylene blue was injected into the left atrium for the assessment of the area at risk in vivo (ARV). The animals were then sacrificed, the heart removed and coronary arteriograms made after injection into the left coronary ostium of a BaSO4-gelatin mass to delineate the post-mortem area at risk (ARPM). The hearts were then cut in sections and the infarct's (I) area visualized with nitroblue tetrazolium C1. The left ventricle (LV) and I were also weighed, ARV, ARPM as well as LV and I areas were determined by planimetry. Body weight and LV mass were similar in both groups, I mass however, was markedly lower in molsidomine than in control dogs. Percentages I/LV mass and area were also significantly lower in the treated than in the control animals, and there was a significant correlation between the mass and planimetric methods for determining I size. ARPM/LV % was similar in both groups and I/ARPM % was smaller in molsidomine than in control animals, however this difference was not statistically significant. Molsidomine markedly reduced ARV/LV % which resulted in similar I/ARV ratios both in the treated and control groups. It is concluded: (1) that the direct measurement of I (mass) or the percentages I/LV mass or area are similarly useful for the detection of a pharmacological effect of I size. ARPM is unaffected by drug treatment and thus provides a valid reference point for the assessment of I. ARV may be altered by a pharmacological intervention and thus may give false negative results when used as the basis for expressing I size. (2) Molsidomine is a potent agent for reducing I size.
Animals↗
Comparison of the effects of molsidomine, nitroglycerin and isosorbide dinitrate on experimentally induced coronary artery thrombosis in the dog.
Platelet activation and aggregation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Molsidomine (M), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) have been found to inhibit platelet aggregation in vitro. In the present study, the activity of these compounds was investigated in a model of coronary artery thrombosis in vivo. Dogs were anesthetized, thoracotomized, and their heart was exposed. An electrode was inserted into the left circumflex coronary artery and set to rest on the intima. Electrical stimulation (9 V, 150 microA) lasted for 6 h. Compounds (each in 2 dose levels) were given as an i.v. infusion starting 30 min after the beginning of the stimulation and lasting for the duration of the experiment. All control (saline-treated) animals underwent thrombotic occlusion of the coronary artery as assessed by flow measurement. On the other hand, 2/8 dogs treated with the lower M dose and 4/8 dogs treated with the higher M dose did not have a coronary occlusion. Neither ISDN nor NTG, at both doses, prevented the coronary occlusion. In control animals thrombus wet weight was 74.43 +/- 11.25 mg. M reduced the thrombus weight in a dose-related manner, while ISDN (marginally) and NTG (significantly at the higher dose) increased this parameter. Following the coronary thrombosis, all control animals developed myocardial infarcts as assessed by the tetrazolium technique. Similarly all animals treated with ISDN and with NTG (at both doses) showed infarcts. However, 3/8 M-dogs did not have a myocardial infarction in the lower as well as in the higher dose groups. The hemodynamic changes induced by the 3 compounds were similar in magnitude. Thus M but not ISDN or NTG showed in this in-vivo study antithrombotic and consequently antiischemic activity.
Animals↗
The effect of carbocromene on strophanthin-induced ventricular tachycardia in dogs.
The antiarrhythmic effect of carbocromene (Intensain) was studied in 17 anaesthetized dogs. Ventricular tachycardia was induced by infusion of K-strophanthin (mean dose: 154 mug/kg i.v.). In 25 out of 26 experiments carbocromene (4 mg/kg i.v.) was effective. Ventricular tachycardia was converted to sinus rhythm in 16 experiments, to atrial tachycardia in 6 experiments and to junctional tachycardia in 3 experiments. The favourable effect started 8 to 50 seconds after the injection with lower doses of carbocromene (3 and 2 mg/kg i.v.) in time intervals of 5 minutes resulted in similar positive effects leading after 2 or 3 injections finally to a second phase of drug effect where ventricular tachycardia was strongly modified for about 30 minutes. The results favour the therapeutic use of this drug in patients with arrhythmia especially with arrhythmias caused by digitalis.
Animals↗
Effects of oral carbocromene pretreatment on infarct size following experimental coronary artery occlusion.
This study examines the acute effects of the antianginal drug carbocromene (chromonar) in dogs (20 mg/kg p.o., twice daily for 8 weeks) on mortality, hemodynamics, coronary collateral blood flow, and myocardial infarct size. Following the chronic pretreatment and during acute phase of the experiments, the animals received an intravenous bolus of 4 mg/kg of carbocromene 15 min prior to left anterior descending coronary artery occlusion, and 40 micrograms/kg/min as an infusion during occlusion and reperfusion. Total mortality 2 days postocclusion was 50% in saline control experiments but 20% in carbocromene-treated animals (p less than 0.05). Hemodynamics were not significantly changed during drug administration except for a significant ST-segment elevation during vessel occlusion. Coronary collateral blood flow increased after carbocromene treatment by 30% (p less than 0.05) in the ischemic endocardial region and by 60% (p less than 0.02) in the border zone of the area at risk of infarction. Flow in nonischemic myocardium did not change so that "coronary steal" was not observed. At reperfusion, a flow increase occurred in the ischemic and border zones. Myocardial infarct size was 24% smaller after carbocromene than in control animals (p less than 0.02) when compared to the AR, and 46% smaller (p less than 0.01) in relation to the total left ventricle. We conclude that carbocromene administered orally before acute coronary artery occlusion and intravenously during occlusion and subsequent reperfusion can reduce infarct size by salvage of lateral and subepicardial border zones.
Administration, Oral↗
Effects of catecholamines on cardiovascular actions of molsidomine in anesthetized dogs.
We measured over a 2-h period the effects of molsidomine (0.5 mg/kg i.v.) on pulmonary artery and left ventricular (LV) end-diastolic pressures and internal heart dimension (preload), LV systolic and peripheral blood pressures and total peripheral resistance (afterload), and heart rate, LV dP/dt, stroke volume, and cardiac output (heart performance) of dogs anesthetized with pentobarbital. The hemodynamic effects of molsidomine were influenced by intravenous infusion of 0.10 or 0.20 micrograms/kg/min norepinephrine or 3 or 6 micrograms/kg/min dopamine. Molsidomine decreased preload, stroke volume, and cardiac output for over 2 h and ventricular and peripheral pressures for 45 min. Peripheral resistance, heart rate, and LV dP/dtmax were not altered. Low doses of norepinephrine and dopamine reversed the effect of molsidomine on afterload. However, neither catecholamine influenced the reduced end-diastolic filling pressure after molsidomine. The diminished stroke volume was elevated by either catecholamine so that cardiac output eventually increased. These results indicate that both norepinephrine and dopamine can reverse the certain effects of intravenously administered molsidomine, probably by increasing cardiac contractile force, cardiac output, and peripheral resistance. A combination of molsidomine's preload lowering effects with dopamine's effects on afterload may be useful for the treatment of patients with myocardial failure.
Anesthesia↗
Cardioprotective effects of carbocromen in awake and anesthetized dogs with amitriptyline poisoning.
We studied the effects of the antianginal drug carbocromen (4 mg/kg bolus plus 80 micrograms/kg/min i.v.) on amitriptyline (400 micrograms/kg/min i.v.) toxicity. In anesthetized dogs, amitriptyline increased heart rate, left ventricular (LV) end-diastolic pressure, and the PR and QT intervals, the QRS complex, and the S-T segments of the peripheral electrocardiogram. Blood pressure, LV pressure, and LV dP/dtmax fell considerably. Survival time was 37 +/- 4 min in amitriptyline-treated dogs and 64 +/- 3 min (p less than 0.05) in those receiving amitriptyline plus carbocromen. The amount of amitriptyline consumed until death increased from 14.8 to 25.6 mg/kg (p less than 0.05) with carbocromen. In conscious dogs, the hemodynamic impact of intraatrial amitriptyline was similar to that in anesthetized animals, and changes in stroke volume resembled those of dP/dt. Cardiac output was not altered, and peripheral resistance decreased moderately. Carbocromen prevented most of the typical amitriptyline effects on the heart and circulation. Sustained ventricular arrhythmia occurred at 29 +/- 4 min with amitriptyline infusion but was delayed to 58 +/- 3 min (p less than 0.05) when carbocromen was added. These experiments demonstrate (a) amitriptyline intoxication produced ventricular tachyarrhythmia and cardiac failure if high agent concentrations were achieved; (b) these rhythm disorders were associated with slowing of intraventricular conduction, which could be enhanced by carbocromen; and (c) carbocromen might be an effective therapy for amitriptyline-caused arrhythmia with cardiovascular collapse.
Amitriptyline↗
Protection by carbocromene and molsidomine against arrhythmias occurring during coronary artery occlusion and reperfusion in dogs.
We studied the effects of carbocromene (4 mg/kg plus 40 micrograms/kg/min i.v.) and molsidomine (0.1 mg/kg plus 2 micrograms/kg/min i.v.) on arrhythmias occurring during 90-min occlusion and 30-min reperfusion of the left anterior descending coronary artery in anesthetized dogs. Both drugs reduced the incidence of left ventricular (LV) premature depolarization during ligation (39% after carbocromene and 33% after molsidomine vs. 80% in controls; both p less than 0.05) and tachycardia (44% after carbocromene and 38% after molsidomine vs. 85% in controls; p less than 0.05). During reperfusion, the incidence of LV fibrillation was reduced in the carbocromene- (6 vs. 38% in controls; p less than 0.05) and molsidomine-treated dogs (10 vs. 38% in controls; p less than 0.05). The high incidence of ectopic activity and the ST segment elevation occurring after coronary ligation in control animals were prevented by both drugs. The hemodynamic deterioration after coronary occlusion, i.e., increase in blood pressure, LV systolic and end-diastolic pressures, LV dP/dtmax, and tachycardia observed in controls, was prevented by carbocromene. Molsidomine reduced blood pressure and LV pressure by 18 and 27% (p less than 0.05), respectively, during coronary occlusion. During reperfusion, no hemodynamic alterations occurred in the drug-treated animals. We conclude that carbocromene reduced the electrophysiologic consequences of acute ischemia by hemodynamic and anti-ischemic effects on heart metabolism. Molsidomine protected the jeopardized heart by a similar attenuation of hemodynamic derangement after coronary occlusion and perhaps by influencing prostanoid release from the ischemic myocardium.
Anesthesia↗