Effects of N-Ethoxycarbonyl-3-Mqrpholinosydno-Nimine (Sin-10) on the Cardiovascular System

Abstract

Sydnonimine derivatives, a series of mesoionic compounds, have a peculiar feature in their molecular structure and biological activities. The smooth muscle relaxing action of the compounds has been reported on the rat duodenum and the guinea-pig ileum by Oehme et al. (1) and hypotensive effect by Daeniker and Druey (2).Recently, 3-substituted sydnonimines were newly synthetized (3) and were found to have potent vasodepressor activities (4, 5). Of these compounds, a derivative, whose imino radical at 5 position was acylated with ethoxycarbonyl group to make N-ethoxy carbonyl-3-morpholinosydnonimine (SIN-10), became more stable and was reported to produce a potent and persistent hypotension in anesthetized dogs and rabbits (4, 5).The present study deals with the effects of SIN-10 on cardiovascular system and the analysis of mechanism of action involved in hypotensive effect of the drug in anesthetized dogs and cats. METHODSExperiments were carried out using adult mongrel dogs weighing 5.9-11.5 kg and cats weighing 2.0-4.3 kg of either sex anesthetized with pentobarbital sodium (30 mg/kg, i.v.).Respiration was recorded with a pressure transducer connected with tracheal cannula . Blood pressure was measured from the femoral or common carotid artery by means of an electronic manometer. An intracorporeal probe was attached to each of the common carotid, femoral, renal and pulmonary artery, and blood flow was measured with a square wave electromagnetic flowmeter. (Nihon Kohden MF-5).Coronary circulation and myocardial metabolism were investigated using isolated perfused dog heart. The heart of a dog was isolated and a glass cannula was inserted into each of the aorta and pulmonary artery. With another dog as a donor , its common carotid artery was connected with the aortic cannula of the isolated heart . The coronary venous blood was allowed to flow out through the pulmonary artery cannula into a blood reservoir and returned to the femoral vein of the donor dog . Heparin (10 mg/kg) was used to prevent blood coagulation. Drugs were infected into coronary a .rterv_

Hypotensive Action of N-Ethoxycarbonyl-3-Morpholinosydnonimine, Sin-10

“…In isolated, perfused dog hearts, Takenaka et al (13) observed that intracoronary SIN 10 1 mg did not exert any appreciable changes in perfusion pressure, coronary blood flow, myocardial contractile force, heart rate, myocardial oxygen consumption and redox potentials. It can be assumed, therefore, that the fall in peak LV dp/dt during the hypo tension by SIN-10 might be caused from a fall in aortic pressure and stroke volume.…”

Effect of molsidomine on the coronary circulation in anesthetized dogs

“…The antianginal effects of molsidomine probably are due to a reduction in external cardiac work resulting from diminished preload and -to a lesser degree -afterload. More previously, Takenaka et al (16) have shown that molsidomine did reduce mean coronary flow in isolated hearts with changing perfusion pressures. The fall in coronary flow after molsidomine was not accompanied by changes in coronary sinus blood oxygen content so that the flow reduction most likely reflects the consequences of reduced myocardial oxygen demand.…”

Molsidomine – an Effective Antianginal Drug

“…The hemodynamic response to molsidomine in patients with un complicated myocardial infarction is charac terized by a marked reduction in right atrial and pulmonary capillary wedge pressures [ 10], which suggests that there is probably a concomitant reduction in ventricular dia stolic volumes. Indeed, a number of experi mental [16,20,21] and clinical studies [5,7,9,22] have suggested a pronounced and sus tained venodilating activity of molsidomine, which is associated with decreased ventricu lar filling pressures as well as decreased dia stolic and systolic ventricular dimensions. Thus, it is probable that molsidomine causes more reduction of left ventricular wall ten sion and further decrease in myocardial oxy gen requirements than can be explained by the fall in arterial pressure alone.…”