phosphoramidon and Myocardial-Infarction

Topics: Animals; Aspartic Acid Endopeptidases; Benzazepines; Benzofurans; Drug Design; Endothelin-Converting Enzymes; Glycopeptides; Heart Failure; Humans; Hypertension; Metalloendopeptidases; Mice; Mice, Knockout; Myocardial Infarction; Organophosphonates; Phenylalanine; Tetracyclines; Tetrazoles

To investigate the protective effects of phosphoramidon on the experimental myocardial injury in rats.. Thirty-six Wistar rats were randomly divided into 3 groups of 12: the control group (Control), the isoproterenol group (ISO) and the protection group (PA). All rats were anesthetized after 24 hours and the blood was sampled from the carotid artery. The activities of creatine phosphokinase (CPK) and lactic dehydrogenase (LDH) in the serum and the contents of ET in the plasma were detected; then the hearts were isolated and the total layers of apical myocardium were solidified, embedded, sectioned, stained with HE and graded pathologically.. The serum activities of CPK and LDH, and the plasmatic content of ET in the ISO group were significantly higher than those in the control group and PA group (P < 0.05); the degree of myocardial pathological damage in the ISO group was significantly higher than that in the control group (P < 0.01), while the degree of damage in the PA group was lower than that in the ISO group (P < 0.05).. Endothelin is involved in the pathologic process of experimental myocardial injury in rats. Phosphoramidon can protect the myocardial injury in rats and its mechanism may be to inhibit ECE and reduce the endothelins production.

Topics: Animals; Creatine Kinase; Endothelins; Female; Glycopeptides; L-Lactate Dehydrogenase; Male; Metalloendopeptidases; Myocardial Infarction; Myocardium; Random Allocation; Rats; Rats, Wistar

We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt). SM-19712 inhibited endothelin converting enzyme (ECE) solubilized from rat lung microsomes with an IC50 value of 42 nM and, at 10 - 100 microM, had no effect on other metalloproteases such as neutral endopeptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 microM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 microM. In anesthetized rats, either intravenous (1-30 mg/kg) or oral (10-30 mg/kg) administration of SM-19712 dose-dependently suppressed the pressor responses induced by big ET-1. In acute myocardial infarction of rabbits subjected to coronary occlusion and reperfusion, SM-19712 reduced the infarct size, the increase in serum concentration of ET-1 and the serum activity of creatinine phosphokinase. The present study demonstrates that SM-19712 is a structurally novel, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a valuable new tool for elucidating the pathophysiological role of ECE.

Topics: Acute Disease; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Lung; Male; Metalloendopeptidases; Myocardial Infarction; Pressoreceptors; Rabbits; Rats; Rats, Sprague-Dawley; Substrate Specificity; Sulfonamides; Sulfonylurea Compounds; Swine

The aim of this work was to investigate the influence of endothelin on myocardial ischemia and reperfusion in anaesthetized dogs. Animals were submitted to left thoracotomy and 120 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Arterial blood pressure and electrocardiogram (ECG) were recorded in order to analyze heart rate (HR)-pressure product and production of ectopic beats. Infarcted areas were identified by a macroscopic staining method and infarct size was expressed as percentage of risk zone. To inhibit the effects of endothelin in a group of animals, we administered intravenously an endothelin synthesis inhibitor (phosphoramidon) and in another group, an endothelin-1 A receptor blocker (BQ-123). Phosphoramidon decreased the HR-pressure product during reperfusion period, and both, phosphoramidon and BQ-123 decreased infarct size by 40% and the number of ventricular ectopic beats by 88% and 68%, respectively, as compared to the saline treated dogs. In conclusion, endothelin seems to play a deleterious role on the myocardium submitted to ischemia and reperfusion.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Disease; Dogs; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glycopeptides; Injections, Intravenous; Myocardial Infarction; Myocardial Reperfusion; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Ventricular Fibrillation; Ventricular Premature Complexes

Previous results from our laboratory have suggested that morphine can attenuate neutrophil activation in patients with acute myocardial infarction. To elucidate if morphine preconditioning (PC) has the same effects via activation of neutrophil endopeptidase 24.11 (NEP), we measured serum levels of intercellular adhesion molecule-1 (ICAM-1), gp100MEL14 and NEP in adult Wistar rats subjected to ten different protocols (n = 10 for each) at baseline, immediately after and 2 h after morphine PC. All groups were subjected to 30 min of occlusion and 2 h of reperfusion. Similarly, morphine-induced PC was elicited by 3-min drug infusions (100 micrograms/kg) interspersed with 5-min drug-free periods before the prolonged 30-min occlusion. Infarct size (IS), as a percentage of the area at risk (AAR), was determined by triphenyltetrazolium staining. Pretreatment with morphine increased NEP activities (9.86 +/- 1.98 vs. 5.12 +/- 1.10 nmol/mg protein in control group; p < 0.001). Naloxone (mu-opioid receptor antagonist) (4.82 +/- 1.02 nmol/mg protein) and phosphoramidon (NEP inhibitor) (4.66 +/- 1.00 nmol/mg protein) inhibited morphine-activated NEP, whereas glibenclamide (ATP-sensitive potassium channel antagonist) and chelerythrine (protein kinase C inhibitor) had no effects. The ICAM-1 and gp100MEL14 of the third sampling were lowest for those with morphine PC (280 +/- 30 ng/ml and 2.2 +/- 0.7 micrograms/ml; p < 0.001), but naloxone (372 +/- 38 ng/ml and 3.8 +/- 0.9 micrograms/ml) and phosphoramidon (382 +/- 40 ng/ml and 4.2 +/- 1.1 micrograms/ml) abolished the above phenomenon. IS/AAR were definitely lowest for those with morphine PC (24 +/- 7%; p < 0.05). Morphine preconditioning increases NEP activities to attenuate shedding of gp100MEL14 and to ICAM-1 and, thus, provides myocardial protection.

Topics: Alkaloids; Animals; Benzophenanthridines; Glyburide; Glycopeptides; Hypoglycemic Agents; Intercellular Adhesion Molecule-1; Ischemic Preconditioning, Myocardial; L-Selectin; Male; Morphine; Myocardial Infarction; Naloxone; Narcotic Antagonists; Narcotics; Neprilysin; Neutrophil Activation; Neutrophils; Phenanthridines; Potassium Channel Blockers; Protease Inhibitors; Protein Kinase C; Random Allocation; Rats; Rats, Wistar