phosphoramidon and Ischemia

Ischemia followed by reperfusion has a number of clinically significant consequences. A number of pathophysiological processes appear to be involved in ischemia/reperfusion (I/R) injury. The mitogen activated protein kinases (MAPK) are integral components of the parallel MAP kinase cascades activated in response to a variety of cellular stress inducing ischemia/ATP depletion and inflammatory cytokines. Many studies suggest that members of the MAP kinase family in particular Jun N-terminal kinase (JNK) are activated in kidney following ischemia/reperfusion of this tissue. The present study underlines the therapeutic potential of the combination of N-acetyl cysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor and phosphoramidon (P), an endothelin-1 converting enzyme inhibitor in ameliorating the MAPK induced damage during renal ischemia/reperfusion injury. Our previous results showed that 90 min of ischemia followed by reperfusion caused very severe injury and that the untreated animals had 100% mortality after the 3rd day whereas there was improved renal function and 100% survival of animals in the three drug combination treatment group. The present study, mainly on tissue sections, further supports the protection provided by the triple drug therapy. A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult. Pretreatment with a combination of N-acetyl cysteine, sodium nitroprusside, and phosphoramidon completely inhibits all three classes of MAPK and ameliorates AP-1 whereas individual or a combination of any two drugs is not as effective.

Topics: Acetylcysteine; Animals; Disease Models, Animal; Glycopeptides; Immunohistochemistry; Ischemia; Ischemic Preconditioning; JNK Mitogen-Activated Protein Kinases; Male; Mitogen-Activated Protein Kinases; Nitroprusside; Phosphorylation; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Survival Rate; Time Factors; Transcription Factor AP-1

Effects of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl- 1-1-phenyl- 1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt), a novel endothelin converting enzyme (ECE) inhibitor, on ischemic acute renal failure (ARF) in rats were examined in comparison with those of phosphoramidon, a conventional ECE inhibitor. ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Intravenous bolus injection of SM-19712 (3, 10, 30 mg/kg) prior to the occlusion attenuated dose-dependently the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were dose-dependently attenuated by SM-19712. Protective effects of phosphoramidon (10 mg/kg) on ARF-induced functional and tissue damages were less potent than that of the same dose of SM-19712. Endothelin-1 (ET-1) content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after reperfusion, and this elevation was completely suppressed by the higher dose of SM-19712. Our findings support the view that renal ET-1 plays an important role in the development of ischemia/reperfusion-induced renal injury. SM-19712 may be useful in the treatment of ischemic ARF.

Topics: Acute Kidney Injury; Animals; Aspartic Acid Endopeptidases; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Inhibitors; Glycopeptides; Ischemia; Kidney Function Tests; Male; Metalloendopeptidases; Protective Agents; Rats; Rats, Sprague-Dawley; Sulfonamides; Sulfonylurea Compounds

In this study, the effects of BQ123 (an ET(A) receptor antagonist), bosentan (a nonselective ET(A)-ET(B) antagonist), and phosphoramidon (an endothelin converting enzyme inhibitor) were investigated on intestinal mucosal lesion formation and changes in tissue PGE2 and LTC4 levels due to intestinal ischemia-reperfusion (I/R) injury in rats. Following 30 min of ischemia, the substances were given via the inferior caval vein, and 10 min later the intestine was subjected to reperfusion for 30 min. The intestinal specimens were evaluated both microscopically and the tissue PGE2 and LTC4 levels were obtained for each group. The histopathologic examination revealed a significant reduction in tissue injury in both BQ123 and phosphoramidon pretreated groups compared with the control group. Bosentan, on the contrary, did not decrease the injury. The pharmacologic examination revealed a significant reduction of PGE2-like activity in both BQ123 and phosphoramidon pretreated groups, compared with the control group, while LTC4-like activity remained unchanged except for an increase in the bosentan pretreated group.

Topics: Animals; Bosentan; Dinoprostone; Endothelin Receptor Antagonists; Endothelins; Female; Glycopeptides; Histocytochemistry; Intestinal Mucosa; Intestines; Ischemia; Leukotriene C4; Male; Peptides, Cyclic; Rats; Reperfusion Injury; Sulfonamides

Recently increased production of endothelin-1 has been implicated in the pathogenesis of gastric ischemia-reperfusion injury. We have investigated the effects of endothelin converting enzyme inhibition on local gastric ischemia-reperfusion injury in rats by using two metalloprotease inhibitors, phosphoramidon and thiorphan. In presence of exogenous 0.15M HCI intragastrically, local ischemia was induced by the clamping of left gastric artery for 15 min and reperfusion was done for 30 min. In separate group of rats, phosphoramidon (10-60 mg/kg) or thiorphan (60 mg/kg) were given as i.v. bolus injection immediately before the induction of ischemia. Phosphoramidon dose dependently attenuated the macroscopic and microscopic mucosal injuries while thiorphan did not. These results indicate that phosphoramidon-sensitive endothelin converting enzyme activity is highly present in stomach and phosphoramidon, by inhibiting the conversion of big endothelin-1 to endothelin-1 attenuated the gastric mucosal damage in this model.

Topics: Animals; Aspartic Acid Endopeptidases; Endothelin-Converting Enzymes; Enzyme Inhibitors; Gastric Mucosa; Glycopeptides; Ischemia; Male; Metalloendopeptidases; Rats; Rats, Wistar; Reperfusion Injury; Thiorphan

Infusion (0.46 mumol/kg/min) of the endothelin (ET)-converting-enzyme inhibitor, phosphoramidon (P), protected function and structure after 30 min renal ischemia in rats more than treatment (5 mumol/kg/min) with the ETA receptor antagonist, BMS-182874 (B). The glomerular filtration rate (GFR; 0.7 +/- 0.12 ml/min) and renal plasma flow (RPF) decreased approximately 40% at 2 h reflow versus controls (C: 1.2 +/- 0.12). B weakly protected the GFR (0.8 +/- 0.07 ml/min); P restored it (1.1 +/- 0.05). Both compounds reduced tubular injury at 2 h reflow; P ameliorated glomerular changes. At 24 h the GFR (0.6 +/- 0.06 ml/min) and RPF decreased 67% versus C (1.8 +/- 0.08). B did not protect the GFR and RPF. P partially protected the GFR (0.9 +/- 0.07 ml/min) but not RPF, and reduced tubular injury. The results suggest that both ETA and non-ETA receptors mediate ET-induced changes in ischemic renal failure.

Topics: Animals; Blood Pressure; Creatinine; Dansyl Compounds; Endothelin Receptor Antagonists; Glomerular Filtration Rate; Glycopeptides; Iodine Radioisotopes; Ischemia; Kidney; Male; Rats; Rats, Sprague-Dawley; Renal Plasma Flow; Time Factors

1. Chronic hypoxic rats are always polycythaemic. It is possible that an increase in packed cell volume may enhance erythrocyte trapping with a consequent increase in renal damage after renal ischaemia. These experiments were designed to assess renal functional changes after renal arterial occlusion in chronic hypoxic rats. 2. Chronic hypoxic rats were prepared by exposure (15h/day) to an altitude chamber (5486m) for 4 weeks. 3. After 45 min of left renal arterial occlusion, there were significant decreases in the excretion of potassium, p-aminohippurate and inulin and in the p-aminohippurate extraction ratio in 12 sea level ischaemic insulted kidneys. In 12 chronic hypoxic rats, the same parameters were changed after left renal ischaemia but only the p-aminohippurate ratio was significantly altered. 4. Administrations of 1 or 5 mg/kg phosphoramidon did not cause any significant improvement in the measured renal parameters in both kidneys and in both groups of rats after ischaemia. 5. In the second experiment, the rats were challenged by rapid infusion of 10 ml of saline intravenously, and urine was collected for 90 min from each ureter. Four hours after left renal arterial occlusion, the insulted kidney showed increased water and sodium excretion in both sea level and chronic hypoxic rats. However, 24 h after left renal ischaemia, the responses of sea level and chronic hypoxic rats were different. Urinary excretion was significantly reduced in sea level rats, but was almost normal in chronic hypoxic rats. 6. This report suggests that some beneficial factors after chronic hypoxia might play important roles in reducing the damage after renal ischaemia.

Topics: Acute Kidney Injury; Animals; Body Weight; Chronic Disease; Glycopeptides; Hematocrit; Hypoxia; Insulin; Ischemia; Kidney; Male; p-Aminohippuric Acid; Potassium; Rats; Rats, Sprague-Dawley

Endothelin (ET)-1 is a potent vasoactive peptide elaborated by the vascular endothelial cells. In the present study we examined the effects of ischemia-hypoxia (I/H) on ET-1 release from isolated perfused guinea pig lungs and heart. Guinea pig lungs subjected to 15 min I/H followed by reperfusion and reventilation significantly (P less than .05) augmented ET-1 release from 14.1 +/- 2.7 to 30.4 +/- 5.6, 27.3 +/- 4.0 and 28.0 +/- 5.0 pg/g of dry weight of lung at 15, 30 and 45 min after I/H, respectively. Pretreatment of guinea pigs with phosphoramidon (10 mg/kg i.v.), an ET converting enzyme inhibitor, 10 min before the removal of lungs abrogated the I/H-induced increases in ET-1 release without affecting the base-line values of ET-1. Phosphoramidon also attenuated the elevations in pulmonary insufflation pressure (PIP) produced by I/H. Moreover, infusion of big ET-1 (BET-1; 30 micrograms/over 15 min) into isolated perfused guinea pig lungs enhanced PIP that was abolished by phosphoramidon. Isolated guinea pig hearts subjected to 15 or 30 min of global ischemia exhibited no disturbances in ET-1 release or mechanical activity. In addition, the increases in perfusion pressure elicited by BET-1 infusion (12 micrograms/over 30 min) into isolated guinea pig hearts was unaffected by phosphoramidon. In a separate study in anesthetized guinea pigs, phosphoramidon significantly attenuated the increases in blood pressure and PIP elicited by BET-1 (10 micrograms/kg i.v.); the pressor and PIP responses to ET-1 (4 micrograms/kg i.v.) were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Bacterial Agents; Blood Pressure; Endothelins; Glycopeptides; Guinea Pigs; Heart; Hypoxia; Ischemia; Lung; Male; Myocardium