Protective Effect of SM-19712, a Novel and Potent Endothelin Converting Enzyme Inhibitor, on Ischemic Acute Renal Failure in Rats

Abstract

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.

RETRACTION: Opposite Effects of Pre- and Postischemic Treatments with Nitric Oxide Donor on Ischemia/Reperfusion-Induced Renal Injury

“…against ischemia/reperfusion-induced renal dysfunction and tissue injury, at least in part, through the suppression of endothelin-1 production (Kurata et al, 2004). The overproduction of this peptide in the postischemic kidney is known to be one of the major causal factors of this disease (Wilhelm et al, 1999;Matsumura et al, 2000). In addition, we noted that preischemic treatment with FK409 suppressed the enhancement of renal sympathetic nerve activity in the postischemic kidney (H. Kurata, M. Takaoka, and Y. Matsumura, unpublished data), which is closely related to the renal dysfunction in the postischemic kidney (Fujii et al, 2003).…”

Protective effect of 17β-estradiol on ischemic acute renal failure through the PI3K/Akt/eNOS pathway

“…This restoration of blood flow seems likely to be due to the E 2 -b-induced eNOS activation and NO production and may be at least partly contributive to the renoprotective effect of E 2 -b. Moreover, we have noted that both exogenous and endogenous NO have protective effects against I/R-induced renal dysfunction and tissue injury, through the suppression of endothelin-1 overproduction, 26 which is known to be one of the major causal factors of this disease, 27,28 and that the improvement of ischemic ARF by E 2 -b treatment was followed by the suppression of endothelin-1 overproduction in the post-ischemic kidney. 29 Most recently, we demonstrated that the pre-ischemic treatment with exogenous NO markedly suppressed the renal O 2 À production augmented by I/R, following the attenuation of neutrophil infiltration.…”

Attenuation of Ischemia/Reperfusion-Induced Renal Injury in Mice Deficient in Na+/Ca2+Exchanger

“…Acute Renal Failure and Na ؉ /Ca 2؉ Exchanger dysfunction and tissue injury . In addition, an ET-converting enzyme inhibitor, phosphoramidon (Matsumura et al, 1990a), was found to overcome ischemia/reperfusion-induced renal injury (Vemulapalli et al, 1993;Matsumura et al, 2000). Taken together, it seems likely that the up-regulation of renal ET-1 production and ET A receptormediated actions are responsible for the pathogenesis of ischemic ARF.…”

“…It has been demonstrated that ET-1 content (Shibouta et al, 1990;Matsumura et al, 2000) and ET-1 mRNA expression (Firth and Ratcliffe, 1992;Wilhelm et al, 1999) are elevated in renal tissues after ischemia/reperfusion. Our previous study has shown that daily oral administration of the ET A -selective antagonist ABT-627, but not the ET B -selective antagonist A-192621, had a beneficial effect on ischemia/reperfusion-induced renal 8.…”

“…A potential contribution of ET-1 to the pathology of ischemic ARF has been suggested based on findings indicating that renal ET-1 mRNA expression, ET-1 content, and its affinity for ET receptors are elevated in the postischemic kidney (Firth and Ratcliffe, 1992;Wilhelm et al, 1999). ET Aselective or nonselective ET A /ET B -receptor antagonists and ET-converting enzyme inhibitors are known to attenuate the ischemia/reperfusion-induced impairment of renal function (Gellai et al, 1995;Kuro et al, 2000;Matsumura et al, 2000). Taken together, it seems likely that renal ET-1 overproduction and its ET A receptor-mediated actions are closely related to the pathogenesis of ischemic ARF.…”