Selective Antagonism of the ETA Receptor, but Not the ETB Receptor, Is Protective Against Ischemic Acute Renal Failure in Rats

Abstract

We investigated the effects of ABT-627, a selective ETA-receptor antagonist, and A-192621, a selective ETB-receptor antagonist, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min, 2 weeks after the contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion and thereafter tended to recover gradually. ABT-627 (1 mg/kg, i.v.) administration before ischemia markedly attenuated the renal dysfunction induced by the ischemia/reperfusion, whereas A-192621 (3 mg/kg, i.v.) pretreatment was without effect. Histopathological examination of the kidney of untreated ARF rats revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion. Histologically evident damage was improved by pretreatment with ABT-627, but not with A-192621. Daily oral administration of ABT-627 (10 mg/kg per day), but not A-192621 (30 mg/kg per day), given after the ischemia/reperfusion period also exerted protective effects. These findings clearly indicate that endothelin, acting via the ETA receptor, participates in the pathogenesis of ischemic ARF. Thus, selective ETA-receptor antagonism may be useful in the treatment of human ischemic ARF, whereas selective blockade of the ETB receptor will probably be ineffective.

Sulfenic Acid Modification of Endothelin B Receptor is Responsible for the Benefit of a Nonsteroidal Mineralocorticoid Receptor Antagonist in Renal Ischemia

“…No changes were observed for the mean arterial pressure among the groups (Supplemental Figure 5B). As previously reported, 23 ET B antagonism had no effect on renal IR severity (similar levels of creatinine, renal blood flow, and renal injury in the IR+ BQ-788 group when compared with untreated IR rats) (Figure 3, A-C). Again, MR antagonism with BR-4628 was associated with protection against IR ( Figure 3, A-C).…”

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

“…In the past, several compounds that aim at restoring the endothelin-1/nitric oxide imbalance have been successfully applied to reduce microcirculatory disturbances and liver tissue damage. 18,19,54,70,71 Atrasentan is effective in reducing postischemic microcirculatory disturbances in models of renal, 72 cardiac, 73 and cerebral 74 I/R and we here show that, in combination with the nitric oxide donor L-arginine, it provides maximal improvement of the microcirculation after hepatic I/R. Second, agents that target the HIF-1␣ pathway, including 17-DMAG, are gaining increased attention as novel anticancer drugs.…”

Tempol Protects against Ischemic Acute Renal Failure by Inhibiting Renal Noradrenaline Overflow and Endothelin-1 Overproduction

“…Both selective endothelin ET A and nonselective endothelin ET A /ET B receptor antagonists have been indicated to improve the ischemia/reperfusion-induced renal dysfunction. 17,34,35) Thus, the up-regulation of renal ET-1 production and its ET A receptor-mediated action are likely to contribute to the pathogenesis of ischemic ARF. In the present study, we investigated the effect of tempol on ET-1 overproduction in the kidney subjected to ischemia/reperfusion.…”

“…[4][5][6] In addition, we examined the effect of tempol on renal endothelin-1 (ET-1) overproduction, which is a possible mediator of the pathogenesis of the postischaemic ARF. [15][16][17] …”