Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat.

Abstract

Studies were designed to examine the effect of a selective endothelinA (ETA) receptor antagonist, BQ123, on severe postischemic acute renal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in uninephectomized, chronically instrumented rats by 45-min renal artery occlusion. BQ123 (0.1 mg/kg. min) or vehicle was infused intravenously for 3 h on the day after ischemia. Measurements before infusion (24 h control) showed a 98% decrease in glomerular filtration rate (GFR), increase in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicletreated rats died in 4 d because of continuous deterioration of renal function, resulting in an increase of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ123 significantly improved survival rate (75%) by markedly improving tubular reabsorption of Na' and moderately increasing GFR and K+ excretion. Plasma K+ returned to basal levels by the 5th d after ischemia. Improved tubular function was followed by gradual recovery in GFR and urinary concentrating mechanism.Additional data from renal clearance studies in rats with moderate ARF (30-min ischemia) and in normal rats with intact kidneys showed that ETA receptor blockade increases Nan reabsorption and has no effect on renal hemodynamics. These results indicate that in the rat, the ETA receptor subtype mediates tubular epithelial function, and it plays a significant role in the pathogenesis of ischemia-induced ARF. Treatment with the selective ETA receptor antagonist reverses deteriorating tubular function in established ARF, an effect of possible therapeutic significance. (J. Clin. Invest. 1994. 93:900-906.) Key words: ischemia * moderate and severe acute renal failure * endothelinA receptor * BQ123

Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats

“…Recent studies indicated that the ET-1/ET A receptor system may be an important mediator in the pathogenesis of postischemic acute renal failure, based on findings that ET-1 mRNA expression is markedly enhanced in the postischemic kidney 32 and that a selective ET A receptor antagonist prevents postischemic renal damage, such as decreases in renal blood flow and glomerular filtration rate, and tubular dysfunction. 11,12 Further investigations are required to clarify whether the ABT-627-induced improvement in vascular hypertrophy and renal damage in DOCA-salt hypertension is independent of its antihypertensive activity.…”

“…8,9 We noted the ameliorating effect of FR 139317, an ET A -selective receptor antagonist, on decreased renal function of DOCAsalt hypertensive rats. 10 On the other hand, both ET A -selective and nonselective ET A /ET B receptor antagonists have been reported to prevent various cardiovascular diseases, such as acute ischemic renal failure [11][12][13] and chronic heart failure, 14,15 in animal models. Thus, it remains obscure as to whether blockade of the ET B receptor is beneficial for the treatment of subjects with cardiovascular diseases.…”

Molecular Pharmacology and Pathophysiological Significance of Endothelin

“…To date, the results indicate that ischemia-induced ARF is attenuated by the infusion of anti-endothelin antibody or a receptor antagonist during ischemia or the early phase of reperfusion. In a recent study, however, BQ-123 infused 24 hr after the onset of ischemia was shown to effectively reverse renal damage in rats with ARF, clearly indicating that an ETA antagonist is efficacious even in the treatment of established ARF (182). Furthermore, since the negative actions of endothelin-1 on renal function in ARF are more marked during the maintenance phase than the initial phase after ischemia, endothelin receptor antagonists appear to be more effective in reversing than in preventing renal impairment (183,184).…”

Long-term Sequelae from Acute Kidney Injury: Potential Mechanisms for the Observed Poor Renal Outcomes

“…At least five studies have shown that ET-1 receptor blockade either conferred no functional protection, or worsened post-ischemic AKI [36][37][38][39][40]. In a more recent ischemia-reperfusion model in mice undergoing unilateral ischemia without contralateral nephrectomy, an increase in intrarenal ET-1 production was observed, along with increased expression of the ET A receptor and evidence of ET-1 gene activation alongside progressive histological changes and a 40% loss of renal mass [41].…”