Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity

Abstract

Endothelin (Et) has been implicated in cyclosporine A (CsA) nephrotoxicity. We have previously shown that CsA treatment in rats results in up-regulation of Et receptors specifically within the kidney. The role of Et in vivo CsA nephrotoxicity was therefore studied further with a new competitive antagonist, BQ-123, specific for EtA receptors (EtRA). Systemic administration of CsA in Munich-Wistar rats resulted in marked glomerular hypoperfusion and hypofiltration, with RPF in left and right kidneys falling by some 40% to 1.60 ± 0.25 and 1.73 ± 0.38 ml/min and GFR decreasing by some 20% to 0.61 ± 0.05 and 0.67 ± 0.11 ml/min, respectively. Selective infusion of EtRA into the left renal artery following systemic CsA treatment had no effect on this hemodynamic pattern (RPF 1.58 ± 0.29 and 1.92 ± 0.34 ml/min and GFR 0.60 ± 0.09 and 0.70 ± 0.08 ml/min in left and right kidneys, respectively, P = NS vs. CsA period). By contrast, intrarenal infusion of EtRA prior to systemic administration of CsA resulted in a strikingly different pattern of renal hemodynamics. Thus, EtRA pretreatment in the left kidney protected against glomerular dysfunction following CsA: RPF was maintained, 3.23 ± 0.28 ml/min versus 2.96 ± 0.31 (P = NS EtRA vs. EtRA + CsA), as was the GFR, 1.04 ± 0.16 ml/min versus 1.12 ± 0.09 (P = NS). However, the contralateral right kidneys of these rats, not pretreated with EtRA, showed no protective effect: RPF decreased from 3.15 ± 0.34 ml/min to 2.39 ± 0.19 and GFR from 1.04 ± 0.10 ml/min to 0.85 ± 0.07 (P < 0.05). Infusion of saline instead of EtRA was without protective effect, and EtRA itself did not alter systemic or renal hemodynamics. Systemic EtRA in a dose comparable to the intrarenal infusion given before CsA treatment was not protective: RPF fell from 3.36 ± 0.23 ml/min to 1.96 ± 0.33 (P < 0.005), and GFR decreased from 0.94 ± 0.06 ml/min to 0.67 ± 0.12 (P < 0.05). These studies support that local Et activation is pivotal in acute CsA nephrotoxicity. Local pretreatment with a specific EtA antagonist can largely prevent this CsA-induced glomerular hypofiltration and hypoperfusion.