PREVENTION OF ACUTE CYCLOSPORINE NEPHROTOXICITY BY VERAPAMIL AND ATRIAL-NATRIURETIC-FACTOR IN THE RAT

Nephrotoxicity is the most common and important side-effect of cyclosp orin (CsA) therapy. CsA alters renal haemodynamics with a reduction in renal blood flow (RBF) and glomerular filtration rate (GFR) and a sig nificant increase in renal vascular resistances (RVR). The present exp erimental study investigates whether verapamil or atrial natriuretic f actor (ANF) are able to prevent the nephrotoxicity of CsA. All studies were conducted in an in-situ autoperfused rat kidney model which allo ws continuous measurement of renal blood flow without dissection of th e renal artery. CsA as a 40 mg/kg bolus dose significantly decreased R BF (from 2.15 +/- 0.1 and 2.19 +/- 0.1 before CsA, to 1.29 +/- 0.16 ml /min/100 g BW, 60 min after CsA administration) (P<0.05), and GFR (fro m 0.14 +/- 0.1 and 0.13 +/- 0.01 before CsA to 0.08 +/- 0.01 ml/min/10 0 g BW, 60 min after CsA administration) (P < 0.05). CsA significantly increased RVR (from 9.5 +/- 0.73 and 9.8 +/- 0.78 before CsA, to 16.7 +/- 2.9 mmHg x min/ml 60 min after CsA administration) (P < 0.05). Ve rapamil pretreatment (as continuous intrarenal infusion at the rate of 1.25 mug/kg/min) attenuated the fall in GFR (from 0.16 +/- 0.01 and 0 .19 +/- 0.03 ml/min/100 g before CsA to 0.20 +/- 0.05 ml/min/100 g BW, 60 min after CsA administration) (NS) and in RBF (from 2.42 +/- 0.2 a nd 2.6 +/- 0.22 ml/min/100 g before CsA to 1.79 +/- 0.17 ml/min/100 g BW, 60 min after CsA administration (P<0.05). Pretreatment with ANF (a s continuous intrarenal infusion at the rate of 2.5 mug/kg/min) protec ted GFR (from 0.11 +/- 0.02 and 0.18 +/- 0.03 ml/min/100 g before CsA, to 0.11 +/- 0.03 ml/min/100 g BW, 60 min after CsA administration) (N S) and RVR (from 9.53 +/- 0.6 and 8.95 +/- 0.74 mmHg x min/ml before C sA to 11.93 +/- 1.19 mmHg x min/ml, 60 min after CsA administration)(N S) and attenuated the fall in RBF (from 2.17 +/- 0.11 and 2,2 +/- 0.14 ml/min/100 g before CsAto 1.56 +/- 0.25 ml/min/100 g BW 60 min after CsA administration)(P<0.05) when compared with initial values. These s tudies suggest that verapamil and ANF can prevent CsA-induced renal to xicity. Further studies should evaluate their usefulness in clinical p ractice.