S3226, a novel NHE3 inhibitor, attenuates ischemia-induced acute renal failure in rats

Background. Acute renal failure (ARF) remains a major problem in clinical n ephrology characterized by sudden loss of the kidney function due to ischem ia, trauma, and/or nephrotoxic drugs. The current therapy of ARF is symptom atic with mortality rates exceeding 50%. The aim of this study was to inves tigate the effects of an intravenous infusion of S3226 (3-[2-(3-guanidino-2 -methyl-3-oxopropenyl)-5-methyl-phenyl]- N-isopropylidene-2-methyl-acrylami de dihydrochloride), a selective Na+/H+ exchange subtype 3 (NHE3) blocker, in ischemia-induced ARF in rats. In a second series of experiments cytosoli c pH (pHi) changes in the kidney during ARF were continuously measured by m eans of nuclear magnetic resonance spectroscopy (MRS). Methods. ARF was induced by bilateral occlusion of renal arteries for 40 mi nutes in three groups of anaesthetized Wistar rats. Control rats (N = 12) w ere infused with saline (6.25 mL/kg over 30 min) before occlusion and the c ompound groups (each N = 12) were infused with S3226 at a dose of 20 mg/kg over 30 minutes either before initiation of ischemia or immediately after r elease of clamps. Plasma creatinine (P-Cr), creatinine clearance (C-Cr), ur ine volume, sodium, and potassium excretion were determined up to seven day s after release of clamps. In the second series of experiments in anaesthet ized rats the left kidney was exposed by flank incision and fixed in a non- magnetic device. An inflatable cuff was positioned around the pedicle to in duce ischemia without removing animals from the magnet. A double-tuned H-1- P-31 home-built surface coil was placed above the exposed kidney for the de tection of pHi. Results. At day 1 after ischemia C-Cr in the control group was significantl y lower as compared to S3226-treated animals (control 0.30 +/- 0.05 vs. bef ore 0.90 +/- 0.26 and reperfusion 0.83 +/- 10.15 mL/min/kg, respectively). P-Cr increased from 18 +/- 0.1 mu mol/L before occlusion to 245 +/- 7 mu mo l/L in the control. The increase in P-Cr was significantly lower in the S32 26 treated groups on days 1, 2, and 3 post-infusion. Fractional sodium excr etion decreased significantly from 8.17% in the control to 1.42% and 1.88% in the treated groups. Renal pHi was significantly decreased by 0.15 units versus control during reperfusion. Histological examination of the kidneys on day 7 revealed pronounced reduction of tubular necrosis, dilatation, pro tein casts and cellular infiltration. Conclusions. These results demonstrate that an intravenous administration o f S3226 acutely improves GFR and kidney function and structure in both trea ted groups. In addition, in a separate set of studies S3226 significantly d ecreased post-occlusion renal pHi values. Thus, the inhibition of NHE3 with S3226 may be beneficial in treatment of ischemic ARF.