S3226, a novel NHE3 inhibitor, attenuates ischemia-induced acute renal failure in rats.
BACKGROUND
Acute renal failure (ARF) remains a major problem in clinical nephrology characterized by sudden loss of the kidney function due to ischemia, trauma, and/or nephrotoxic drugs. The current therapy of ARF is symptomatic with mortality rates exceeding 50%. The aim of this study was to investigate the effects of an intravenous infusion of S3226 (3-[2-(3-guanidino-2-methyl-3-oxopropenyl)-5-methyl-phenyl]-N-isopropylidene-2-methyl-acrylamide dihydrochloride), a selective Na+/H+ exchange subtype 3 (NHE3) blocker, in ischemia-induced ARF in rats. In a second series of experiments cytosolic pH (pHi) changes in the kidney during ARF were continuously measured by means of nuclear magnetic resonance spectroscopy (MRS).


METHODS
ARF was induced by bilateral occlusion of renal arteries for 40 minutes in three groups of anaesthetized Wistar rats. Control rats (N = 12) were infused with saline (6.25 mL/kg over 30 min) before occlusion and the compound 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 release of clamps. Plasma creatinine (PCr), creatinine clearance (CCr), urine volume, sodium, and potassium excretion were determined up to seven days after release of clamps. In the second series of experiments in anaesthetized 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 induce ischemia without removing animals from the magnet. A double-tuned 1H-31P home-built surface coil was placed above the exposed kidney for the detection of pHi.


RESULTS
At day 1 after ischemia CCr in the control group was significantly lower as compared to S3226-treated animals (control 0.30 +/- 0.05 vs. before 0.90 +/- 0.26 and reperfusion 0.83 +/- 0.15 mL/min/kg, respectively). PCr increased from 18 +/- 0.1 micromol/L before occlusion to 245 +/- 7 micromol/L in the control. The increase in PCr was significantly lower in the S3226 treated groups on days 1, 2, and 3 post-infusion. Fractional sodium excretion 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, protein casts and cellular infiltration.


CONCLUSIONS
These results demonstrate that an intravenous administration of S3226 acutely improves GFR and kidney function and structure in both treated groups. In addition, in a separate set of studies S3226 significantly decreased post-occlusion renal pHi values. Thus, the inhibition of NHE3 with S3226 may be beneficial in treatment of ischemic ARF.
Hropot
M
M
Aventis Pharma Deutschland GmbH, Frankfurt am Main, Germany. max.hropo@aventis.com
Juretschke
H P
HP
Langer
K H
KH
Schwark
J R
JR
D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006146:Guanidines / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008689:Methacrylates / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
C118956:3-(2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methylphenyl)-N-isopropylidene-2-methyl-acrylamide dihydrochloride; D006146:Guanidines; D008689:Methacrylates; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers