Simvastatin and L-arginine preserve renal function after ischemia/reperfusion injury.
BACKGROUND
HMG-CoA reductase inhibitors have been shown to have beneficial renal hemodynamic effects by increasing renal blood flow, independent of their lipid-lowering properties. Currently in organ transplantation, the calcineurin inhibitor cyclosporine A (CyA) is the immunosuppressant of choice. However, its use is limited by its nephrotoxic effects, namely its renal vasoconstrictor properties. The purpose of this study was to determine the effect of an HMG-CoA reductase inhibitor, simvastatin (Zocor), on renal function in rats and on urinary nitrite/nitrate production following ischemia/reperfusion injury (I/R) with concomitant cyclosporine treatment. In addition, L-NAME (N(G)-nitro-L-arginine methyl ester) and L-arginine were administered with CyA to the rats to test the hypothesis that simvastatin's beneficial effects were due to nitric oxide.


METHODS
Male Wistar rats (250 g) were anesthetized and the supra-aorta clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into five groups: 1) controls, no ischemia, no treatment (CTRL, n = 8); 2) ischemia (ISCH) plus cyclosporine A only (CyA, 5 mg/kg/day i.p., n = 8); 3) ischemia plus CyA and simvastatin (SIM, 10 mg/kg/day, gavage, n = 8); 4) ischemia plus simvastatin plus L-NAME plus CyA (10 mg/kg/day, gavage, n = 8), and 5) ischemia plus simvastatin plus L-arginine (2% in drinking water, n = 7) plus CyA. Five to 7 days after I/R injury, the glomerular filtration rate (GFR) was determined using urinary iohexol clearance. Urinary nitrite/nitrate production was determined using nitrate reductase and the Greiss reaction. Data are expressed as mean +/- SEM, and intergroup comparisons were made using one-way analysis of variance.


RESULTS
The GFR values (mL/min) for all five groups are as follows: 1) CTRL = 1.25 +/- 0.10; 2) ISCH plus CyA only = 0.45 +/- 0.06 (P < 0.05 versus CTRL, ISCH only and simvastatin and cyclosporine and simvastatin plus L-arginine and cyclosporine); 3) CyA and SIM = 0.78 +/- 0.09, CyA and L-NAME = 0.62 +/- 0.12, and CyA and L-arginine and SIM = 1.57 +/- 0.12. Results in the control were significantly different from results in the ischemic only and the L-NAME groups (P < 0.05). The L-arginine plus cyclosporine and simvastatin group was significantly higher than the ischemic only group, ischemic plus simvastatin and cyclosporine and the L-NAME plus cyclosporine group (P < 0.05). No significant differences could be detected in the urinary nitric oxide concentrations.


CONCLUSIONS
: After I/R injury and cyclosporine treatment, simvastatin and L-arginine preserved renal function, compared with cyclosporine treatment alone, because simvastatin and L-arginine may not have a direct vasoconstrictor effect on the renal microcirculation. They may be suppressing endothelin or increasing other vasodilator mediators such as the vasodilator prostaglandins and/or nitric oxide.
Inman
Sharon R
SR
Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio 45701, USA. inmans@ohio.edu
Davis
Nancy A
NA
Mazzone
Maria E
ME
Olson
Kristen M
KM
Lukaszek
Victoria A
VA
Yoder
Kristy N
KN
D000818:Animals; D001120:Arginine / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D019821:Simvastatin / Q000627:therapeutic use*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D019821:Simvastatin; D019331:NG-Nitroarginine Methyl Ester