Nephrol Dial Transplant (1999) 14: 2634-2638
© 1999 European Renal Association-European Dialysis and Transplant Association
Effects of L-arginine on cyclosporin-induced alterations of vascular NO/cGMP generation
1 Departments of Physiology, 2 Internal Medicine and 3 Pharmacology, Chonnam University Medical School, Kwangju, Korea
Correspondence and offprint requests to: Ki Chul Choi, M.D., Department of Internal Medicine, Chonnam University Medical School, 8 Hak-dong, Kwangju 501-757, Korea.
Background. Cyclosporin (CsA)-induced vascular dysfunction has been attributed to a diminished role of the nitric oxide (NO)/cGMP-mediated vasodilator mechanism. The present study was aimed at investigating whether L-arginine, the substrate of NO synthesis, ameliorates CsA-induced vascular dysfunction.
Methods. Male Sprague–Dawley rats were used throughout the study. The thoracic aorta was isolated from normal rats and acutely treated with CsA (10-4 mol/l, 60 min) in vitro, or the aorta was taken from rats treated with CsA (25 mg/kg/day, i.m., 1 week). The vascular relaxation response to acetylcholine, and tissue levels of NO metabolites and cGMP were determined. The vascular expression of NO synthase (NOS) isoforms was also determined by western blot analysis.
Results. Acute treatment with CsA in vitro markedly attenuated the vasorelaxation response to acetylcholine, which was completely restored by L-arginine. The vascular accumulation of NO metabolites in response to acetylcholine was decreased significantly by CsA, which was prevented by cotreatment with L-arginine. CsA decreased the cGMP accumulation in response to both acetylcholine and sodium nitroprusside. L-Arginine restored, although not completely, acetylcholine-stimulated cGMP generation, whereas it did not affect sodium nitroprusside-stimulated cGMP generation. Following chronic CsA treatment in the whole animal, the vasorelaxation response to acetylcholine was decreased significantly along with tissue levels of NO metabolites; this was preserved by L-arginine-supplementation. Vascular expression of iNOS protein was decreased by CsA treatment along with decreased tissue accumulation of NO metabolites. L-Arginine supplementation did not modify the altered expression of NOS proteins.
Conclusion. These results suggest that CsA causes an L-arginine-sensitive vascular dysfunction which is associated with impaired generation of NO and cGMP.
Keywords: cGMP; cyclosporin; L-arginine; nitric oxide
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