Reciprocal regulation of cyclic GMP content by cyclic GMP-phosphodiesterase and guanylate cyclase in SHR with CsA-induced nephrotoxicity.
1. The effect of the immunosuppressant drug, cyclosporin A (CsA), on the nitric oxide (NO)-cyclic GMP pathway was examined in spontaneous hypertensive rats (SHR). 2. CsA (50 mg kg(-1)) treatment for 14 days induced typical CsA nephrotoxicity, which was characterized by morphological changes in the glomerulus and proximal tubule as well as an abnormality of creatinine clearance, FENa and BUN. 3. CsA significantly decreased both NOS activity in the kidney and NOx contents in urine, but significantly increased cyclic GMP content in the kidney. 4. A marked change in two kinds of enzyme, which contribute towards the increase in cyclic GMP in tissue, namely, a decrease in cyclic GMP-phosphodiesterase activity and increase in guanylate cyclase activity, was observed in the kidney treated with CsA. 5. In the isolated perfused kidney, a decreased in perfusion pressure induced by SNP in the kidney isolated from CsA group was significantly greater than that of control. 6. There seem to exist a reciprocal mechanism to maintain cyclic GMP content via both a decrease in cyclic GMP degradation and an increase in synthesis of cyclic GMP in the kidney treated with CsA. This mechanism is likely to be playing an important role to regulate the homeostasis in the kidney with CsA nephrotoxicity.
Hosogai
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N
Medical Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Yodogawa, Kashima, Osaka, 532-8514, Japan. naomi_hosogai@po.fujisawa.co.jp
Seki
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J
Goto
T
T
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D009599:Nitroprusside / Q000494:pharmacology; D010477:Perfusion; D011312:Pressure; D051381:Rats; D011918:Rats, Inbred SHR; D014665:Vasodilator Agents / Q000494:pharmacology
D007166:Immunosuppressive Agents; D009566:Nitrates; D009573:Nitrites; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; D006152:Cyclic GMP