Phosphodiesterase type 5 inhibition ameliorates nephrotoxicity induced by cyclosporin A in spontaneous hypertensive rats

• Published in: European journal of pharmacology Vol. 477; no. 2; pp. 171 - 178
• Main Authors: Hosogai, Naomi, Tomita, Masayuki, Hamada, Kaori, Ogawa, Toshikazu, Hirosumi, Jiro, Manda, Toshitaka, Mutoh, Seitaro
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 12.09.2003; Elsevier
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Aorta - metabolism; Benzamides - pharmacology; Biological and medical sciences; Blood Platelets - metabolism; Body Weight - drug effects; cGMP; Cyclic GMP - blood; Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 5; Cyclosporine - antagonists & inhibitors; Cyclosporine - pharmacology; Drug toxicity and drugs side effects treatment; FR226807; Guanylate Cyclase - metabolism; Immunosuppressive Agents - antagonists & inhibitors; Immunosuppressive Agents - pharmacology; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney Diseases - chemically induced; Kidney Diseases - physiopathology; Kidney Diseases - prevention & control; Male; Medical sciences; Nitric Oxide Synthase - metabolism; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase type 5 inhibitor; Phosphoric Diester Hydrolases - metabolism; Potassium - blood; Rats; Rats, Inbred SHR; Sodium - blood; Toxicity: urogenital system; Phosphodiesterase type 5 inhibitor; FR226807; cGMP; Hypertension; Urinary system disease; Rat; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; Toxicity; Rodentia; Enzyme inhibitor; Cardiovascular disease; 3',5'-GMP; Esterases; Phosphoric diester hydrolases; Kidney; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; CGMP; Hydrolases; Ciclosporin; Immunosuppressive agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2003.08.014

Our recent study suggests that there is a reciprocal mechanism to maintain cGMP content, via both a decrease in cGMP degradation (decrease in cGMP-phosphodiesterase activity) and an increase in synthesis of cGMP (increase in guanylate cyclase activity) in the kidney of cyclosporin A-treated rats. We undertook this study to clarify the role of cGMP-phosphodiesterase in cyclosporin A nephrotoxicity by evaluating N-(3,4-dimethoxybenzyl)-2-{[(1 R)-2-hydroxy-1-methylethyl]amino}-5-nitrobenzamide (FR226807), a phosphodiesterase type 5 inhibitor, in an animal model. Male spontaneous hypertensive rats (SHR) were treated with cyclosporin A (50 mg/kg) for 2 weeks or with cyclosporin A and FR226807 (3.2 mg/kg or 10 mg/kg) for 2 weeks. Cyclosporin A-treated rats showed renal dysfunction and histological change compared with vehicle-treated rats. Administration of FR226807 improved the renal dysfunction (increase in serum creatinine and fractional excretion of sodium, and decrease in creatinine clearance) as well as the pathological changes (tubular vacuolization) induced by cyclosporin A in SHR. At the molecular level, administration of FR226807 resulted in a further increase in cGMP content in the kidney, aorta and platelets from cyclosporin A-treated rats. Our present study demonstrates that cGMP-phosphodiesterase plays an important role in the cyclosporin A nephrotoxicity and also suggests that further inhibition of cGMP-phosphodiesterase is a potential pharmacological target for preventing cyclosporin A nephrotoxicity.