CYCLOSPORINE-A-INDUCED INCREASE IN GLOMERULAR CYCLIC-GMP IN RATS AND THE INVOLVEMENT OF THE ENDOTHELIN(B) RECEPTOR

1 A transient two fold increase in the cyclic GMP content was observed in rat freshly isolated glomeruli 6 to 9 h after a single subcutaneou s injection of 20 mg kg(-1) cyclosporine A (CsA) in conscious animals. 2 In vitro stimulation with endothelin 3 (ET-3) of isolated glomeruli obtained from CsA-untreated rats resulted in a dose-dependent increas e in cyclic GMP content. The increase observed with 10 nM ET-3 was sim ilar to that observed in glomeruli isolated 9 h after in vivo CsA admi nistration. 3 The rise in glomerular cyclic GMP content after in vivo CsA injection was prevented by in vivo treatment with L-NAME (10 mg kg (-1)) or by in vitro calcium deprivation of the incubation medium. 4 T he stimulating effects of CsA on glomerular cyclic GMP content were in hibited by in vivo administration of the ETB receptor antagonist BQ-78 8 (2 mg kg(-1)) but not by the ETA receptor antagonist BQ-123 (2 mg kg (-1)). 5 The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 mu M) and by ET-3 (100 nM) was slightl y lower (approximately by 20-25%, P<0.05) in glomeruli from CsA-treate d rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 mu M sodium nitroprusside was similar in bot h groups. 6 A single subcutaneous injection of CsA did not significant ly alter the glomerular mRNA expression of constitutive endothelial NO synthase (eNOS), as evaluated by RT-PCR, whereas the mRNA expression of the inducible NO synthase (iNOS), which follows pretreatment with l ipopolysaccharide, was prevented. 7 These results indicate that in viv o administration of a single dose of cyclosporine A transiently increa ses the cyclic GMP content of freshly isolated glomeruli, and that act ivation of ETB receptors and stimulation of the NO pathway are involve d in this process. Furthermore, a single administration of CsA does no t impair eNOS mRNA expression and only slightly reduces NO-dependent g lomerular cyclic GMP production.