Cyclosporine A-induced increase in glomerular cyclic GMP in rats and the involvement of the endothelin(B) receptor

Ivan Tack, Encarna Marin-Castano, Jean Loup Bascands, Christiane Pecher, Jean Louis Ader, Jean Pierre Girolami

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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 subcutaneous 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 increase in cyclic GMP content. The increase observed with 10 nM ET-3 was similar to that observed in glomeruli isolated 9 h after in vivo CsA administration. 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. The stimulating effects of CsA on glomerular cyclic GMP content were inhibited by in vivo administration of the ET(B) receptor antagonist BQ-788 (2. mg kg-1) but not by the ET(A) receptor antagonist BQ-123 (2 mg kg-1). 5. The maximum increase in glomerular cyclic GMP content induced in vitro by acetylcholine (100 μM) and by ET-3 (100 nM) was slightly lower (approximately by 20-25%, P < 0.05) in glomeruli from CsA-treated rats than in glomeruli from untreated rats. In contrast, the maximum increase achieved with 1 μM sodium nitroprusside was similar in both groups. 6. A single subcutaneous injection of CsA did not significantly 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 lipopolysaccharide, was prevented. 7. These results indicate that in vivo administration of a single dose of cyclosporine A transiently increases the cyclic GMP content of freshly isolated glomeruli, and that activation of ET(B) receptors and stimulation of the NO pathway are involved in this process. Furthermore, a single administration of CsA does not impair eNOS mRNA expression and only slightly reduces NO-dependent glomerular cyclic GMP production.

Original languageEnglish (US)
Pages (from-to)433-440
Number of pages8
JournalBritish Journal of Pharmacology
Volume121
Issue number3
DOIs
StatePublished - 1997

Keywords

  • Cyclic GMP
  • Cyclosporine A
  • Endothelins
  • Glomerulus
  • Kidney
  • Nitric oxide
  • Nitric oxide synthases

ASJC Scopus subject areas

  • Pharmacology

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