Excess L-arginine restores endothelium-dependent relaxation impaired by monocrotaline pyrrole

Wei Cheng, Masahiro Oike, Masakazu Hirakawa, Keizo Ohnaka, Tetsuya Koyama, Yushi Ito

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

The pyrrolizidine alkaloid plant toxin monocrotaline pyrrole (MCTP) causes pulmonary hypertension in experimental animals. The present study aimed to examine the effects of MCTP on the endothelium-dependent relaxation. We constructed an in vitro disease model of pulmonary hypertension by overlaying MCTP-treated bovine pulmonary artery endothelial cells (CPAEs) onto pulmonary artery smooth muscle cell-embedded collagen gel lattice. Acetylcholine (Ach) induced a relaxation of the control CPAEs-overlaid gels that were pre-contracted with noradrenaline, and the relaxation was inhibited by L-NAME, an inhibitor of NO synthase (NOS). In contrast, when MCTP-treated CPAEs were overlaid, the pre-contracted gels did not show a relaxation in response to Ach in the presence of 0.5 mM L-arginine. Expression of endothelial NOS protein, Ach-induced Ca2+ transients and cellular uptake of L-[3H]arginine were significantly smaller in MCTP-treated CPAEs than in control cells, indicating that these changes were responsible for the impaired NO production in MCTP-treated CPAEs. Since cellular uptake of L-[3H]arginine linearly increased according to its extracellular concentration, we hypothesized that the excess concentration of extracellular L-arginine might restore NO production in MCTP-treated CPAEs. As expected, in the presence of 10 mM L-arginine, Ach showed a relaxation of the MCTP-treated CPAEs-overlaid gels. These results indicate that the impaired NO production in damaged endothelial cells can be reversed by supplying excess L-arginine.

Original languageEnglish
Pages (from-to)187-194
Number of pages8
JournalToxicology and Applied Pharmacology
Volume207
Issue number3
DOIs
Publication statusPublished - Sep 15 2005

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

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