The vascular effects of different arginase inhibitors in rat i/ated aorta and mesenteric arteries

N. N. Huynh, E. E. Harris, J. F P Chin-Dusting, K. L. Andrews

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35 Citations (Scopus)

Abstract

Background and purpose: Arginase and nitric oxide (NO) synthase share the common substrate L-arginine, and arginase inhibition is proposed to increase NO production by increasing intracellular levels of L-arginine. Many different inhibitors are used, and here we have examined the effects of these inhibitors on vascular tissue. Experimental approach: Each arginase inhibitor was assessed by its effects on i/ated rings of aorta and mesenteric arteries from rats by: (i) their ability to preserve the tolerance to repeated applications of the endothelium-dependent agonist acetylcholine (ACh); and (ii) their direct vasorelaxant effect. Key results: In both vessel types, tolerance (defined as a reduced response upon second application) to ACh was reversed with addition of L-arginine, (S)-(2-boronethyl)-L-cysteine HCl (BEC) or N G-Hydroxy-L- arginine (L-NOHA). On the other hand, N ω-hydroxy-nor-L-arginine (nor-NOHA) significantly augmented the response to ACh, an effect that was partially reversed with L-arginine. No effect on tolerance to ACh was observed with L-valine, nor-valine or D,L, α-difluoromethylornithine (DFMO). BEC, L-NOHA and nor-NOHA elicited endothelium-independent vasorelaxation in both endothelium intact and denuded aorta while L-valine, DFMO and nor-valine did not. Conclusions and implications: BEC and L-NOHA, but not nor-NOHA, L-valine, DFMO or nor-valine, significantly reversed tolerance to ACh possibly conserving L-arginine levels and therefore increasing NO bioavailability. However, both BEC and L-NOHA caused endothelium-independent vasorelaxation in rat aorta, suggesting that these inhibitors have a role beyond arginase inhibition alone. Our data thus questions the interpretation of many studies using these antagonists as specific arginase inhibitors in the vasculature, without verification with other methods.

Original languageEnglish
Pages (from-to)84-93
Number of pages10
JournalBritish Journal of Pharmacology
Volume156
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Keywords

  • Aorta
  • Arginase
  • L-arginine
  • Mesenteric arteries
  • Nitric oxide
  • Vasorelaxation

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