期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 156, 期 1, 页码 84-93出版社
WILEY
DOI: 10.1111/j.1476-5381.2008.00036.x
关键词
arginase; L-arginine; aorta; mesenteric arteries; nitric oxide; vasorelaxation
资金
- National Health and Medical Research Council of Australia
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 isolated 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-omega-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, alpha-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.
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