Newly Published
Perioperative Medicine  |   December 2017
L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta
Author Notes
  • From the Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China; Applied Science and Environmental Studies, School of Science and Technology, The Open University of Hong Kong, Kowloon, Hong Kong Special Administrative Region, China (E.S.W.W.); and the State Key Laboratory of Pharmaceutical Biotechnologies, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China (S.W.S.L., P.M.V.).
  • Part of the work presented in this article has been presented as posters at the Joint Meeting ESH-ISH Hypertension 2014, Athens, Greece, June 13–16, 2014; the 4th Scientific Meeting of the Asian Society for Vascular Biology, Hong Kong, November 20–21, 2010; and WorldPharma2010, Copenhagen, Denmark, July 17–23, 2010.
    Part of the work presented in this article has been presented as posters at the Joint Meeting ESH-ISH Hypertension 2014, Athens, Greece, June 13–16, 2014; the 4th Scientific Meeting of the Asian Society for Vascular Biology, Hong Kong, November 20–21, 2010; and WorldPharma2010, Copenhagen, Denmark, July 17–23, 2010.×
  • Submitted for publication June 26, 2017. Accepted for publication November 13, 2017.
    Submitted for publication June 26, 2017. Accepted for publication November 13, 2017.×
  • Research Support: Supported by General Research Fund (773509M) from the Research Grant Council of the Hong Kong Special Administrative Region, China, and by Seed Funding for Basic Research (201111159042) from the University Research Committee of the University of Hong Kong, Hong Kong Special Administrative Region, China.
    Research Support: Supported by General Research Fund (773509M) from the Research Grant Council of the Hong Kong Special Administrative Region, China, and by Seed Funding for Basic Research (201111159042) from the University Research Committee of the University of Hong Kong, Hong Kong Special Administrative Region, China.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Leung:2/F, Laboratory Block, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, Pokfulam, Hong Kong, China. swsleung@hku.hk. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pharmacology
Perioperative Medicine   |   December 2017
L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta
Anesthesiology Newly Published on December 21, 2017. doi:10.1097/ALN.0000000000002032
Anesthesiology Newly Published on December 21, 2017. doi:10.1097/ALN.0000000000002032
Abstract

Background: The α2-adrenergic sedative/anesthetic agent dexmedetomidine exerts biphasic effects on isolated arteries, causing endothelium-dependent relaxations at concentrations at or below 30 nM, followed by contractions at higher concentrations. l-arginine is a common substrate of endothelial nitric oxide synthase and arginases. This study was designed to investigate the role of l-arginine in modulating the overall vascular response to dexmedetomidine.

Methods: Isometric tension was measured in isolated aortic rings of Sprague Dawley rats. Cumulative concentrations of dexmedetomidine (10 nM to 10 μM) were added to quiescent rings (with and without endothelium) after previous incubation with vehicle, Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; nitric oxide synthase inhibitor), prazosin (α1-adrenergic antagonist), rauwolscine (α2-adrenergic antagonist), l-arginine, (S)-(2-boronethyl)-l-cysteine hydrochloride (arginase inhibitor), NG-hydroxy-l-arginine (arginase inhibitor), urea and/or ornithine. In some preparations, immunofluorescent staining, immunoblotting, or measurement of urea content were performed.

Results: Dexmedetomidine did not contract control rings with endothelium but evoked concentration-dependent increases in tension in such rings treated with l-NAME (Emax 50 ± 4%) or after endothelium-removal (Emax 74 ± 5%; N = 7 to 12). Exogenous l-arginine augmented the dexmedetomidine-induced contractions in the presence of l-NAME (Emax 75 ± 3%). This potentiation was abolished by (S)-(2-boronethyl)-l-cysteine hydrochloride (Emax 16 ± 4%) and NG-hydroxy-l-arginine (Emax 18 ± 4%). Either urea or ornithine, the downstream arginase products, had a similar potentiating effect as l-arginine. Immunoassay measurements demonstrated an upregulation of arginase I by l-arginine treatment in the presence of l-NAME (N = 4).

Conclusions: These results suggest that when vascular nitric oxide homeostasis is impaired, the potentiation of the vasoconstrictor effect of dexmedetomidine by l-arginine depends on arginase activity and the production of urea and ornithine.