Arginase II inhibition prevents nitrate tolerance

Khong, S. M. L., Andrews, K. L., Huynh, N. N., Venardos, K., Aprico, A., Michell, D. L., Zarei, M., Moe, K. T., Dusting, G. J., Kaye, D. M. and Chin-Dusting, J. P. F. 2012, Arginase II inhibition prevents nitrate tolerance, British journal of pharmacology, vol. 166, no. 7, pp. 2015-2023.

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Title Arginase II inhibition prevents nitrate tolerance
Author(s) Khong, S. M. L.
Andrews, K. L.
Huynh, N. N.
Venardos, K.
Aprico, A.
Michell, D. L.
Zarei, M.
Moe, K. T.
Dusting, G. J.
Kaye, D. M.
Chin-Dusting, J. P. F.
Journal name British journal of pharmacology
Volume number 166
Issue number 7
Start page 2015
End page 2023
Total pages 9
Publisher John Wiley & Sons
Place of publication West Sussex, England
Publication date 2012-08
ISSN 0007-1188
Keyword(s) glyceryl trinitrate
nitrate tolerance
nitric oxide
reactive oxygen species
Summary BACKGROUND AND PURPOSE Nitrate tolerance, the loss of vascular responsiveness with continued use of nitrates, remains incompletely understood and is a limitation of these therapeutic agents. Vascular superoxide, generated by uncoupled endothelial NOS (eNOS), may play a role. As arginase competes with eNOS for L-arginine and may exacerbate the production of reactive oxygen species (ROS), we hypothesized that arginase inhibition might reduce nitrate tolerance.

EXPERIMENTAL APPROACH Vasodilator responses were measured in aorta from C57Bl/6 and arginase II knockout (argII –/–) mice using myography. Uncoupling of eNOS, determined as eNOS monomer : dimer ratio, was assessed using low-temperature SDS-PAGE and ROS levels were measured using L-012 and lucigenin-enhanced chemiluminescence.

KEY RESULTS Repeated application of glyceryl trinitrate (GTN) on aorta isolated from C57Bl/6 mice produced a 32-fold rightward shift of the concentration–response curve. However this rightward shift (or resultant tolerance) was not observed in the presence of the arginase inhibitor (s)-(2-boronethyl)-L-cysteine HCl (BEC; 100 µM) nor in aorta isolated from argII –/– mice. Similar findings were obtained after inducing nitrate tolerance in vivo. Repeated administration of GTN in human umbilical vein endothelial cells induced uncoupling of eNOS from its dimeric state and increased ROS levels, which were reduced with arginase inhibition and exogenous L-arginine. Aortae from GTN tolerant C57Bl/6 mice exhibited increased arginase activity and ROS production, whereas vessels from argII –/– mice did not.

CONCLUSION AND IMPLICATIONS Arginase II removal prevents nitrate tolerance. This may be due to decreased uncoupling of eNOS and consequent ROS production.
Language eng
Field of Research 069999 Biological Sciences not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2012, The Authors
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