TY - JOUR
T1 - Role of inducible nitric oxide synthase in endothelium-independent relaxation to raloxifene in rat aorta
AU - Wong, Chi Ming
AU - Au, Chak Leung
AU - Tsang, Suk Ying
AU - Lau, Chi Wai
AU - Yao, Xiaoqiang
AU - CAI, Zongwei
AU - CHUNG, Chi Kong Arthur
N1 - Funding Information:
C.M.W. was the recipient of a CUHK Postgraduate Studentship. This work is supported by National Natural Science Foundation of China (General Program 21577115 to C.M.W. and 21477101 to A.C.C.); the Research Grant Council of Hong Kong (GRF 463612 and 14104314 to A.C.C.); Faculty Research Grants from the Hong Kong Baptist University (FRG2/15-16/067 to A.C.C.); Hong Kong Health and Medical Research Fund (HMRF/03144376 to A.C.C.); and HKASO research grant 2015-16 to A.C.C. We thank Aster Lai-Fong Chan for excellent technical assistance in immunohistochemistry study.
PY - 2017/4
Y1 - 2017/4
N2 - Background and Purpose: Raloxifene can induce both endothelium-dependent and -independent relaxation in different arteries. However, the underlying mechanisms by which raloxifene triggers endothelium-independent relaxation are still incompletely understood. The purpose of present study was to examine the roles of NOSs and Ca2+ channels in the relaxant response to raloxifene in the rat isolated, endothelium-denuded aorta. Experimental Approach: Changes in isometric tension, cGMP, nitrite, inducible NOS protein expression and distribution in response to raloxifene in endothelium-denuded aortic rings were studied by organ baths, radioimmunoassay, Griess reaction, western blot and immunohistochemistry respectively. Key Results: Raloxifene reduced the contraction to CaCl2 in a Ca2+-free, high K+-containing solution in intact aortic rings. Raloxifene also acutely relaxed the aorta primarily through an endothelium-independent mechanism involving NO, mostly from inducible NOS (iNOS) in vascular smooth muscle layers. This effect of raloxifene involved the generation of cGMP and nitrite. Also, it was genomic in nature, as it was inhibited by a classical oestrogen receptor antagonist and inhibitors of RNA and protein synthesis. Raloxifene-induced stimulation of iNOS gene expression was partly mediated through activation of the NF-κB pathway. Raloxifene was more potent than 17β-estradiol or tamoxifen at relaxing endothelium-denuded aortic rings by stimulation of iNOS. Conclusions and Implications: Raloxifene-mediated vasorelaxation in rat aorta is independent of a functional endothelium and is mediated by oestrogen receptors and NF-κB. This effect is mainly mediated through an enhanced production of NO, cGMP and nitrite, via the induction of iNOS and inhibition of calcium influx through Ca2+ channels in rat aortic smooth muscle.
AB - Background and Purpose: Raloxifene can induce both endothelium-dependent and -independent relaxation in different arteries. However, the underlying mechanisms by which raloxifene triggers endothelium-independent relaxation are still incompletely understood. The purpose of present study was to examine the roles of NOSs and Ca2+ channels in the relaxant response to raloxifene in the rat isolated, endothelium-denuded aorta. Experimental Approach: Changes in isometric tension, cGMP, nitrite, inducible NOS protein expression and distribution in response to raloxifene in endothelium-denuded aortic rings were studied by organ baths, radioimmunoassay, Griess reaction, western blot and immunohistochemistry respectively. Key Results: Raloxifene reduced the contraction to CaCl2 in a Ca2+-free, high K+-containing solution in intact aortic rings. Raloxifene also acutely relaxed the aorta primarily through an endothelium-independent mechanism involving NO, mostly from inducible NOS (iNOS) in vascular smooth muscle layers. This effect of raloxifene involved the generation of cGMP and nitrite. Also, it was genomic in nature, as it was inhibited by a classical oestrogen receptor antagonist and inhibitors of RNA and protein synthesis. Raloxifene-induced stimulation of iNOS gene expression was partly mediated through activation of the NF-κB pathway. Raloxifene was more potent than 17β-estradiol or tamoxifen at relaxing endothelium-denuded aortic rings by stimulation of iNOS. Conclusions and Implications: Raloxifene-mediated vasorelaxation in rat aorta is independent of a functional endothelium and is mediated by oestrogen receptors and NF-κB. This effect is mainly mediated through an enhanced production of NO, cGMP and nitrite, via the induction of iNOS and inhibition of calcium influx through Ca2+ channels in rat aortic smooth muscle.
UR - http://www.scopus.com/inward/record.url?scp=85013956670&partnerID=8YFLogxK
U2 - 10.1111/bph.13733
DO - 10.1111/bph.13733
M3 - Journal article
C2 - 28138957
AN - SCOPUS:85013956670
SN - 0007-1188
VL - 174
SP - 718
EP - 733
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -