Chronic Production of Peroxynitrite in the Vascular Wall Impairs Vasorelaxation Function in SHR/NDmcr-cp Rats, an Animal Model of Metabolic Syndrome

Journal of Pharmacological Sciences

Kazuki Nakamura¹  Masaru Kunitomo¹  Kazumasa Shinozuka¹  Satomi Kagota¹  Yukari Tada¹  Namie Nejime¹ 

[1] Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, Japan

关键词: peroxynitrite;    angiotensin II;    metabolic syndrome;    NADPH oxidase;    oxidative stress;   

DOI  :  10.1254/jphs.08273FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(38)Cited-By(17)We have previously reported that peroxynitrite is involved in dysfunction of nitric oxide (NO)-mediated vasorelaxation in SHR/NDmcr-cp rats (SHR-cp), which display typical symptoms of metabolic syndrome. This study investigated whether peroxynitrite is actually generated in the vascular wall with angiotensin II–induced NADPH-oxidase activation, thus contributing to the dysfunction. In isolated mesenteric arteries of male 18-week-old SHR-cp, relaxations in response to acetylcholine and sodium nitroprusside were impaired compared with that in Wistar-Kyoto rats. This impaired relaxation was not restored by treatment with apocynin, an NADPH-oxidase inhibitor. Protein expression of endothelial NO synthase increased while that of soluble guanylyl cyclase (sGC) decreased in the artery. We observed increased production of superoxide anions and peroxynitrite from the artery and their inhibition by apocynin, and also increased contents of nitrotyrosine, a biomarker of peroxynitrite, in mesenteric arteries and angiotensin II in aortas. Long-term (8 weeks) administration of telmisartan, an angiotensin II type 1–receptor antagonist, prevented the impaired vasorelaxation, decreased sGC expression and increased nitrotyrosine content in mesenteric arteries. These findings suggest that in the vascular wall of SHR-cp, peroxynitrite is continually produced by the reaction of NO with NADPH oxidase–derived superoxide via angiotensin II and gradually denatures sGC protein, leading to vasorelaxation dysfunction.

【 授权许可】

Unknown