Chronic production of peroxynitrite in the vascular wall impairs vasorelaxation function in SHR/NDmcr-cp rats, an animal model of metabolic syndrome.
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.
Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. skagota@mukogawa-u.ac.jp
Satomi
S
Kagota
Yukari
Y
Tada
Namie
N
Nejime
Kazuki
K
Nakamura
Masaru
M
Kunitomo
Kazumasa
K
Shinozuka
D000109:Acetylcholine / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001808:Blood Vessels / Q000378:metabolism*; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D007124:Immunoenzyme Techniques; D049449:Luminescence; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000503:physiopathology*; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects; D009599:Nitroprusside / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000077333:Telmisartan; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D030421:Peroxynitrous Acid; D009599:Nitroprusside; C002744:3-nitrotyrosine; D014443:Tyrosine; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000109:Acetylcholine; D000077333:Telmisartan