Coronary vascular dysfunction promoted by oxidative‐nitrative stress in SHRSP.Z‐Lepr fa /IzmDmcr rats with metabolic syndrome

• Published in: Clinical and experimental pharmacology & physiology Vol. 37; no. 11; pp. 1035 - 1043
• Main Authors: Kagota, Satomi, Fukushima, Kazuhito, Umetani, Keiji, Tada, Yukari, Nejime, Namie, Nakamura, Kazuki, Mori, Hidezo, Sugimura, Kazuro, Kunitomo, Masaru, Shinozuka, Kazumasa
• Format: Journal Article
• Language: English
• Published: 01-11-2010
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/j.1440-1681.2010.05432.x

1. Metabolic syndrome is an independent risk factor for cardiovascular disease. SHRSP.Z‐Lepr
fa
/IzmDmcr (SHRSP fatty) rat, established as a new rat model of metabolic syndrome, spontaneously develops obesity, severe hypertension and shows hypertriglyceridaemia, hypercholesterolaemia and abnormal glucose tolerance. Using SHRSP fatty rats, we examined whether or not oxidative stress was correlated with vascular dysfunction in small and large calibre coronary arteries in
ex vivo
beating hearts, isolated mesenteric arteries and aortas in comparison with normal rats, Wistar–Kyoto rats (WKY). Vasodilation of coronary arteries was determined by microangiography of the Langendorff heart.
2. Compared with WKY, acetylcholine (ACh) and sodium nitroprusside (SNP)‐induced relaxations were impaired in the coronary arteries of SHRSP fatty rats. The mesenteric arteries and aorta of SHRSP fatty rats showed impaired relaxation responses to ACh and SNP, decreased 3′,5′‐monophosphate (cGMP) production, and reduced soluble guanylyl cyclase protein expression. Superoxide release, angiotensin II and 3‐nitrotyrosine contents were increased.
3. SHRSP fatty rats were orally administered olmesartan, an angiotensin II receptor type 1 (AT
1
) antagonist, and amlodipine, a calcium channel blocker, at doses of 5 and 8 mg/kg per day, respectively, for 8 weeks. Both olmesartan and amlodipine reduced blood pressure, but only olmesartan prevented the development of abnormal vascular and biochemical parameters in the SHRSP fatty rats.
4. The results showed that in the SHRSP fatty rats, the impaired nitric oxide‐ and cGMP‐mediated relaxation of vascular smooth muscle cells were linked to AT
1
receptor‐induced oxidative‐nitrative stress, which occurred concurrently with severe hypertension and metabolic abnormalities
in vivo
.