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

Abstract

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 8mg/kg per day, respectively, for 8weeks. 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.

Characterization of Cardiac Size and Function in SHRSP.Z-Leprfa/IzmDmcr Rats, a New Animal Model of Metabolic Syndrome

“…10,25,26) We reported that impairment of coronary microcirculation associated with activation of angiotensin type I receptor occurred in SHRSP-fatty. 8) In the present study, we found that collagen type I accumulated in the ventricles along with diastolic dysfunction in SHRSPfatty. Collagen type I confers rigidity while collagen type III contributes to tissue elasticity, and an increase in the ratio of collagen type I to type III is known to be associated with increased myocardial stiffness in hypertensive rats with diastolic heart failure.…”

“…In previous studies we have proposed that peroxynitrite played a critical role in development of cardiovascular events in SHRSP-fatty. 8,[34][35][36][37] Additional studies are needed to be clarified involvement of MMPs, MLC-1 and peroxynitrite in progression of ventricular diastolic dysfunction in SHRSPfatty.…”

“…To date SHRSP-fatty have been used in studies that evaluated dysfunction of vasodilation mechanisms, cardiovascular remodeling, and atherogenic dyslipidemia in metabolic syndrome. [6][7][8] The aim of the present study was to characterize the cardiac structure and function in SHRSP-fatty. Increased cardiac stiffness induced by disturbed myocardial collagen turnover is suggested as one of the mechanisms of cardiac abnormalities in hypertension and diabetes.…”

Enhanced Nitric Oxide Synthase Activation via Protease-Activated Receptor 2 Is Involved in the Preserved Vasodilation in Aortas from Metabolic Syndrome Rats

“…Aortic rings were prepared for myograph experiments as described previously [10]. For each aortic ring, a stable level of isometric contraction was established by addition of phenylephrine (0.1 µ M ) before measuring relaxations following the addition of increasing cumulative concentrations (final bath concentrations) of PAR2 agonist 2-furoyl- LIGRLO-amide (2fly; 0.1 n M -3 μ M ) [21], muscarinic agonist acetylcholine (ACh; 0.1 n M -3 μ M ) or nitrovasodilator sodium nitroprusside (SNP; 0.1 n M -1 μ M ).…”

“…In this model, coronary and mesenteric arteries and aortas show vascular dysfunction that is characterized by impaired NO-cGMP-dependent vasodilation resulting from decreased soluble guanylate cyclase (sGC) expression [10,11]. However, even under these conditions, PAR2-mediated vasodilation is preserved in mesenteric arteries from SHRSP.ZF [12].…”