Liraglutide treatment improves the coronary microcirculation in insulin resistant Zucker obese rats on a high salt diet.

Obesity, hypertension and prediabetes contribute greatly to coronary artery disease, heart failure and vascular events, and are the leading cause of mortality and morbidity in developed societies. Salt sensitivity exacerbates endothelial dysfunction. Herein, we investigated the effect of chronic glucagon like peptide-1 (GLP-1) receptor activation on the coronary microcirculation and cardiac remodeling in Zucker rats on a high-salt diet (6% NaCl). Eight-week old Zucker lean (+/+) and obese (fa/fa) rats were treated with vehicle or liraglutide (LIRA) (0.1 mg/kg/day, s.c.) for 8 weeks. Systolic blood pressure (SBP) was measured using tail-cuff method in conscious rats. Myocardial function was assessed by echocardiography. Synchrotron contrast microangiography was then used to investigate coronary arterial vessel function (vessels 50-350 µm internal diameter) in vivo in anesthetized rats. Myocardial gene and protein expression levels of vasoactive factors, inflammatory, oxidative stress and remodeling markers were determined by real-time PCR and Western blotting. We found that in comparison to the vehicle-treated fa/fa rats, rats treated with LIRA showed significant improvement in acetylcholine-mediated vasodilation in the small arteries and arterioles (< 150 µm diameter). Neither soluble guanylyl cyclase or endothelial NO synthase (eNOS) mRNA levels or total eNOS protein expression in the myocardium were significantly altered by LIRA. However, LIRA downregulated Nox-1 mRNA (p = 0.030) and reduced ET-1 protein (p = 0.044) expression. LIRA significantly attenuated the expressions of proinflammatory and profibrotic associated biomarkers (NF-κB, CD68, IL-1β, TGF-β1, osteopontin) and nitrotyrosine in comparison to fa/fa-Veh rats, but did not attenuate perivascular fibrosis appreciably. In a rat model of metabolic syndrome, chronic LIRA treatment improved the capacity for NO-mediated dilation throughout the coronary macro and microcirculations and partially normalized myocardial remodeling independent of changes in body mass or blood glucose

Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via beta(3)AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central beta(1)-adrenergic receptors (AR) (brain) and peripheral beta(2)AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate beta(3)AR. However, the relationship between IH and beta(3)AR in the modification of HPV is unknown. It has been observed that chronic stimulation of beta(3)AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates beta(3)AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O-2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of proinflammatory pulmonary macrophages. In these macrophages, both beta(3)AR and iNOS were upregulated and stimulation of the beta(3)AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of beta(3)AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of beta(3)AR/iNOS signaling in chronic IH

EFFECT OF DITHIOTHREITOL ON Ca^<2+>-ATPase ACTIVITY OF SARCOPLASMIC RETICULUM IN RAT SKELETAL MUSCLE AFTER HIGH-INTENSITY EXERCISE

Although the precise mechanisms underlying the dysfunction of sarcoplasmic reticulum(SR) that occurs during skeletal muscle fatigue remain obscure, it has been hypothesized that it may be attributable to oxidation of critical sulfhydryl groups residing in SR Ca^-ATPase protein by endogenously produced reactive oxygen species. In order to test this hypothesis, SR Ca^-ATPase activities in the absence or presence of the disulfide reducing agent, dithiothreitol(DTT), were examined in muscle homogenates of the soleus muscles(SOL) and the superficial portions of the vastus lateralis muscles(VS) from the rat subjected to exhaustive running at 50 m/min on a 10% grade. Immediately after exercise, the catalytic activity of SR Ca^-ATPase was significantly depressed in VS, but not in SOL. The loss of SR Ca^-ATPase activity observed in VS was fully recovered after treatment with DTT(1 mM). These recovery effects of a potent disulfide reducing agent suggest that important proteins of SR Ca^-ATPase may be oxidized during high-intensity exercise and that the onset of muscular fatigue may be delayed by the improved function of the cellular antioxidan

Treadmill running improves hindlimb arteriolar endothelial function in type 1 diabetic mice as visualized by X-ray microangiography

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