Effect of exercise training on nitric oxide and superoxide/H₂O₂ signaling pathways in collateral-dependent porcine coronary arterioles.

Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station, TX 77843, USA.
Journal of Applied Physiology (Impact Factor: 3.43). 02/2012; 112(9):1546-55. DOI: 10.1152/japplphysiol.01248.2011
Source: PubMed

ABSTRACT Endothelial nitric oxide (NO) synthase (NOS) has been shown to contribute to enhanced vascular function after exercise training. Recent studies have revealed that relatively low concentrations of reactive oxygen species can contribute to endothelium-dependent vasodilation under physiological conditions. We tested the hypothesis that exercise training enhances endothelial function via endothelium-derived vasodilators, NO and superoxide/H(2)O(2), in the underlying setting of chronic coronary artery occlusion. An ameroid constrictor was placed around the proximal left circumflex coronary artery to induce gradual occlusion in Yucatan miniature swine. At 8 wk postoperatively, pigs were randomly assigned to sedentary (pen-confined) or exercise-training (treadmill-run: 5 days/wk for 14 wk) regimens. Exercise training significantly enhanced concentration-dependent, bradykinin-mediated dilation in cannulated collateral-dependent arterioles (∼130 μm diameter) compared with sedentary pigs. NOS inhibition reversed training-enhanced dilation at low bradykinin concentrations in collateral-dependent arterioles, although increased dilation persisted at higher bradykinin concentrations. Total and phosphorylated (Ser(1179)) endothelial NOS protein levels were significantly increased in arterioles from collateral-dependent compared with the nonoccluded region, independent of exercise. The H(2)O(2) scavenger polyethylene glycol-catalase abolished the training-enhanced bradykinin-mediated dilation in collateral-dependent arterioles; similar results were observed with the SOD inhibitor diethyldithiocarbamate. Fluorescence measures of bradykinin-stimulated H(2)O(2) levels were significantly increased by exercise training, independent of occlusion. The NADPH inhibitor apocynin significantly attenuated bradykinin-mediated dilation in arterioles of exercise-trained, but not sedentary, pigs and was associated with significantly increased protein levels of the NADPH subunit p67phox. These data provide evidence that, in addition to NO, the superoxide/H(2)O(2) signaling pathway significantly contributes to exercise training-enhanced endothelium-mediated dilation in collateral-dependent coronary arterioles.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Hypertension is a complex disease that constitutes an important public health problem and demands many studies in order to understand the molecular mechanisms involving his pathophysiology. Therefore, an increasing number of studies have been conducted and new therapies are continually being discovered. In this context, exercise training has emerged as an important non-pharmacological therapy to treat hypertensive patients, minimizing the side effects of pharmacological therapies and frequently contributing to allow pharmacotherapy to be suspended. Several mechanisms have been associated with the pathogenesis of hypertension, such as hyperactivity of the sympathetic nervous system and renin-angiotensin aldosterone system, impaired endothelial nitric oxide production, increased oxygen-reactive species, vascular thickening and stiffening, cardiac hypertrophy, impaired angiogenesis, and sometimes genetic predisposition. With the advent of microRNAs (miRNAs), new insights have been added to the perspectives for the treatment of this disease, and exercise training has been shown to be able to modulate the miRNAs associated with it. Elucidation of the relationship between exercise training and miRNAs in the pathogenesis of hypertension is fundamental in order to understand how exercise modulates the cardiovascular system at genetic level. This can be promising even for the development of new drugs. This article is a review of how exercise training acts on hypertension by means of specific miRNAs in the heart, vascular system, and skeletal muscle.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Test the hypothesis that exercise training increases the contribution of BKCa channels to endothelium‐mediated dilation in coronary arterioles from collateral‐dependent myocardial regions of chronically occluded pig hearts and may function downstream of H2O2. Methods An ameroid constrictor was placed around the proximal left circumflex coronary artery to induce gradual occlusion in Yucatan miniature swine. Eight weeks postoperatively, pigs were randomly assigned to sedentary or exercise training (treadmill; 14 week) regimens. ResultsExercise training significantly enhanced bradykinin‐mediated dilation in collateral‐dependent arterioles (~125 μm diameter) compared with sedentary pigs. The BKCa‐channel blocker, iberiotoxin alone or in combination with the H2O2 scavenger, polyethylene glycol catalase, reversed exercise training‐enhanced dilation in collateral‐dependent arterioles. Iberiotoxin‐sensitive whole‐cell K+ currents (i.e., BKCa‐channel currents) were not different between smooth muscle cells of nonoccluded and collateral‐dependent arterioles of sedentary and exercise trained groups. Conclusions These data provide evidence that BKCa‐channel activity contributes to exercise training‐enhanced endothelium‐dependent dilation in collateral‐dependent coronary arterioles despite no change in smooth muscle BKCa‐channel current. Taken together, our findings suggest that a component of the bradykinin signaling pathway, which stimulates BKCa channels, is enhanced by exercise training in collateral‐dependent arterioles and suggest a potential role for H2O2 as the mediator.
    Microcirculation 02/2013; 20(2). DOI:10.1111/micc.12016 · 2.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This article reviews the existing knowledge about the effects of physical exercise on nitric oxide (NO) production in the cardiopulmonary system. The authors review the sources of NO in the cardiopulmonary system; involvement of three forms of NO synthases (eNOS, nNOS, and iNOS) in exercise physiology; exercise-induced modulation of NO and/or NOS in physiological and pathophysiological conditions in human subjects and animal models in the absence and presence of pharmacological modulators; and significance of exercise-induced NO production in health and disease. The authors suggest that physical activity significantly improves functioning of the cardiovascular system through an increase in NO bioavailability, potentiation of antioxidant defense, and decrease in the expression of reactive oxygen species-forming enzymes. Regular physical exercises are considered a useful approach to treat cardiovascular diseases. Future studies should focus on detailed identification of (i) the exercise-mediated mechanisms of NO exchange; (ii) optimal exercise approaches to improve cardiovascular function in health and disease; and (iii) physical effort thresholds.
    Frontiers in Cell and Developmental Biology 01/2014; 2:73. DOI:10.3389/fcell.2014.00073