Exercise and the resulting increase in transport capacity is thought to reduce the risk of coronary artery disease. A significant portion of increased transport capacity is due to increased blood flow resulting from adaptations in coronary vascular structure and functional mechanisms. One site for exercise-induced adaptation resides in the smooth muscle (SM) and may include 1) altered sensitivity to vasoactive agents and metabolic regulatory products, and 2) changes in intrinsic Ca control mechanisms. For instance, contractile responses of conduit epicardial SM to norepinephrine and endothelin (ET-1) are reduced and sensitivity to adenosine (ADO) induced vasodilation increased by endurance exercise training (EX). Adaptations in coronary SM responses to vasoactive agents could reflect chronic alterations in receptor- coupled signal transduction mechanisms. This proposal, therefore, will focus on EX-induced adaptations in pharmacomechanical coupling of porcine coronary SM exposed to the vasoconstrictor, ET-1, and the vasorelaxants, ADO and sodium nitroprusside (SNP). We hypothesize that endothelin receptors directly activate both phospholipase C and D (PLC and PLD), thereby producing second messengers that release Ca from the sarcoplasmic reticulum (inositol trisphosphate (IP3)), and stimulate cellular Ca entry and/or increase the sensitivity of the contractile machinery to Ca (diacylglycerol, phosphatidic acid). We further hypothesize that EX decreases second messenger production due to altered signal transduction coupling both directly to ET-1 and indirectly through ADO and/or SNP receptor-induced reduction in PLC and PLD activity. These investigations will utilize 0.3-2.0 mm epicardial arteries and isolated SM cells from sedentary and the EX pig model studied in the PPG.
The specific aims to be addressed will: 1) determine the dependency of EX related changes in ET-1 induced contractions and ADO induced relaxations on Ca-release and entry mechanisms; 2) distinguish EX-induced changes in receptor- phospholipase coupling (e.g. ET-1-PLC) from changes in second messenger- effector coupling (e.g. IP3-SR Ca-release) using isolated SM cells and coronary rings permeabilized with Staphylococcus aureas alpha-toxin; 3) determine whether EX reduces second messenger production from PLC (PIP2 selective) and PLD in response to ET-1; 4) determine whether EX-induced adaptations in epicardial coronary arteries include an enhanced vasodilatory and cAMP response to ADO; and 5) determine the concentration dependent effects of ADO, SNP, cAMP and cGMP on ET-1 pharmacomechanical coupling. The end-points to be measured include: contraction (intact and permeabilized vessels), 42K and 45Ca fluxes, Ca-activity (fura-2 method), PLC and PLD products (inositol phosphates, phosphatidylethanol, phosphatidic acid) and cyclic nucleotides (cAMP, cGMP). Achievement of the specific aims will provide new information concerning coronary SM adaptations to EX. Furthermore, we anticipate these studies will provide basic information concerning pharmacomechanical coupling in coronary arteries and in the long term, provide a foundation for future investigations of mechanistic alterations associated with coronary artery disease and the beneficial effects of EX.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL052490-03
Application #
6242383
Study Section
Project Start
1997-05-01
Project End
1998-04-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Type
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
Masseau, I; Bowles, D K (2015) Carotid Endothelial VCAM-1 Is an Early Marker of Carotid Atherosclerosis and Predicts Coronary Artery Disease in Swine. J Biomed Sci Eng 8:789-796
Heaps, Cristine L; Robles, Juan Carlos; Sarin, Vandana et al. (2014) Exercise training-induced adaptations in mediators of sustained endothelium-dependent coronary artery relaxation in a porcine model of ischemic heart disease. Microcirculation 21:388-400
Hamilton, Marc T; Hamilton, Deborah G; Zderic, Theodore W (2014) Sedentary behavior as a mediator of type 2 diabetes. Med Sport Sci 60:11-26
Bender, Shawn B; de Beer, Vincent J; Tharp, Darla L et al. (2014) Reduced contribution of endothelin to the regulation of systemic and pulmonary vascular tone in severe familial hypercholesterolaemia. J Physiol 592:1757-69
Simmons, Grant H; Padilla, Jaume; Jenkins, Nathan T et al. (2014) Exercise training and vascular cell phenotype in a swine model of familial hypercholesterolaemia: conduit arteries and veins. Exp Physiol 99:454-65
Gole, Hope K A; Tharp, Darla L; Bowles, Douglas K (2014) Upregulation of intermediate-conductance Ca2+-activated K+ channels (KCNN4) in porcine coronary smooth muscle requires NADPH oxidase 5 (NOX5). PLoS One 9:e105337
McKenney, Mikaela L; Schultz, Kyle A; Boyd, Jack H et al. (2014) Epicardial adipose excision slows the progression of porcine coronary atherosclerosis. J Cardiothorac Surg 9:2
Fain, John N; Company, Joseph M; Booth, Frank W et al. (2013) Exercise training does not increase muscle FNDC5 protein or mRNA expression in pigs. Metabolism 62:1503-11
de Beer, Vincent J; Merkus, Daphne; Bender, Shawn B et al. (2013) Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability. J Appl Physiol (1985) 115:1767-76
Congdon, Kimberly A; Hammond, Ashley S; Ravosa, Matthew J (2012) Differential limb loading in miniature pigs (Sus scrofa domesticus): a test of chondral modeling theory. J Exp Biol 215:1472-83

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