The maintenance of tone underlying circulatory regulation by vascular smooth muscle (VSM) is closly coupled to metabolism. Knowledge of the substrates utilized and control points, two poorly understood aspects central to understanding vascular metabolism, will be addressed by this project. While VSM is primarily an oxidative tissue, the substrate has not been unambiguously identified. The nature of the oxidative tissue, the substrate has not been unambiguously identified. The nature of the oxidative substrate will be assessed using measurement of O2 consumption and CO2 production to establish the respiratory quotient (RQ). The hypothesis that substrate utilization is dependent on metabolic demand will be tested by measuring the RQ as a function of substrate, mode of stimulation and contractility. Utilizing the overall direction set by RQ studies, substrate radioisotopes will be used to completely specify utilization patterns. A second major gap in our understanding of vascular metabolism relates to the observation that under fully oxygenated conditions, most of the glucose entering VSM is catabolized only to lactate. This aerobic glycolysis has often been proposed as an index of vascular myopathy; however, recent evidence from my laboratory indicats that it is related to Na-K transport in normal VSM. The control points for aerobic glycolysis will be determined and the hypothesis that Na-K transport is specifically coupled to glycolysis will be tested. This will include determination, under conditions in which glycolysis is altered by varying Na-K transport, of the role of glucose transport as a rate-limiting step, and from measurements of glycolytic intermediates, the rate-limiting enzymatic steps. To specify carbohydrate catabolism, the role of glycogenolysis will be assessed by direct measurement of glycogen breakdown and its control by measurement of the activation of glycogen phosphorylase. Vessels from both pulmonary and systemic circulations will be studied with the long-term goal of relating specific substrate utilization patterns to normal vascular function so that potentially more sensitive metabolic changes can be used in addition to contractility to detect and characterize vascular myopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL023240-07
Application #
3337192
Study Section
Physiology Study Section (PHY)
Project Start
1978-07-01
Project End
1986-06-30
Budget Start
1984-12-01
Budget End
1986-06-30
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Szymanski, P T; Ferguson, D G; Paul, R J (2002) Polylysine binding to unphosphorylated smooth muscle myosin enhances formation and stabilizes myosin filaments in vitro. Acta Physiol Scand 174:337-46
Shimizu, S; Bowman, P S; Thorne 3rd, G et al. (2000) Effects of hypoxia on isometric force, intracellular Ca(2+), pH, and energetics in porcine coronary artery. Circ Res 86:862-70
Shimizu, S; Paul, R J (1999) Hypoxia and alkalinization inhibit endothelium-derived nitric oxide but not endothelium-derived hyperpolarizing factor responses in porcine coronary artery. J Pharmacol Exp Ther 291:335-44
Tosun, M; Paul, R J; Rapoport, R M (1998) Role of extracellular Ca++ influx via L-type and non-L-type Ca++ channels in thromboxane A2 receptor-mediated contraction in rat aorta. J Pharmacol Exp Ther 284:921-8
Shimizu, S; Paul, R J (1997) The endothelium-dependent, substance P relaxation of porcine coronary arteries resistant to nitric oxide synthesis inhibition is partially mediated by 4-aminopyridine-sensitive voltage-dependent K+ channels. Endothelium 5:287-95
Tosun, M; Paul, R J; Rapoport, R M (1997) Intracellular Ca2+ elevation and contraction due to prostaglandin F2alpha in rat aorta. Eur J Pharmacol 340:203-8
Foy, R A; Shimizu, S; Paul, R J (1997) The effects of hypoxia on pHi in porcine coronary artery endothelium and smooth muscle. A novel method for measurements in endothelial cells in situ. Circ Res 80:21-7
Wingard, C J; Paul, R J; Murphy, R A (1997) Energetic cost of activation processes during contraction of swine arterial smooth muscle. J Physiol 501 ( Pt 1):213-23
Liu, L H; Paul, R J; Sutliff, R L et al. (1997) Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. J Biol Chem 272:30538-45
Lorenz, J N; Paul, R J (1997) Dependence of Ca2+ channel currents on endogenous and exogenous sources of ATP in portal vein smooth muscle. Am J Physiol 272:H987-94

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