The overall goal of this application is to study the specific major classes of hypotheses which may underlie the vasodilatory effect of hypoxia in porcine coronary arteries (hypoxic vasodilatation). The specific, hypothetical, oxygen sensing areas to be studied would be intracellular calcium, changes in pH, alteration of calcium sensitivity of the contractile apparatus and limitation of metabolism and high energy phosphagens. The proposed studies will include measurements of the effect of hypoxia on intracellular calcium and pH using ratiometric fluorescent dye techniques and the relationship between intracellular calcium, myosin light chain phosphorylation and isometric force and the effect on metabolism and phosphagen profiles and content utilizing analytical isotachophoresis. The preliminary data carried out to date suggest that none of the major mechanisms previously proposed including the sodium pump, and ATP-dependent potassium channels, for example, actually underlie the hypoxic vasorelaxation in porcine coronary artery. In addition, initial evidence also suggests that with stimulation by KCL calcium does not change or is actually increased by hypoxia despite a decrease in isometric force. These results suggest the existence of a novel type of oxygen sensing mechanism in porcine coronary artery smooth muscle. In addition there are new data presented in the application which suggest that pH may strongly influence vessel response to hypoxia. In addition, these workers have identified three distinct types of endothelium-dependent oxygen sensing responses in the coronary artery and, their proposed studies therefore also include tests of the hypotheses that alterations of endothelial cell calcium, pH, or energy metabolism underlie these various endothelium dependent response to oxygen. The information is important not only to the basic understanding of vascular physiology but also developing a rational therapeutic approach to vascular pathology including vasospastic disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Experimental Cardiovascular Sciences Study Section (ECS)
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University of Cincinnati
Schools of Medicine
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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
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
Shimizu, S; Shimizu, K; Paul, R J (1997) Cold storage induces an endothelium-independent relaxation to hypoxia/reoxygenation in porcine coronary arteries. J Vasc Res 34:399-407
Obara, K; Bowman, P S; Ishida, Y et al. (1997) Effects of hypoxia on [Ca2+]i, pHi and myosin light chain phosphorylation in guinea-pig taenia caeci. J Physiol 503 ( Pt 2):427-33
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

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