The studies in this proposal are designed to provide insight into mechanisms by which responses of the coronary microvasculature can affect perfusion of ischemic myocardium. The goal of these studies is to define functional responses of the coronary resistance vessels in myocardial regions distal to a flow limiting coronary artery stenosis or in regions perfused by collateral channels that can influence the development of myocardial ischemia and which might be amenable to therapeutic intervention. Studies will be performed in chronically instrumented dogs in which coronary artery flow is measured with a Doppler flowmeter while regional systolic contractile function is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurement of nitric oxide (NO) production by the coronary vasculature. Initial studies will determine whether exercise stimulates NO production, and whether exercise in the presence of a coronary stenosis which results in myocardial ischemia causes a further increase in NO production. A subsequent study will examine-interactions between metabolic coronary vasodilator mechanisms mediated by K+ATP channel opening and adenosine to determine whether blockade of metabolic vasodilator mechanisms augments coronary NO production. A second group of studies will examine responses of coronary resistance vessels which are perfused through collateral channels. Collateral vessel development will be induced with repeated brief coronary occlusions or by placement of an ameroid constrictor on the left anterior descending coronary artery. An initial study will determine whether ACIA-riboside can selectively increase adenosine production in collateralized myocardium, thereby augmenting perfusion of the collateral-dependent region during exercise. A second study will measure NO production by collateral vessels and distal coronary vasculature perfused by collaterals in vivo, to determine whether NO production is decreased in coronary vessels which are perfused through collateral channels. A third protocol will determine whether basal or stimulated NO production is decreased in coronary microvessels isolated from a collateral- dependent myocardial region. A final protocol will determine whether there is decreased expression of constitutive endothelial NO synthase mRNA or protein in the collateral-dependent region, and whether the collateral-dependent region demonstrates expression of inducible NO synthase mRNA or protein.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL020598-24
Application #
6030486
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1992-07-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
24
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Chen, Yingjie; Zhang, Ping; Li, Jingxin et al. (2014) Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium. Am J Physiol Heart Circ Physiol 306:H356-62
Zhang, Ping; Xu, Xin; Hu, Xinli et al. (2013) DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. PLoS One 8:e79444
Hu, Xinli; Xu, Xin; Lu, Zhongbing et al. (2011) AMP activated protein kinase-?2 regulates expression of estrogen-related receptor-?, a metabolic transcription factor related to heart failure development. Hypertension 58:696-703
Zhang, Ping; Hu, Xinli; Xu, Xin et al. (2011) Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Akt. Arterioscler Thromb Vasc Biol 31:890-7
Hu, Xinli; Atzler, Dorothee; Xu, Xin et al. (2011) Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine. Arterioscler Thromb Vasc Biol 31:1540-6
Zhang, Ping; Hou, Mingxiao; Li, Yunfang et al. (2009) NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart. Am J Physiol Heart Circ Physiol 296:H840-6
Hu, Xinli; Xu, Xin; Huang, Yimin et al. (2008) Disruption of sarcolemmal ATP-sensitive potassium channel activity impairs the cardiac response to systolic overload. Circ Res 103:1009-17
Liu, Zhenguo; Jiang, Yuehua; Hao, Hong et al. (2007) Endothelial nitric oxide synthase is dynamically expressed during bone marrow stem cell differentiation into endothelial cells. Am J Physiol Heart Circ Physiol 293:H1760-5
Traverse, Jay H; Chen, YingJie; Hou, MingXiao et al. (2007) Effect of K+ATP channel and adenosine receptor blockade during rest and exercise in congestive heart failure. Circ Res 100:1643-9
Traverse, Jay H; Nesmelov, Yuri E; Crampton, Melanie et al. (2006) Measurement of myocardial free radical production during exercise using EPR spectroscopy. Am J Physiol Heart Circ Physiol 290:H2453-8

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