An investigation of the physiological mechanisms underlying coronary and myocardial responses to non-ischemic and ischemic hypoxia is proposed. The left anterior descending coronary artery of the anesthetized dog will be perfused with blood of controlled oxygen content (non-ischemic hypoxia) or have its flow occluded (ischemic hypoxia). Blood will be deoxygenated by an extracorporeal canine lung. Coronary arterial and venous oxygen tension and content, blood flow (flowmeter and microsphere distribution), myocardial oxygen tension (polarographic technique), contractile function (ultrasonic segment-length gauge), concentrations of nucleosides and high energy phosphates (HPLC), and epicardial electrograms will be measured. Perturbations of myocardial oxygen supply/demand relationships will be performed during non-ischemic hypoxia to differentiate mechanisms due to oxygen deficient from those due to vasoactive metabolites. These mechanisms will be further clarified by determining during non-ischemic hypoxia the action of agents which alter the vasodilator response to brief ischemia and/or exogenous adenosine (adenosine deaminase, aminophylline, dipyridamole, nifedipine). Mechanisms which determine the rate of recovery of vascular tone following myocardial hypoxia will be also investigated. Further studies will determine long term (4 hr) effects of non-ischemic myocardial hypoxia on coronary hemodynamic parameters (regional flow, small vessel blood volume, collateral conductance) and on myocardial contractile function and concentrations of nucleosides and high energy phosphates. By comparing these findings with measurements after a similar period of ischemic hypoxia, the importance of hypoxia per se and metabolite build-up during long term ischemia will be defined. Recovery of coronary hemodynamic function, myocardial contractile function, and concentrations of nucleosides and high energy phosphates during reoxygenation following an extended period of non-ischemic hypoxia will be determined and compared with recovery of these parameters during reperfusion following a similar period of ischemic hypoxia. The investigation is in accordance with long term objectives 1) to define mechanisms which adjust coronary blood flow to meet myocardial oxygen requirements; and 2) to define the vulnerability of these mechanisms to ischemic and hypoxic insult. The results will have clinical relevance to conditions of myocardial ischemia and systemic hypoxemia, therapeutic interventions to treat these conditions, and consequences of reoxygenation of hypoxic myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL035027-01
Application #
3348504
Study Section
Cardiovascular Study Section (CVA)
Project Start
1985-04-01
Project End
1990-03-31
Budget Start
1985-04-01
Budget End
1986-03-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Texas College of Osteopathic Medicine
Department
Type
Schools of Osteopathy
DUNS #
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Setty, Srinath; Tune, Johnathan D; Downey, H Fred (2004) Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res 64:431-6
Setty, Srinath; Tune, Johnathan D; Downey, H Fred (2002) Nitric oxide modulates right ventricular flow and oxygen consumption during norepinephrine infusion. Am J Physiol Heart Circ Physiol 282:H696-703
Hart, B J; Bian, X; Gwirtz, P A et al. (2001) Right ventricular oxygen supply/demand balance in exercising dogs. Am J Physiol Heart Circ Physiol 281:H823-30
Setty, S; Bian, X; Tune, J D et al. (2001) Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle. Am J Physiol Heart Circ Physiol 281:H831-7
Bian, X; Fu, M; Mallet, R T et al. (2000) Myocardial oxygen consumption modulates adenosine formation by canine right ventricle in absence of hypoxia. J Mol Cell Cardiol 32:345-54
Hart, B J; Bian, X; Mallet, R T et al. (2000) Hyperlipidemia with hypoglycemia reduces myocardial oxygen utilization efficiency but not contractile function during coronary hypoperfusion. J Mol Cell Cardiol 32:1539-52
Yi, K D; Downey, H F; Bian, X et al. (2000) Dobutamine enhances both contractile function and energy reserves in hypoperfused canine right ventricle. Am J Physiol Heart Circ Physiol 279:H2975-85
Jingjing, L; Srinivasan, B; Bian, X et al. (2000) Vascular endothelial growth factor is increased following coronary artery occlusion in the dog heart. Mol Cell Biochem 214:23-30
Hart, B J; Bian, X; Williams Jr, A G et al. (1999) A method for producing regional hypoglycemia in blood perfused tissue. Mol Cell Biochem 200:177-81
Bian, X; Downey, H F (1999) Right coronary pressure modulates right ventricular systolic stiffness and oxygen consumption. Cardiovasc Res 42:80-6

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