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.
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