Limitations in the completeness of autoregulatory flow adjustments may play an important role in the pathophysiology of ischemic heart disease. Preliminary studies by the applicant indicate that vasodilator reserve is not always exhausted, either regionally or globally, when coronary pressure is reduced below the autoregulatory range at constant metabolic demand. These surprising observations seem consonant, in retrospect, with the limited related data available in the literature. The present application is intended to define mechanisms which limit autoregulatory flow responses by addressing the following points: (1) Do reductions in regional blood flow at controlled coronary pressures between 30 and 70 mm Hg represent a limitation of the autoregulatory response to reductions in perfusion pressure which occurs despite residual local vasodilator reserve? (2) What are the interactions among regional myocardial flow, function and metabolic demand over a wide range of perfusion pressures? Is there an intrinsic mechanism which adjusts regional metabolism (through decreases in myocardial function) to match a limited coronary flow and help maintain a supply-demand balance which minimizes myocardial ischemia? (3) How complete are autoregulatory flow adjustments to pressure over a wide range of coronary perfusion pressures? Does the level of myocardial oxygen demand influence the completeness of flow adjustment? What are the maximum constrictor, as well as dilator, limits of intrinsic flow regulation? (4) Do basal levels of adrenergic constrictor tone influence resting coronary flow and/or coronary autoregulatory responses? What is the role of alpha adrenergic tone in limiting autoregulatory responses distal to a coronary stenosis?
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