ADENOSINE & K/ATP CHANNEL CONTROL OF CORONARY BLOOD FLOW

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When cardiac oxygen metabolism increases, as during exercise, there is a simultaneous increase in coronary blood flow that supplies more oxygen to the heart. Normally there is a very close match between the increase in oxygen supply and oxygen demand. How this match occurs is the fundamental question in coronary physiology. In humans with coronary artery disease, the oxygen supply is inadequate, and the resulting myocardial ischemia causes anginal chest pain. It is postulated that adenosine and/or K+ATP channels (which interact with adenosine) are involved in the feedback control of coronary blood flow that normally maintains an adequate oxygen supply to the heart. The key element in testing the adenosine hypothesis is an estimation of interstitial adenosine concentration, which cannot be directly measured. Indicator-dilution experiments will be used to obtain the parameters for a mathematical model that will then be used to calculate the interstitial adenosine concentration from coronary blood flow and the venous plasma adenosine concentration. The role of adenosine will be tested with a selective adenosine receptor blocking agent, 8-phenyltheophyl-line, and the role of K+ATP channels with the selective channel blocking agent, glibenclamide. The use of these blocking agents in combination with adenosine concentration measurements will critically test the role of adenosine and/or K+ATP channels in controlling coronary blood flow during catecholamine stimulation of the heart, cardiac pacing and exercise. The significance of this research is that the basic mechanism of coronary control will be studied. An understanding of normal physiological control is important in itself but is also relevant to pathological states.