At rest the myocardium extracts approximately 75% of the oxygen delivered by coronary blood flow. Thus there is little extraction reserve when myocardial oxygen consumption is augmented severalfold during exercise. There are local metabolic feedback and sympathetic feedforward control mechanisms that match coronary blood flow to myocardial oxygen consumption. Despite intensive research the local feedback control mechanism remains unknown. Physiological local metabolic control is not due to adenosine, ATP-dependent K(+) channels, nitric oxide, prostaglandins, or inhibition of endothelin. Adenosine and ATP-dependent K(+) channels are involved in pathophysiological ischemic or hypoxic coronary dilation and myocardial protection during ischemia. Sympathetic beta-adrenoceptor-mediated feedforward arteriolar vasodilation contributes approximately 25% of the increase in coronary blood flow during exercise. Sympathetic alpha-adrenoceptor-mediated vasoconstriction in medium and large coronary arteries during exercise helps maintain blood flow to the vulnerable subendocardium when cardiac contractility, heart rate, and myocardial oxygen consumption are high. In conclusion, several potential mediators of local metabolic control of the coronary circulation have been evaluated without success. More research is needed.

Background: Human plasma ATP concentration is reported in many studies as roughly 1000 nmol/L. The present study tested the hypothesis that the measured plasma ATP concentration is lower if ATP release from formed blood elements is inhibited during blood sample processing. A second hypothesis was that pretreatment with aspirin to inhibit platelets would reduce the measured plasma concentration of ATP.

The hypothesis that exercise-induced coronary vasodilation is a result of sympathetic activation of coronary smooth muscle beta-adrenoceptors was tested. Ten dogs were chronically instrumented with a flow transducer on the circumflex coronary artery and catheters in the aorta and coronary sinus. During treadmill exercise, coronary venous oxygen tension decreased with increasing myocardial oxygen consumption, indicating an imperfect match between myocardial blood flow and oxygen consumption. This match was improved after alpha-adrenoceptor blockade with phentolamine but was significantly worse than control after alpha + beta-adrenoceptor blockade with phentolamine plus propranolol. The response after alpha-adrenoceptor blockade included local metabolic vasodilation plus a beta-adrenoceptor vasodilator component, whereas the response after alpha + beta-adrenoceptor blockade contained only the local metabolic vasodilator component. The large difference in coronary venous oxygen tensions during exercise between alpha-adrenoceptor blockade and alpha + beta-adrenoceptor blockade indicates that there is significant feedforward beta-adrenoceptor coronary vasodilation in exercising dogs. Coronary venous and estimated myocardial interstitial adenosine concentrations did not increase during exercise before or after alpha + beta-adrenoceptor blockade, indicating that adenosine levels did not increase to compensate for the loss of feedforward beta-adrenoceptor-mediated coronary vasodilation. These results indicate a meaningful role for feedforward beta-receptor-mediated sympathetic coronary vasodilation during exercise.

The purpose of this investigation was to quantitatively evaluate the role of adenosine in coronary exercise hyperemia. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus, and a flow probe on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Coronary blood flow, myocardial oxygen consumption, heart rate, and aortic pressure were measured at rest and during graded treadmill exercise with and without adenosine receptor blockade with either 8-phenyltheophylline (8-PT) or 8-p-sulfophenyltheophylline (8-PST). In control vehicle dogs, exercise increased myocardial oxygen consumption 4.2-fold, coronary blood flow 3.8-fold, and heart rate 2.5-fold, whereas mean aortic pressure was unchanged. Coronary venous plasma adenosine concentration was little changed with exercise, and the estimated interstitial adenosine concentration remained well below the threshold for coronary vasodilation. Adenosine receptor blockade did not significantly alter myocardial oxygen consumption or coronary blood flow at rest or during exercise. Coronary venous and estimated interstitial adenosine concentration did not increase to overcome the receptor blockade with either 8-PT or 8-PST as would be predicted if adenosine were part of a high-gain, negative-feedback, local metabolic control mechanism. These results demonstrate that adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise.

The goal of this study was to identify the most important variables affecting bioluminescent ATP, ADP and AMP measurements in plasma and to develop an assay that takes these variables into account. Blood samples were drawn from conscious dogs. A 'stop solution' containing EDTA was prepared, which greatly retarded plasma ATP degradation by chelating Mg(+2) and Ca(+2) that are co-factors for many ATPases. Stop solution and blood were mixed using a two-syringe withdrawal system. Samples were centrifuged twice in order to remove red blood cells, and ATP was measured in the supernatant using the firefly luciferase assay. Sample pH was adjusted to the optimal range (7.75-7.95) and Mg(2+) (necessary for the luciferase reaction) was added back to the sample within the luminometer 2 s prior to luciferase addition. Four assay tubes were prepared for each plasma sample, containing standard additions of 0-15 pmol added ATP, in order to quantify native plasma ATP content. In separate plasma/stop solution samples ADP + ATP was measured after converting ADP to ATP via the pyruvate kinase reaction, and AMP + ADP + ATP was measured after addition of both myokinase and pyruvate kinase. Addition of forskolin and isobutylmethylxanthine (IBMX) to the stop solution to inhibit platelets resulted in lower ATP concentrations. Measurement of ATP and haemoglobin from lysed erythrocytes revealed that haemolysis exerts a strong influence on plasma ATP concentration that must be taken into account.