Quantitative relation between interstitial adenosine concentration and coronary blood flow

The effect of exogenous and endogenous adenosine in controlling coronary flow was determined using an axially distributed mathematical model of the myocardium to estimate interstitial adenosine concentration from coronary arterial and venous adenosine values. The left main coronary artery was perfused at constant pressure in closed-chest, anesthetized dogs, and exogenous adenosine was infused intracoronary to increase coronary flow. Basal interstitial adenosine was 92 nmol/L, just at the threshold for increasing coronary flow. An increase in interstitial adenosine concentration of only 62% was sufficient to increase coronary flow from 5% to 50% of maximal flow. The possible contribution of an endothelial dilator secondary to activation of adenosine receptors on endothelial cells was tested by comparing the response to exogenous intracoronary adenosine infusion with increases in endogenous adenosine produced by inhibition of adenosine kinase and adenosine deaminase. If adenosine increases coronary flow by an endothelial mechanism, then the interstitial ED₅₀ of exogenous adenosine would be lower than that for endogenous adenosine due to the postulated additional endothelial dilator. The interstitial ED₅₀ for exogenous adenosine was 156 nmol/L, not different from the endogenous ED₅₀ of 150 nmol/L. In conclusion, basal interstitial adenosine concentration is at the threshold of a remarkably steep dose-response curve for increasing coronary blood flow. No evidence was found for an endothelium-mediated vasodilator mechanism secondary to adenosine receptor activation of endothelial cells in vivo. The steep adenosine dose-response curve indicates that measurements of adenosine concentration should be interpreted with caution, because small changes in adenosine concentration cause large changes in coronary flow.