Quantitative integration of different sites of adenosine metabolism in the heart

Adenosine is a biologically active metabolite that evokes numerous potent actions in the heart and other tissues. A better understanding of the regulation of the local adenosine concentration seems mandatory to permit specific manipulation of the adenosine tissue concentration. To achieve this a combined experimental and model analysis approach was developed. Experiments carried out in isolated perfused guinea pig hearts, coronary endothelial, and smooth muscle cells and data were analyzed with an axially distributed, 4-region mathematical model of adenosine metabolism and transport. This approach permitted us to obtain a comprehensive parameter set that adequately described cardiac adenosine metabolism. The parameter values that gave the optimal fits to experimental results indicated that adenosine production was largest in the cytosol, while extracellular adenosine production accounted for approximately 8% of total cardiac adenosine production. However, despite the much higher intracellular rate of adenosine production, the concentration gradient of adenosine across cell membranes was directed toward the cytosol under physiological conditions, i.e., when the cytosolic adenosine concentration was low. This was due to the high rate of intracellular adenosine removal which exceeded intracellular production. The endothelial region contributed approximately 5% to total cardiac adenosine production. Despite this small contribution endothelial cells may effectively control the vascular adenosine concentration over a wide concentration range (5-500 nM). In conclusion, a combination of experimental and modeling approaches may provide unique insights into capillary-tissue exchange and metabolism of adenosine. In the future this may reveal realistic concentration-effect relationships for adenosine in the heart. These achievements seem critical in order to design strategies which permit a specific manipulation of substrates with high turnover rates in biological tissues.