Interaction between adenosine and flow-induced dilation in coronary microvascular network

Previous studies have demonstrated that coronary microvessels are regulated by at least three possible means: metabolite-induced, shear-induced, and pressure-induced (myogenic) mechanisms. Adenosine, a putative metabolic vasodilator, preferentially dilates downstream coronary microvessels, whereas the shear-sensitive mechanism is detected predominantly in upstream larger microvessels. However, the interaction of these mechanisms and the significance of the heterogeneous vascular responsiveness in flow regulation have not been evaluated. These tasks cannot be performed experimentally because of several confounding factors that cannot be separated. Therefore, the present study employed a data-based modeling approach to investigate the role of response heterogeneity in a coronary vascular network and to test the hypothesis that shear-sensitive mechanism or the myogenic mechanisms will enhance the vascular sensitivity to adenosine due to the heterogeneity of the vascular responsiveness. We obtained necessary data and developed empirical models for the responsiveness of single vessels to pressure, shear stress, and adenosine. With the single-vessel models, a network model was established based on the branching pattern of coronary microvessels, mass balance, and fluid mechanics laws. Model simulation predicted an enhanced vascular response to adenosine in the network. Such an enhancement is caused by the heterogeneous vascular response to adenosine and the predominant flow-induced dilation in the large arterioles. Preferential dilation of the downstream small arterioles to adenosine initiates an increase in flow and a decrease in pressure at upstream vessels. The increased flow activates the shear-sensitive mechanism of the upstream large arterioles and further enhances the flow This hemodynamic interaction contributes up to similar to 20% of the adenosine-induced flow increase and also reduces the adenosine-induced pressure drop. In contrast to the shear-sensitive mechanism, myogenic response contributes relatively little to the vascular response to adenosine. These results suggest that various vascular regulation mechanisms and the response heterogeneity of vessels of different sizes may act in an integrative fashion for the optimal control of microvascular perfusion.