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

Abstract

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 approximately 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.

Theoretical model of blood flow autoregulation: roles of myogenic, shear-dependent, and metabolic responses

“…2A, the shear-dependent response reverses myogenic autoregulation, with flow rate increasing more rapidly than pressure. The present results are in agreement with findings of previous models (4,20) in which autoregulation was substantially weaker when shear-dependent responses were included.…”

“…Two previous modeling studies have considered the contributions of both myogenic and shear-dependent responses to autoregulation (4,20). In both models, the inclusion of shear-dependent re- sponses led to substantially weaker autoregulation than would be the case with no shear-dependent response.…”

“…A second difference is that both previous models expressed the myogenic response as a function of intravascular pressure. Liao and Kuo (20) expressed vessel diameter as an explicit function of pressure, whereas Cornelissen et al (4) expressed the myogenic tone as a sigmoidal function of pressure. In the present study, myogenic tone is assumed to depend on wall tension and not directly on pressure.…”

“…Any shear-dependent vasodilation results in increased wall tension according to the law of Laplace and thereby generates a myogenic response. Finally, neither of these studies (4,20) considered the myogenic and shear-dependent responses in conjunction with a metabolic response. The main finding of the present study that the combined action of the metabolic and myogenic responses is required to overcome the effect of the shear-dependent response and achieve autoregulation of flow with increasing arterial pressure depends on the analysis of the simultaneous effects of all three mechanisms.…”

Another role for nitric oxide in blood flow control?

“…Mathematical modeling has added in understanding how these mechanisms contribute to flow control [2,5,6,8,9,14]. In these studies, diameter control is modeled for individual vessels, and the vascular tree is simplified in a number of representative compartments in series in which blood vessel segments of a certain diameter are arranged parallel.…”