Microcirculatory anatomy can explain the illusory cooperativity seen in the flow response to exogenous adenosine

Abstract

OBJECTIVETo demonstrate that illusory cooperativity can arise in the microcirculation as a result of competition and spatial localization.Adenosine in the myocardial interstitium binds to adenosine A2A receptors on vascular smooth muscle, leading to reduced tone and increased myocardial blood flow. The relationship between the concentration of supplied adenosine and the increase in flow is very steep (Hill coefficient 5–7), suggesting strong receptor binding site cooperativity. In fact, this apparent cooperativity may be illusory, and can arise solely from the anatomic geometry and cellular composition of myocardial tissue. Along the path from capillary to arteriolar smooth muscle cell, adenosine faces a permeability barrier (the endothelial clefts) and a diffusion distance (back from capillary to arteriole). Cellular transporters and metabolic enzymes compete for adenosine all along this path, influencing not only the apparent ED50 of arterially supplied adenosine, but also the shape of the dose‐response curve. Using a mathematical model, we demonstrate the independent influences of competition and access barriers (permeability barriers and diffusion distances), as well as how these effects can combine to make the dose‐response curve for a single binding site receptor (Hill coefficient 1) appear extremely cooperative.