Adenosine in the Local Regulation of Blood Flow: Current Controversies

Summary

Three experimental approaches have been taken to test the adenosine hypothesis: adenosine receptor blockade, adenosine deaminase (ADA), and estimation of interstitial adenosine concentration. Methylxanthines, which block adenosine receptors, reduce coronary reactive hyperemia but have no effect on cardiac functional hyperemia and hypoxic vasodilation. They also have controversial effects on skeletal muscle vasodilation. The explanations for the lack of effect of adenosine receptor blockers include an increase in adenosine formation which overwhelms the blockade and the possibility that adenosine contributes to but is not necessary for most local regulatory responses. ADA is used to lower interstitial adenosine ([ADO]i). It has no effect on basal coronary tone or the response to graded reduction in perfusion pressure. It reduces but does not eliminate coronary reactive hyperemia and the vasodilation in response to increased metabolism and systemic hypoxia. It reduces exercise vasodilation in the cremaster muscle. Negative results with ADA may have been obtained because the flux of adenosine is higher than expected and there was not enough ADA to lower [ADO]i. [ADO]i is estimated by measurements of adenosine release from the epicardial surface or into the venous effluent ([ADO]v). We have developed a mathematical model relating [ADO]i and [ADO]v and have used indicator dilution experiments to measure capillary transport parameters for adenosine. The relationship between [ADO]i and [ADO]v is primarily sensitive to the transport parameter for adenosine through interendothelial cell gaps. Further work is needed to gain information about [ADO]i under a variety of experimental conditions.

Supported by: USPHS grants HL 25779, HL24232, and HL662249