Adenosine and the regulation of cerebral blood flow

Objectives: This review summarizes the 30 year effort of my collaborator and mentor Dr J. W. Phillis to establish the role of adenosine in the regulation of cerebral blood flow. Methods: While most of the experiments described utilized the rat cerebral cortex as a model, several different and complementary methodologies were employed. Superfusate samples were collected from the cortical surface and analysed for purines using HPLC. Laser-Doppler flowmetry was utilized to measure blood flow in the pial vasculature, while pial diameters were monitored by videomicroscopy. An additional series of experiments looked at coronary blood flow in a Langendorff preparation. Results: Adenosine is released from the cortex in response to decreased nutrient supply (hypoxial ischemia) and during conditions that mimic alterations in the extracellular environment associated with increased metabolism. The application of pharmacological agents that alter adenosine metabolism resulted in the appropriate alterations in ECF adenosine levels and also in blood flow. Selective blockade of the adenosine A(2A) receptor reduced the pial vasodilation evoked by hypercapnoea. Results from the isolated rat heart, utilizing similar agents, support a role for adenosine in the regulation of coronary blood flow during respiratory and metabolic acidosis. Discussion: Adenosine is released when there is a mismatch between supply and demand. If the effects of adenosine are blocked with receptor antagonists, the vasodilation is also reduced. However, the effects of adenosine on the hyperemia evoked by hypercapnoea are complicated by the arousal evoked by adenosine receptor antagonists and the effects of upstream regulation.