Adenosine and Adenine Nucleotides as Regulators of Cerebral Blood Flow: Roles of Acidosis, Cell Swelling, and KATP Channels

A considerable volume of evidence implicates the purine adenosine in the regulation of cerebral blood flow during states such as hypotension, neural activation, hypoxia/ischemia, and hypercapnia/acidosis. The aim of this review is to describe developments in our understanding of the roles that adenosine and the adenine nucleotides play in cerebral blood flow control, with some comparisons to coronary blood flow. The first part of the review focuses on the categorization of receptors for adenosine (A1, A2A, A2B, and A3) and the adenine nucleotides, ATP and ADP (P2X and P2Y). Frequently used agonists and antagonists for these different receptors are mentioned. A description follows of the distribution of these different receptors in cerebral arterioles. The second part of the review initially deals with the literature on the release of adenosine and adenine nucleotides into the extracellular space of the brain, describing the various techniques used to make these measurements and assessing the pitfalls associated with their use. This is followed by a discussion of the factors affecting purine release, which include cell swelling and acidosis. The third section evaluates the role of smooth muscle potassium channels in controlling arteriolar diameter. There is evidence for an important role of KATP and KCa channels, but less is known about the contributions of voltage-dependent (KV) and inwardly rectifying (KIR) channels. This section ends with a discussion on the reported inhibitory effect of nitric oxide synthase inhibitors on the KATP channel and the consequences of such an action for the interpretation of much of the published work on nitric oxide as a regulator of cerebral blood flow. The fourth section evaluates the data supporting a role of adenosine and ATP in the regulation of cerebral blood flow during autoregulation, hypotension, neural activity, hypoxia/ ischemia, and hypercapnia. Studies using antagonists and potentiators of adenosine's actions have led to the conclusion that adenosine is involved in vascular flow control, matching metabolic activity to blood flow in all of these conditions, possibly with the exceptions of autoregulation at mean arterial blood pressures above approximately 60 mmHg. Evidence is presented for a major role of A2A, and a more limited role of A2B receptors, in balancing blood flow with metabolism. The primary effect of receptor occupancy is activation of KATP and KCa channels with smooth muscle relaxation and elevated blood flow rates. There are presently fewer data on ATP's participation in flow control, but recent evidence regarding glial cell control of cerebral arteriolar diameter suggests that this may be an important mechanism. The semi-final section, which briefly describes the evidence for a comparable role of adenosine in regulating coronary blood flow, is followed by a concluding statement reaffirming the importance of adenosine as a cerebral blood flow regulator.