Role of Adenosine A2 Receptors in Regulation of Cerebral Blood Flow during Induced Hypotension

Abstract

The mechanisms responsible for vascular autoregulation in the brain during changes in mean arterial blood pressure are ambiguous. Potentially, adenosine, a purine nucleoside and potent vasodilator, may be involved as earlier studies have documented an increase in brain adenosine concentrations with cerebral ischemia and hypotension. Consequently, we tested the hypothesis that adenosine is involved in vasodilatation during hypotension within the autoregulatory range (>50 mm Hg) by exposing adenosine 2a receptor (A2aR) knockout and wild type (WT) mice to short (2 to 5 mins) periods of hypotension. We found that autoregulation was significantly (P<0.05) impaired by 29% in A2a knockout mice as compared with WT animals. Furthermore, the A2R antagonist (A2a>A2b:10-85>1), ZM-241385, in a dose (1, 5, 10 mg/kg, intraperitoneally)-related manner, attenuated autoregulation in WT mice. In knockout mice treated with ZM-2413585 (5 and 10 mg/kg), autoregulation was further impaired indicating that A2b receptors also participated in cerebral vasodilatation. Treatment with dipyridamole (1.0 mg/kg) that increases extracellular concentrations of adenosine improved autoregulation in the A2aR knockout mice. We would conclude that adenosine through both A2a and A2b receptors is involved in physiologic vascular regulation during hypotension even within the autoregulatory range.

Adenosine A2A Receptor Contributes to Ischemic Brain Damage in Newborn Piglet

“…23 Although these null mice have been reported to have a normal ratio of ipsilateral-to-contralateral LDF during an H-I insult, 5 it is possible that the absolute level of CBF was reduced in both hemispheres during H-I and recovery because of arterial hypotension and impaired cerebral vasodilation to hypotension and hypoxia with loss of cerebrovascular A 2A receptors. 24 Interestingly, we found that cardiac resuscitation was difficult in piglets treated with SCH 58261 before the induction of H-I. The antagonist likely impaired coronary vasodilation to H-I and thereby could have augmented the ischemic insult to the heart.…”

Role of The Purinergic Neuromodulation System in Epilepsy

“…There might also be an additional contribution from A 2A R in cells other than neurons or glia: for instance, in the case of ischemic models, there is a contribution of neuronal A 2A R as well as of A 2A R located in peripheral myeloid derived cells [250]. Recent studies also found a striking ability of caffeine to control the integrity and functionality of the blood brain barrier [251,252], which is likely to be an effect operated by the abundant endothelial A 2A R. Finally, given the role of A 2A R in controlling cerebral vessels [253][254][255][256][257][258], it is possible that the A 2A R-mediated vascular control might also contribute to neuroprotection.…”

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…Adenosine (ADO) is a cellular metabolite that is formed by the breakdown of intracellular and extracellular adenine nucleotides that are physiologically present at nanomolar concentration inside and outside the cells (Fredholm, 2007). It represents an endogenous modulator of brain functions acting to fine-tune inhibitory and excitatory synaptic transmission (Ribeiro et al, 2010), glial function (Boison et al, 2010), and blood flow (Kusano et al, 2010); moreover, in the nervous system, the level of extracellular ADO rises upon brain damage which follows stroke, ischemia, and epileptic seizures (Ribeiro et al, 2003). Acting through four different G-protein-coupled receptors (A 1 R, A 2A R, A 2B R, and A 3 R), extracellular ADO determines the outcome of different brain injuries, mediating neuroprotective or neurotoxic effects.…”