1. ¹Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
2. ²The Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3. ³Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

Correspondence: Dr RC Koehler, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 600 North Wolfe Street/Blalock 1404, Baltimore, Maryland 21287-4961, USA. E-mail: rkoehler@jhmi.edu

⁴These authors contributed equally to this work.

Received 26 February 2007; Revised 16 April 2007; Accepted 23 April 2007; Published online 23 May 2007.

Abstract

Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A_2A and A_2B receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A_2B, mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A_2B receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by 50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A_2B receptor antagonist. In contrast, A_2A and A₃ receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A_2B receptors, rather than A_2A or A₃ receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A_2B receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A_2B receptor linkage to the synthesis and release of vasodilatory EETs.