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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Contribution of adenosine A_2A and A_2B receptors and heme oxygenase to AMPA-induced dilation of pial arterioles in rats

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland

Submitted 26 October 2005 ; accepted in final form 23 March 2006

Nitric oxide (NO) has been implicated in mediation of cerebral vasodilation during neuronal activation and, specifically, in pharmacological activation of N-methyl-D-aspartate (NMDA) and kainate receptors. Possible mediators of cerebral vasodilation to -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) have not been well studied in mature brain, although heme oxygenase (HO) activity has been implicated in newborn pigs. In anesthetized rats, 5 min of topical superfusion of 30 and 100 µM AMPA on the cortical surface through a closed cranial window resulted in increases in pial arteriolar diameter. The dilatory response to AMPA was not inhibited by superfusion of an NO synthase inhibitor, a cyclooxygenase-2 inhibitor, or a cytochrome P-450 epoxygenase inhibitor, all of which have been shown to inhibit the cortical blood flow response to sensory activation. However, the 48 ± 13% dilation to 100 µM AMPA was attenuated 56–71% by superfusion of the adenosine A_2A receptor antagonist ZM-241385, the A_2B receptor antagonist alloxazine, and the HO inhibitor chromium mesoporphyrin. Combination of the latter three inhibitors did not attenuate the dilator response more than the individual inhibitors, whereas an AMPA receptor antagonist fully blocked the vasodilation to AMPA. These results indicate that cortical pial arteriolar dilation to AMPA does not require activation of NO synthase, cyclooxygenase-2, or cytochrome P-450 epoxygenase but does depend on activation of adenosine A_2A and A_2B receptors. In addition, CO derived from HO appears to play a role in the vascular response to AMPA receptor activation in mature brain by a mechanism that is not additive with that of adenosine receptor activation.

carbon monoxide; cerebral circulation; cyclooxygenase; epoxygenase; neurovascular coupling; nitric oxide

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