Cellular signalling pathways mediating dilation of porcine pial arterioles to adenosine A2A receptor activation
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AIMS: Adenosine is a potent vasodilator contributing to cerebral blood flow regulation during metabolic stress. However, the distribution of adenosine receptor subtypes and underlying signalling mechanisms for dilation of pial arterioles remain unclear. The present study aimed at addressing these issues. METHODS AND RESULTS: Isolated porcine pial arterioles were subjected to study of vasomotor function, localization of adenosine receptors, and production of nitric oxide (NO). Concentration-dependent vasodilation to adenosine was inhibited by A₂A receptor antagonist ZM241385 but not by A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. A₂A receptors were detected in endothelium and smooth muscle of pial arterioles via immunohistochemistry. Adenosine significantly increased arteriolar production of NO, and the induced dilation was insensitive to KATP channel blocker glibenclamide but was attenuated by endothelial denudation, NO synthase inhibitor L-NAME, or guanylyl cyclase inhibitor ODQ in a similar manner. Both inward rectifier potassium (Kir) channel inhibitor barium and cAMP signalling inhibitor Rp-8-Br-cAMPS attenuated adenosine-induced dilation. In the presence of L-NAME or the absence of endothelium, addition of Rp-8-Br-cAMPS but not barium further reduced adenosine-induced responses. Barium diminished endothelium-independent vasodilation to NO donor sodium nitroprusside. Comparable to the adenosine-induced response, vasodilation to A₂A receptor agonist CGS21680 was attenuated by endothelial removal, ZM241385, L-NAME, barium, or Rp-8-Br-cAMPS, but not by glibenclamide. CONCLUSION: Adenosine evokes dilation of porcine pial arterioles via parallel activation of endothelial and smooth muscle A₂A receptors. Stimulation of endothelial NO production activates smooth muscle guanylyl cyclase for vasodilation by opening Kir channels. Adenosine also activates smooth muscle cAMP signalling leading to vasodilation.
author list (cited authors)
Hein, T. W., Xu, W., Ren, Y. i., & Kuo, L.