Endothelium‐dependent relaxation and endothelial hyperpolarization by P2Y receptor agonists in rat‐isolated mesenteric artery

<jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>Vasorelaxation and hyperpolarization of endothelial cells by adenosine 5′‐[<jats:italic>β</jats:italic>‐thio]diphosphate (ADP<jats:italic>β</jats:italic>S) and adenosine 5′‐[<jats:italic>γ</jats:italic>‐thio]triphosphate (ATP<jats:italic>γ</jats:italic>S) were studied in rat‐isolated mesenteric artery. Effects from stimulation of P2X receptors were avoided by desensitization with <jats:italic>α,β</jats:italic>‐methylene adenosine triphosphate.</jats:p></jats:list-item> <jats:list-item><jats:p>ADP<jats:italic>β</jats:italic>S caused concentration‐ and endothelium‐dependent relaxations of methoxamine‐precontracted small (third generation) and main mesenteric artery. These were inhibited by <jats:italic>N</jats:italic><jats:sup><jats:italic>ω</jats:italic></jats:sup>‐nitro‐<jats:sc>L</jats:sc>‐arginine methyl ester (<jats:sc>L</jats:sc>‐NAME) or a combination of apamin plus charybdotoxin (inhibitors of Ca<jats:sup>2+</jats:sup>‐activated K<jats:sup>+</jats:sup> channels); <jats:sc>L</jats:sc>‐NAME, apamin and charybdotoxin applied together abolished the response.</jats:p></jats:list-item> <jats:list-item><jats:p>ATP<jats:italic>γ</jats:italic>S induced limited relaxation (35% of methoxamine‐induced tone at 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>) of small mesenteric artery, which was sensitive to <jats:sc>L</jats:sc>‐NAME or endothelium denudation. However, it almost completely relaxed the main mesenteric artery over an extended concentration range (>6 orders of magnitude) in an endothelium‐dependent manner. This relaxation was inhibited by either <jats:sc>L</jats:sc>‐NAME or a combination of apamin with charybdotoxin, and abolished by a combination of all the three inhibitors.</jats:p></jats:list-item> <jats:list-item><jats:p>The P2Y<jats:sub>1</jats:sub> receptor antagonist MRS 2179 (2′‐deoxy‐<jats:italic>N</jats:italic><jats:sup>6</jats:sup>‐methyladenosine 3′,5′‐bisphosphate; 0.3–3 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>) caused parallel rightward shifts of the concentration/relaxation curve to ADP<jats:italic>β</jats:italic>S (pA<jats:sub>2</jats:sub>=7.1). However, MRS 2179 did not inhibit, but potentiated, relaxant responses to ATP<jats:italic>γ</jats:italic>S. MRS 2179 did not affect the contractile responses ATP<jats:italic>γ</jats:italic>S in small mesenteric artery; ATP<jats:italic>γ</jats:italic>S did not contract the main mesenteric artery.</jats:p></jats:list-item> <jats:list-item><jats:p>ADP<jats:italic>β</jats:italic>S hyperpolarized the endothelium of the main mesenteric artery in a concentration‐dependent manner. This was unaffected by <jats:sc>L</jats:sc>‐NAME but antagonized by MRS 2179. ATP<jats:italic>γ</jats:italic>S also hyperpolarized the mesenteric artery endothelium in a concentration‐dependent manner but, when ATP<jats:italic>γ</jats:italic>S was applied at 10 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>, its effect was potentiated by MRS 2179 (3 <jats:italic>μ</jats:italic><jats:sc>M</jats:sc>).</jats:p></jats:list-item> <jats:list-item><jats:p>It is concluded that both relaxation and hyperpolarization to ADP<jats:italic>β</jats:italic>S are mediated by P2Y<jats:sub>1</jats:sub> receptors and that the endothelial hyperpolarization is related to the <jats:sc>L</jats:sc>‐NAME‐resistant relaxation. Relaxation to the P2Y<jats:sub>2</jats:sub> agonist ATP<jats:italic>γ</jats:italic>S shows regional variation along the mesenteric vasculature. The mechanisms for potentiation of relaxation and hyperpolarization by ATP<jats:italic>γ</jats:italic>S are unknown, but may indicate interactions between P2Y receptor subtypes.</jats:p></jats:list-item> </jats:list> </jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2003) <jats:bold>139</jats:bold>, 661–671. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0705271">10.1038/sj.bjp.0705271</jats:ext-link></jats:p>