P 2 Y 2 receptor activation decreases blood pressure via intermediate conductance potassium channels and connexin 37

Aims Nucleotides are important paracrine regulators of vascular tone. We previously demonstrated that activation of P 2 Y 2 receptors causes an acute, NO ‐independent decrease in blood pressure, indicating this signalling pathway requires an endothelial‐derived hyperpolarization ( EDH ) response. To define the mechanisms by which activation of P 2 Y 2 receptors initiates EDH and vasodilation, we studied intermediate‐conductance ( KC a3.1, expressed in endothelial cells) and big‐conductance potassium channels ( KC a1.1, expressed in smooth muscle cells) as well as components of the myoendothelial gap junction, connexins 37 and 40 ( C x37, C x40), all hypothesized to be part of the EDH response. Methods We compared the effects of a P 2 Y 2/4 receptor agonist in wild‐type ( WT ) mice and in mice lacking KC a3.1, KC a1.1, C x37 or C x40 under anaesthesia, while monitoring intra‐arterial blood pressure and heart rate. Results Acute activation of P 2 Y 2/4 receptors (0.01–3 mg kg −1 body weight i.v.) caused a biphasic blood pressure response characterized by a dose‐dependent and rapid decrease in blood pressure in WT (maximal response % of baseline at 3 mg kg −1 : −38 ± 1%) followed by a consecutive increase in blood pressure (+44 ± 11%). The maximal responses in KC a3.1 −/− and C x37 −/− were impaired (−13 ± 5, +17 ± 7 and −27 ± 1, +13 ± 3% respectively), whereas the maximal blood pressure decrease in response to acetylcholine at 3  μ g kg −1 was not significantly different ( WT : −53 ± 3%; KC a3.1 −/− : −52 ± 3; C x37 −/− : −53 ± 3%). KC a1.1 −/− and C x40 −/− showed an identical biphasic response to P 2 Y 2/4 receptor activation compared to WT . Conclusions The data suggest that the P 2 Y 2/4 receptor activation elicits blood pressure responses via distinct mechanisms involving KC a3.1 and C x37.