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Connexin 37 and KCa3.1 contribute to P2Y 2 receptor initiated endothelial‐derived hyperpolarization (1079.15)
Author(s) -
Sharik Meaghen,
Burt Janis,
Ruth Peter,
Rieg Timo
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1079.15
Subject(s) - hyperpolarization (physics) , connexin , gap junction , p2y receptor , medicine , vasodilation , endocrinology , receptor , agonist , chemistry , endothelium derived hyperpolarizing factor , paracrine signalling , microbiology and biotechnology , biology , biochemistry , intracellular , organic chemistry , nuclear magnetic resonance spectroscopy
Nucleotides such as ATP and UTP are important paracrine regulators of vascular tone. Importantly, we previously demonstrated that in vivo activation of P2Y 2 receptors (activated by ATP/UTP) causes an acute NO‐independent decrease in blood pressure (BP), indicating this signaling pathway requires an endothelial‐derived hyperpolarization (EDH) response. To define the mechanisms by which in vivo activation of P2Y 2 receptors initiates EDH and vasodilation, we studied connexin 37 and 40 (Cx37, Cx40), both part of the myoendothelial gap junction, as well as big‐conductance (KCa1.1, expressed in smooth muscle cells) and intermediate‐conductance K channels (KCa3.1, expressed in endothelial cells), all hypothesized to be part of the EDH response. We compared the effects of the P2Y 2/4 receptor agonist, INS45973, in wild‐type (WT) mice and mice lacking Cx37, Cx40, KCa1.1, or KCa3.1 (n=4‐5/genotype) under anesthesia, while monitoring intra‐arterial BP. Acute application of INS45973 (0.01, 0.03, 0.1, 0.3, 1, or 3 mg/kg bw i.v. in 0.5 µl/g bw over 45 sec) dose‐dependently and rapidly (within 15 sec of starting infusion) decreased BP in WT mice (max response % of baseline: ‐38±1%, EC50: 0.8±0.2 mg/kg) for 2‐3 min. Whereas the responses in Cx40‐/‐ and KCa1.1‐/‐ mice were comparable to WT mice (‐41±2%, 0.3±0.1 mg/kg and ‐44±3%, 0.3±0.1 mg/kg, respectively), responses in Cx37‐/‐ and KCa3.1‐/‐ mice were significantly impaired (‐27±1%, 1.2±0.3 mg/kg and ‐13±5%, 1.6±0.8 mg/kg, respectively). Heart rate was not affected in either genotype. Our data indicate that Cx37 and KCa3.1 are required, at least in part, for the P2Y 2 receptor‐initiated EDH response and subsequent vasodilation. Grant Funding Source : 10SDG2610034 and P30DK079337