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Vascul Pharmacol ; 96-98: 53-62, 2017 09.
Article in English | MEDLINE | ID: mdl-28867591

ABSTRACT

Stimulation of calcium-sensing receptors (CaSR) by increasing the external calcium concentration (Ca2+]o) induces endothelium-dependent vasorelaxation through nitric oxide (NO) production and activation of intermediate Ca2+-activated K+ currents (IKCa) channels in rabbit mesenteric arteries. The present study investigates the potential role of heteromeric TRPV4-TRPC1 channels in mediating these CaSR-induced vascular responses. Immunocytochemical and proximity ligation assays showed that TRPV4 and TRPC1 proteins were expressed and co-localised at the plasma membrane of freshly isolated endothelial cells (ECs). In wire myography studies, increasing [Ca2+]o between 1 and 6mM induced concentration-dependent relaxations of methoxamine (MO)-induced pre-contracted tone, which were inhibited by the TRPV4 antagonists RN1734 and HC067047, and the externally-acting TRPC1 blocking antibody T1E3. In addition, CaSR-evoked NO production in ECs measured using the fluorescent NO indicator DAF-FM was reduced by RN1734 and T1E3. In contrast, [Ca2+]o-evoked perforated-patch IKCa currents in ECs were unaffected by RN1734 and T1E3. The TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent relaxation of MO-evoked pre-contracted tone and increased NO production, which were inhibited by the NO synthase inhibitor L-NAME, RN1734 and T1E3. GSK activated 6pS cation channel activity in cell-attached patches from ECs which was blocked by RN1734 and T1E3. These findings indicate that heteromeric TRPV4-TRPC1 channels mediate CaSR-induced vasorelaxation through NO production but not IKCa channel activation in rabbit mesenteric arteries. This further implicates CaSR-induced pathways and heteromeric TRPV4-TRPC1 channels in regulating vascular tone.


Subject(s)
Endothelial Cells/metabolism , Mesenteric Artery, Superior/metabolism , Nitric Oxide/metabolism , Receptors, Calcium-Sensing/metabolism , TRPC Cation Channels/metabolism , TRPV Cation Channels/metabolism , Vasodilation , Animals , Calcium Signaling , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , In Vitro Techniques , Male , Membrane Potentials , Mesenteric Artery, Superior/drug effects , Rabbits , Receptors, Calcium-Sensing/drug effects , TRPC Cation Channels/drug effects , TRPV Cation Channels/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacology
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