Referenced in: none

Automatically associated channels: BKβ , TRP , TRPC , TRPC1

Title: Amplification of EDHF-type vasodilatations in TRPC1-deficient mice.

Authors: Kjestine Schmidt, Galyna Dubrovska, Gorm Nielsen, Gábor Fésüs, Torben R Uhrenholt, Pernille B Hansen, Thomas Gudermann, Alexander Dietrich, Maik Gollasch, Cor de Wit, Ralf Köhler

Journal, date & volume: Br. J. Pharmacol., 2010 Dec , 161, 1722-33

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20718731

Abstract
TRPC1 channels are expressed in the vasculature and are putative candidates for intracellular Ca(2+) handling. However, little is known about their role in endothelium-dependent vasodilatations including endothelium-derived hyperpolarizing factor (EDHF) vasodilatations, which require activation of Ca(2+) -activated K(+) channels (K(Ca)). To provide molecular information on the role of TRPC1 for K(Ca) function and the EDHF signalling complex, we examined endothelium-dependent and independent vasodilatations, K(Ca) currents and smooth muscle contractility in TRPC1-deficient mice (TRPC1-/-).Vascular responses were studied using pressure/wire myography and intravital microscopy. We performed electrophysiological measurements, and confocal Ca(2+) imaging for studying K(Ca) channel functions and Ca(2+) sparks.TRPC1 deficiency in carotid arteries produced a twofold augmentation of TRAM-34- and UCL1684-sensitive EDHF-type vasodilatations and of endothelial hyperpolarization to acetylcholine. NO-mediated vasodilatations were unchanged. TRPC1-/- exhibited enhanced EDHF-type vasodilatations in resistance-sized arterioles in vivo associated with reduced spontaneous tone. Endothelial IK(Ca) /SK(Ca)-type K(Ca) currents, smooth muscle cell Ca(2+) sparks and associated BK(Ca)-mediated spontaneous transient outward currents were unchanged in TRPC1-/-. Smooth muscle contractility induced by receptor-operated Ca(2+) influx or Ca(2+) release and endothelium-independent vasodilatations were unaltered in TRPC1-/-. TRPC1-/- exhibited lower systolic blood pressure as determined by tail-cuff blood pressure measurements.Our data demonstrate that TRPC1 acts as a negative regulator of endothelial K(Ca) channel-dependent EDHF-type vasodilatations and thereby contributes to blood pressure regulation. Thus, we propose a specific role of TRPC1 in the EDHF-K(Ca) signalling complex and suggest that pharmacological inhibition of TRPC1, by enhancing EDHF vasodilatations, may be a novel strategy for lowering blood pressure.