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Amplification of EDHF‐type vasodilatations in TRPC1‐deficient mice
Author(s) -
Schmidt Kjestine,
Dubrovska Galyna,
Nielsen Gorm,
Fesüs Gabor,
Uhrenholt Torben R.,
Hansen Pernille B.,
Gudermann Thomas,
Dietrich Alexander,
Gollasch Maik,
de Wit Cor,
Köhler Ralf
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00985.x
Subject(s) - trpc1 , chemistry , medicine , microbiology and biotechnology , biology , biochemistry , transient receptor potential channel , receptor
BACKGROUND AND PURPOSE 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‐/‐). EXPERIMENTAL APPROACH 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. KEY RESULTS 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. CONCLUSIONS AND IMPLICATIONS 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.