Amplification of EDHF-type vasodilatations in TRPC1-deficient mice.
OBJECTIVE
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-/-).


METHODS
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.


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
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.
Schmidt
Kjestine
K
Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany.
Dubrovska
Galyna
G
Nielsen
Gorm
G
Fesüs
Gabor
G
Uhrenholt
Torben R
TR
Hansen
Pernille B
PB
Gudermann
Thomas
T
Dietrich
Alexander
A
Gollasch
Maik
M
de Wit
Cor
C
Köhler
Ralf
R
D000109:Acetylcholine / Q000494:pharmacology; D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000235:genetics / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000473:Alkanes; D001685:Biological Factors; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D011806:Quinolinium Compounds; C411671:TRAM 34; D050052:TRPC Cation Channels; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C096351:transient receptor potential cation channel, subfamily C, member 1; D009569:Nitric Oxide; D000109:Acetylcholine