Amplification of EDHF-type vasodilatations in TRPC1-deficient mice

Kjestine Schmidt, Galyna Dubrovska, Gorm Nielsen, Gabor Fesus, Torben Rene Uhrenholt, Pernille B. Lærkegaard Hansen, Thomas Gudermann, Alexander Dietrich, Maik Gollasch, Cor de Wit, Ralf Köhler

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Summary 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 (STOC) 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.
OriginalsprogEngelsk
TidsskriftBritish Journal of Pharmacology
Vol/bind161
Udgave nummer8
Sider (fra-til)1722-1733
Antal sider12
ISSN0007-1188
DOI
StatusUdgivet - 20. dec. 2010

Fingeraftryk

Vasodilation
Endothelium
Smooth Muscle
Myography
Acetylcholine

Citer dette

Schmidt, K., Dubrovska, G., Nielsen, G., Fesus, G., Uhrenholt, T. R., Hansen, P. B. L., ... Köhler, R. (2010). Amplification of EDHF-type vasodilatations in TRPC1-deficient mice. British Journal of Pharmacology, 161(8), 1722-1733. https://doi.org/10.1111/j.1476-5381.2010.00985.x
Schmidt, Kjestine ; Dubrovska, Galyna ; Nielsen, Gorm ; Fesus, Gabor ; Uhrenholt, Torben Rene ; Hansen, Pernille B. Lærkegaard ; Gudermann, Thomas ; Dietrich, Alexander ; Gollasch, Maik ; de Wit, Cor ; Köhler, Ralf. / Amplification of EDHF-type vasodilatations in TRPC1-deficient mice. I: British Journal of Pharmacology. 2010 ; Bind 161, Nr. 8. s. 1722-1733.
@article{97bd586f600b4a518d3b9eea50bdaf67,
title = "Amplification of EDHF-type vasodilatations in TRPC1-deficient mice",
abstract = "Summary 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 (STOC) 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.",
author = "Kjestine Schmidt and Galyna Dubrovska and Gorm Nielsen and Gabor Fesus and Uhrenholt, {Torben Rene} and Hansen, {Pernille B. L{\ae}rkegaard} and Thomas Gudermann and Alexander Dietrich and Maik Gollasch and {de Wit}, Cor and Ralf K{\"o}hler",
note = "{\circledC} 2010 The Authors. British Journal of Pharmacology {\circledC} 2010 The British Pharmacological Society.",
year = "2010",
month = "12",
day = "20",
doi = "10.1111/j.1476-5381.2010.00985.x",
language = "English",
volume = "161",
pages = "1722--1733",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "John Wiley & Sons Ltd",
number = "8",

}

Schmidt, K, Dubrovska, G, Nielsen, G, Fesus, G, Uhrenholt, TR, Hansen, PBL, Gudermann, T, Dietrich, A, Gollasch, M, de Wit, C & Köhler, R 2010, 'Amplification of EDHF-type vasodilatations in TRPC1-deficient mice', British Journal of Pharmacology, bind 161, nr. 8, s. 1722-1733. https://doi.org/10.1111/j.1476-5381.2010.00985.x

Amplification of EDHF-type vasodilatations in TRPC1-deficient mice. / Schmidt, Kjestine; Dubrovska, Galyna; Nielsen, Gorm; Fesus, Gabor; Uhrenholt, Torben Rene; Hansen, Pernille B. Lærkegaard; Gudermann, Thomas; Dietrich, Alexander; Gollasch, Maik; de Wit, Cor; Köhler, Ralf.

I: British Journal of Pharmacology, Bind 161, Nr. 8, 20.12.2010, s. 1722-1733.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Amplification of EDHF-type vasodilatations in TRPC1-deficient mice

AU - Schmidt, Kjestine

AU - Dubrovska, Galyna

AU - Nielsen, Gorm

AU - Fesus, Gabor

AU - Uhrenholt, Torben Rene

AU - Hansen, Pernille B. Lærkegaard

AU - Gudermann, Thomas

AU - Dietrich, Alexander

AU - Gollasch, Maik

AU - de Wit, Cor

AU - Köhler, Ralf

N1 - © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

PY - 2010/12/20

Y1 - 2010/12/20

N2 - Summary 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 (STOC) 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.

AB - Summary 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 (STOC) 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.

U2 - 10.1111/j.1476-5381.2010.00985.x

DO - 10.1111/j.1476-5381.2010.00985.x

M3 - Journal article

VL - 161

SP - 1722

EP - 1733

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 8

ER -