Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits

Thiazide-like diuretics are one of the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effects. Previous studies have suggested that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK c...

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Autores principales: Martín, Pedro, Moncada, Melisa, Kuntamallappanavar, Guruprasad, Dopico, Alex M., Milesi, María Verónica
Formato: Articulo
Lenguaje:Inglés
Publicado: 2017
Materias:
Ciencias Exactas
BK channel
Slo1
human umbilical artery
thiazide
hydrochlorothiazide
beta-1 subunit
vascular smooth muscle cells
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/167271
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-167271
record_format dspace
spelling I19-R120-10915-1672712024-06-14T20:08:56Z http://sedici.unlp.edu.ar/handle/10915/167271 Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits Martín, Pedro Moncada, Melisa Kuntamallappanavar, Guruprasad Dopico, Alex M. Milesi, María Verónica 2017-11-30 2024-06-14T15:14:47Z en Ciencias Exactas BK channel Slo1 human umbilical artery thiazide hydrochlorothiazide beta-1 subunit vascular smooth muscle cells Thiazide-like diuretics are one of the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effects. Previous studies have suggested that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK channel) is responsible for the thiazide-induced vasodilatory effect. However, direct electrophysiological evidence supporting this claim is lacking. BK channels can be associated with small accessory β-subunits (β1-β4) that confer specific biophysical and pharmacological characteristics to the current phenotype. The β1-subunit is primarily expressed in smooth muscle cells (SMCs). The effect of hydrochlorothiazide (HCTZ) on BK channel activity was measured using patch-clamp electrophysiology on native SMCs from human umbilical artery (HUASMCs) and HEK293T cells expressing the BK channel (with and without the β1-subunit). HCTZ significantly activated the BK current when evaluated using the whole-cell and cell-attached configurations. However, HCTZ did not affect the unitary conductance and open probability of the BK channel in the inside-out configuration, suggesting an indirect mechanism requiring cell integrity. The increase in BK channel activity due to HCTZ was concentration dependent, with an EC50 of 28 μmol/L, and membrane potential did not influence the concentration relationship. Moreover, our data c learly demonstrated that the HCTZ-induced activation of BK channels required the presence of β1-subunits. A β1-subunit-dependent mechanism that requires SMC integrity leads to HCTZ-induced BK channel activation. Instituto de Estudios Inmunológicos y Fisiopatológicos Articulo Articulo http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) application/pdf 371-381
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Exactas
BK channel
Slo1
human umbilical artery
thiazide
hydrochlorothiazide
beta-1 subunit
vascular smooth muscle cells
spellingShingle Ciencias Exactas
BK channel
Slo1
human umbilical artery
thiazide
hydrochlorothiazide
beta-1 subunit
vascular smooth muscle cells
Martín, Pedro
Moncada, Melisa
Kuntamallappanavar, Guruprasad
Dopico, Alex M.
Milesi, María Verónica
Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
topic_facet Ciencias Exactas
BK channel
Slo1
human umbilical artery
thiazide
hydrochlorothiazide
beta-1 subunit
vascular smooth muscle cells
description Thiazide-like diuretics are one of the most commonly used drugs to treat arterial hypertension, with their efficacy being linked to their chronic vasodilatory effects. Previous studies have suggested that activation of the large conductance voltage- and Ca2+-dependent K+ (BK) channel (Slo 1, MaxiK channel) is responsible for the thiazide-induced vasodilatory effect. However, direct electrophysiological evidence supporting this claim is lacking. BK channels can be associated with small accessory β-subunits (β1-β4) that confer specific biophysical and pharmacological characteristics to the current phenotype. The β1-subunit is primarily expressed in smooth muscle cells (SMCs). The effect of hydrochlorothiazide (HCTZ) on BK channel activity was measured using patch-clamp electrophysiology on native SMCs from human umbilical artery (HUASMCs) and HEK293T cells expressing the BK channel (with and without the β1-subunit). HCTZ significantly activated the BK current when evaluated using the whole-cell and cell-attached configurations. However, HCTZ did not affect the unitary conductance and open probability of the BK channel in the inside-out configuration, suggesting an indirect mechanism requiring cell integrity. The increase in BK channel activity due to HCTZ was concentration dependent, with an EC50 of 28 μmol/L, and membrane potential did not influence the concentration relationship. Moreover, our data c learly demonstrated that the HCTZ-induced activation of BK channels required the presence of β1-subunits. A β1-subunit-dependent mechanism that requires SMC integrity leads to HCTZ-induced BK channel activation.
format Articulo
Articulo
author Martín, Pedro
Moncada, Melisa
Kuntamallappanavar, Guruprasad
Dopico, Alex M.
Milesi, María Verónica
author_facet Martín, Pedro
Moncada, Melisa
Kuntamallappanavar, Guruprasad
Dopico, Alex M.
Milesi, María Verónica
author_sort Martín, Pedro
title Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
title_short Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
title_full Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
title_fullStr Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
title_full_unstemmed Activation of smooth muscle BK channels by hydrochlorothiazide requires cell integrity and the presence of BK β1-subunits
title_sort activation of smooth muscle bk channels by hydrochlorothiazide requires cell integrity and the presence of bk β1-subunits
publishDate 2017
url http://sedici.unlp.edu.ar/handle/10915/167271
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AT kuntamallappanavarguruprasad activationofsmoothmusclebkchannelsbyhydrochlorothiaziderequirescellintegrityandthepresenceofbkb1subunits
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