IIFP   25103
INSTITUTO DE ESTUDIOS INMUNOLOGICOS Y FISIOPATOLOGICOS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
BK CHANNEL ACTIVATION IN CHRONIC VASODILATION BY THIAZIDE-LIKE DIURETICS: ROLE OF THE BETA-1 AUXILIARY SUBUNIT
Autor/es:
ENRIQUE N; REBOLLEDO A; MILESI V; MARTÍN, P; ASUAJE A
Lugar:
Foz de Iguazu, Parana Brasil
Reunión:
Congreso; the 48th Brazilian Congress of Pharmacology and Experimental Therapeutics and the 21st Latin American Congress of Pharmacology (SBFTE); 2016
Resumen:
Thiazide-like diuretics are still recommended as first-line antihypertensive therapy, based on their chronic vasodilatory effects. Previous studies suggest activation of the large conductance voltage- and Ca2+- dependent K+ channel (BK channel, Slo 1, MaxiK channel) as responsible for this vasodilator effect, but electrophysiological evidence supporting this is lacking. BK can be accompanied by accessory β-subunits, which confer specific pharmacological characteristics to the channel. The beta-1 subunit is mainly expressed in smooth muscle cells (SMCs). We measured the effect of hydrochlorothiazide (HCTZ) on BK channel activity using the patch-clamp technique in SMCs from human umbilical artery (HUASMCs) and in HEK293 T expressing the BK channel (with and without the beta-1 subunit).In HUASMCs HCTZ (10µM) caused significant activation of the BK current in the whole-cell configuration (528 ± 215 to 1379 ± 132 pA at +40mV, n: 4, p 0.05), suggesting an indirect mechanism. In HEK cells expressing the BK channel (with and without β1-subunit), HCTZ only activates BK channel in the presence of the β1-subunit. This activation was concentration-dependent with an EC50 of 28 µM (pD2=4.546 ± 0.211, n: 5-8). Membrane potential did not influence the concentration relationship on HCTZ-induced BK channel activation. Consistently, HCTZ did not change the BK channel activity when it was evaluated in HEK cells expressing the β1-subunit in the inside-out configuration, where cell integrity is lost.These results suggest that the vasodilatory effects of HCTZ could be due to an indirect activation of the BK channel which depends of the beta-1 subunit expression.