Carvedilol inhibits Kir2.3 channels by interference with PIP2-channel interaction.
Eur J Pharmacol
; 668(1-2): 72-7, 2011 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-21663737
Carvedilol, a ß- and α-adrenoceptor blocker, is used to treat congestive heart failure, mild to moderate hypertension, and myocardial infarction. It has been proposed to block K(ATP) channels by binding to the bundle crossing region at a domain including cysteine at position 166, and thereby plugging the pore region. However, carvedilol was reported not to affect Kir2.1 channels, which lack 166 Cys. Here, we demonstrate that carvedilol inhibits Kir2.3 carried current by an alternative mechanism. Carvedilol inhibited Kir2.3 channels with at least 100 fold higher potency (IC(50)=0.49 µM) compared to that for Kir2.1 (IC(50)>50 µM). Kir2.3 channel inhibition was concentration-dependent and voltage-independent. Increasing Kir2.3 channel affinity for PIP(2), by a I213L point mutation, decreased the inhibitory effect of carvedilol more than twentyfold (IC(50)=11.1 µM). In the presence of exogenous PIP(2), Kir2.3 channel inhibition by carvedilol was strongly reduced (80 vs. 2% current inhibition). These results suggest that carvedilol, as other cationic amphiphilic drugs, inhibits Kir2.3 channels by interfering with the PIP(2)-channel interaction.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Propanolaminas
/
Carbazóis
/
Fosfatidilinositol 4,5-Difosfato
/
Canais de Potássio Corretores do Fluxo de Internalização
/
Bloqueadores dos Canais de Potássio
Limite:
Humans
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
México
País de publicação:
Holanda