当前位置： SCI文献检索 > CIRCULATION RESEARCH期刊下所有文献 > Crosstalk of beta-adrenergic receptor subtypes through Gi blunts beta-adrenergic stimulation of L-type Ca2+ channels in canine heart failure.

Crosstalk of beta-adrenergic receptor subtypes through Gi blunts beta-adrenergic stimulation of L-type Ca2+ channels in canine heart failure.

Abstract：

:The mechanisms underlying the blunted contractile response to beta-adrenergic receptor (beta-AR) stimulation in heart failure (HF) are incompletely understood, especially with regard to beta-AR subtype-specific regulation of L-type Ca2+ channels. We evaluated the impact of HF induced by pacing tachycardia on beta-AR regulation of L-type Ca2+ channels in a canine model. To evaluate changes in the relative subcellular distribution of beta-AR subtypes, left ventricular membranes enriched in surface sarcolemma and T-tubular sarcolemma were prepared. Radioligand binding using [(125)I]cyanopindolol revealed that HF resulted in a comparable decrease in the density of beta1-ARs in both surface and T-tubule sarcolemma (55+/-4%, n=7, P<0.001; and 45+/-10%, n=7, P<0.01, respectively), but no significant change in beta2-AR density was observed. Whole-cell patch clamp studies demonstrated a markedly blunted increase in I(Ca,L) in response to saturating concentrations of the nonselective beta-AR agonist isoproterenol (0.1 micromol/L) in failing myocytes compared with control (129+/-20%, n=11, versus 332+/-35%, n=7; P<0.001). Experiments testing beta1-AR- and beta2-AR-selective stimulation showed that the major component of the blunted response to nonselective beta-AR stimulation in HF was caused by beta2-AR activation, resulting in a pertussis toxin-sensitive, Gi-mediated inhibition of the beta1-AR-induced increase in I(Ca,L). In conclusion, canine HF results in the following: (1) a uniform reduction in beta1-AR density in surface and T-tubule membrane fractions without a change in beta2-AR density; and (2) the emergence of distinct Gi-coupling to beta2-ARs resulting in accentuated antagonism of beta1-AR-mediated stimulation of I(Ca,L). These results have implications for optimizing the use of beta-AR drugs in HF.

journal_name

Circ Res

journal_title

Circulation research

authors

He JQ,Balijepalli RC,Haworth RA,Kamp TJ

doi

10.1161/01.RES.0000181160.31851.05

subject

Has Abstract

pub_date

2005-09-16 00:00:00

pages

566-73

issue

eissn

0009-7330

issn

1524-4571

pii

01.RES.0000181160.31851.05

journal_volume

pub_type

杂志文章

在线工具

Crosstalk of beta-adrenergic receptor subtypes through Gi blunts beta-adrenergic stimulation of L-type Ca2+ channels in canine heart failure.