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Circulation Research. 2005
Published online before print August 11, 2005, doi: 10.1161/01.RES.0000181160.31851.05
A more recent version of this article appeared on September 16, 2005
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Submitted on July 7, 2005
Revised on July 28, 2005
Accepted on August 1, 2005

Crosstalk of {beta}-Adrenergic Receptor Subtypes Through Gi Blunts {beta}-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure

Jia-Qiang He ; Ravi C. Balijepalli ; Robert A. Haworth ; and Timothy J. Kamp *

From the Departments of Medicine (R.C.B., T.J.K.), Physiology (J.-Q.H., T.J.K.), and Surgery (R.A.H.), University of Wisconsin-Madison.

* To whom correspondence should be addressed. E-mail: tjk{at}medicine.wisc.edu.

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 [125I]cyanopindolol revealed that HF resulted in a comparable decrease in the density of {beta}1-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 {beta}2-AR density was observed. Whole-cell patch clamp studies demonstrated a markedly blunted increase in ICa,L in response to saturating concentrations of the nonselective {beta}-AR agonist isoproterenol (0.1 µmol/L) in failing myocytes compared with control (129±20%, n=11, versus 332±35%, n=7; P<0.001). Experiments testing {beta}1-AR- and {beta}2-AR-selective stimulation showed that the major component of the blunted response to nonselective {beta}-AR stimulation in HF was caused by {beta}2-AR activation, resulting in a pertussis toxin-sensitive, Gi-mediated inhibition of the {beta}1-AR-induced increase in ICa,L. In conclusion, canine HF results in the following: (1) a uniform reduction in {beta}1-AR density in surface and T-tubule membrane fractions without a change in {beta}2-AR density; and (2) the emergence of distinct Gi-coupling to {beta}2-ARs resulting in accentuated antagonism of {beta}1-AR-mediated stimulation of ICa,L. These results have implications for optimizing the use of {beta}-AR drugs in HF.
Key words: heart failure • ventricular myocytes • {beta}-adrenergic receptor • calcium channels • electrophysiology


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