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(Circulation Research. 2005;97:566.)
© 2005 American Heart Association, Inc.

Cellular Biology

Crosstalk of ß-Adrenergic Receptor Subtypes Through G_i Blunts ß-Adrenergic Stimulation of L-Type Ca²⁺ Channels in Canine Heart Failure

Jia-Qiang He, Ravi C. Balijepalli, Robert A. Haworth, 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.

Correspondence to Dr Timothy J. Kamp, Dept of Medicine, University of Wisconsin, H6/343 Clinical Science Center, Box 3248, 600 Highland Ave, Madison, WI 53792. E-mail tjk{at}medicine.wisc.edu

The mechanisms underlying the blunted contractile response to ß-adrenergic receptor (ß-AR) stimulation in heart failure (HF) are incompletely understood, especially with regard to ß-AR subtype–specific regulation of L-type Ca²⁺ channels. We evaluated the impact of HF induced by pacing tachycardia on ß-AR regulation of L-type Ca²⁺ channels in a canine model. To evaluate changes in the relative subcellular distribution of ß-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 ß₁-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 ß₂-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 ß-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 ß₁-AR– and ß₂-AR–selective stimulation showed that the major component of the blunted response to nonselective ß-AR stimulation in HF was caused by ß₂-AR activation, resulting in a pertussis toxin–sensitive, G_i-mediated inhibition of the ß₁-AR–induced increase in I_Ca,L. In conclusion, canine HF results in the following: (1) a uniform reduction in ß₁-AR density in surface and T-tubule membrane fractions without a change in ß₂-AR density; and (2) the emergence of distinct G_i-coupling to ß₂-ARs resulting in accentuated antagonism of ß₁-AR–mediated stimulation of I_Ca,L. These results have implications for optimizing the use of ß-AR drugs in HF.

Key Words: heart failure • ventricular myocytes • ß-adrenergic receptor • calcium channels • electrophysiology

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