Crosstalk of -Adrenergic Receptor Subtypes Through Gi Blunts -Adrenergic Stimulation of L-Type Ca Channels in Canine Heart Failure

The mechanisms underlying the blunted contractile response to -adrenergic receptor ( -AR) stimulation in heart failure (HF) are incompletely understood, especially with regard to -AR subtype–specific regulation of L-type Ca channels. We evaluated the impact of HF induced by pacing tachycardia on -AR regulation of L-type Ca channels in a canine model. To evaluate changes in the relative subcellular distribution of -AR subtypes, left ventricular membranes enriched in surface sarcolemma and T-tubular sarcolemma were prepared. Radioligand binding using [I]cyanopindolol revealed that HF resulted in a comparable decrease in the density of 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 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 -AR agonist isoproterenol (0.1 mol/L) in failing myocytes compared with control (129 20%, n 11, versus 332 35%, n 7; P 0.001). Experiments testing 1-AR– and 2-AR–selective stimulation showed that the major component of the blunted response to nonselective -AR stimulation in HF was caused by 2-AR activation, resulting in a pertussis toxin–sensitive, Gi-mediated inhibition of the 1-AR–induced increase in ICa,L. In conclusion, canine HF results in the following: (1) a uniform reduction in 1-AR density in surface and T-tubule membrane fractions without a change in 2-AR density; and (2) the emergence of distinct Gi-coupling to 2-ARs resulting in accentuated antagonism of 1-AR–mediated stimulation of ICa,L. These results have implications for optimizing the use of -AR drugs in HF. (Circ Res. 2005;97:566-573.)