Crosstalk of beta-adrenergic receptor subtypes through Gi blunts beta-adrenergic stimulation of L-type Ca2+ channels in canine heart failure.
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.
He
Jia-Qiang
JQ
Department of Physiology, University of Wisconsin, Madison, WI 53792, USA.
Balijepalli
Ravi C
RC
Haworth
Robert A
RA
Kamp
Timothy J
TJ
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004285:Dogs; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000032:analysis / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000502:physiology*; D012508:Sarcolemma / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology*
D020746:Calcium Channels, L-Type; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol; D000420:Albuterol