G(i)-dependent suppression of beta(1)-adrenoceptor effects in ventricular myocytes from NE-treated guinea pigs.
It has been suggested that there is a preferential coupling in heart muscle between the inhibitory G protein (G(i)) and the beta(2)-subtype of the beta-adrenergic receptor (beta-AR), since pertussis toxin (which inactivates G(i)) reveals latent beta(2)-ARs in rat and mouse myocytes. We have previously shown that guinea pigs treated with norepinephrine (NE) for 7 days have myocytes that are desensitized to beta-AR-agonist stimulation, and that pertussis toxin restores these responses. The purpose of the present investigation was to determine whether pertussis toxin specifically upregulated beta(2)-ARs in myocytes from NE-treated guinea pigs. The sole beta-AR subtype in control guinea pig myocytes was confirmed as beta(1)-AR by radioligand binding, single-cell autoradiography, and concentration-response curves to isoproterenol in contracting myocytes. In contrast, a minor pool of beta(2)-ARs was observed in rat myocytes by use of the same methods. NE treatment decreased the maximum isoproterenol response (relative to high Ca(2+)) from 0.89 +/- 0.06 to 0.58 +/- 0.08 (n = 7, P < 0.01) and the pD(2) (-log EC(50)) from 8.8 +/- 0.2 to 7.5 +/- 0.2 (n = 7, P < 0.01). Pertussis toxin treatment increased the isoproterenol-to-Ca(2+) ratio to 0.88 +/- 0.04 (n = 6, P < 0.05) and the pD(2) to 8.6 +/- 0.3 (P < 0.01). This was not mediated by increases in either number or function of beta(2)-ARs. G(i) is therefore able to modulate beta(1)-AR responses in guinea pig myocytes.
Ranu
H K
HK
Cardiac Medicine, Imperial College School of Medicine at the National Heart and Lung Institute, London, United Kingdom.
Mak
J C
JC
Barnes
P J
PJ
Harding
S E
SE
D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008024:Ligands; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D037342:Pertussis Toxin; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D008024:Ligands; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D009638:Norepinephrine