Agonist-specific activation of the beta2-adrenoceptor/Gs-protein and beta2-adrenoceptor/Gi-protein pathway in adult rat ventricular cardiomyocytes.
In rat ventricular cardiomyocytes beta2-adrenoceptors (AR) couple to Gs- and Gi-protein, and evidence has accumulated that beta2-AR agonists can differentially activate either Gs- or Gs- and Gi-protein. In this study, in isolated adult rat ventricular cardiomyocytes, we assessed the effects of pertussis toxin (PTX) on beta2-AR agonist (terbutaline (TER), salbutamol (SAL) and fenoterol (FEN)) evoked inhibition of phenylephrine (PE)-induced increase in the rate of protein synthesis (assessed as [3H]phenylalanine incorporation) to find out which beta2-AR agonist activates selectively Gs- or Gs- and Gi-protein. PE (1 microM) increased the rate of protein synthesis from 100% to 130+/-2% (n = 34). FEN, TER and SAL (1 nM-10 microM) inhibited PE-induced increase in the rate of protein synthesis concentration-dependently. FEN inhibited PE effects almost completely (from 132+/-3 to 101+/-1%), whereas TER and SAL caused only partial inhibition (from 131+/-2 to 114+/-2 and 129+/-1 to 111+/-2%, respectively). Pretreatment of cardiomyocytes with PTX (250 ng ml(-1) for 16 h at 37 degrees C) did not affect FEN effects, but converted TER- and SAL-evoked partial inhibition into complete inhibition. Inhibitory effects of the three beta2-AR agonists were markedly attenuated by beta1-AR selective antagonist CGP 20712A (CGP) (300 nM); in contrast, beta2-AR selective antagonist ICI 118,551 (55 nM) inhibited the inhibitory effects of the three beta2-AR agonists only in PTX-pretreated cardiomyocytes,with beta1-AR blocked by CGP. We conclude that, in adult rat ventricular cardiomyocytes, FEN activates selectively the Gs protein-pathway, while TER and SAL activate the Gs- and Gi-protein pathways. Part of the effects of these three beta2-AR agonists appears to be mediated by beta1-AR.
Institute of Pharmacology and Toxicology, Martin-Luther-University Halle-Wittenberg, Magdeburger Strasse 4, D-06097 Halle, Saale, Germany.
Klaus
K
Pönicke
Ferdinand
F
Gröner
Ingrid
I
Heinroth-Hoffmann
Otto-Erich
OE
Brodde
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D005280:Fenoterol / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000819:agonists*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010649:Phenylalanine / Q000378:metabolism; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013726:Terbutaline / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D009124:Muscle Proteins; D011412:Propanolamines; D010656:Phenylephrine; D005280:Fenoterol; C026777:ICI 118551; D010649:Phenylalanine; C049763:CGP 20712A; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs; D013726:Terbutaline; D000420:Albuterol