Noradrenaline-induced increase in protein synthesis in adult rat cardiomyocytes: involvement of only alpha1A-adrenoceptors.
Adult rat ventricular cardiomyocytes contain alpha1A- and alpha1B-adrenoceptors (ARs, 20%:80%, assessed by [3H]prazosin binding). We studied which alpha1-AR subtype mediates noradrenaline (NA)-induced increase in rate of protein synthesis, and which signalling pathway is involved. NA (10-9-10-4 M) concentration-dependently increased inositol phosphate (IP) formation (pEC50-value=6.1+/-0.1, n=5) and protein synthesis (assessed as [3H]phenylalanine incorporation; pEC50-value=6.6+/-0.1, n=6). NA-induced IP-formation was partly inhibited by the alpha1B-AR antagonist chloroethylclonidine (CEC, 30 microM; 33+/-9% inhibition, n=5); following CEC-treatment the alpha1A-AR-selective 5-methyl-urapidil (5-MU) inhibited NA-induced IP-formation with a pKi-value of 9.2+/-0.2 (n=6); the alpha1D-AR-selective BMY 7378 was only a weak antagonist (pKi-value <7). NA-induced increase in protein synthesis was insensitive to CEC whereas 5-MU inhibited it with a pKi-value of 9.1+/-0.2 (n=6). NA (1 microM)-induced increase in protein synthesis was inhibited by the protein kinase C (PKC) inhibitor bisindolylmaleimide (IC50-value: 206 nM), the PI 3-kinase inhibitors wortmannin (IC50=3.4 nM) and LY 294002 (IC50=10 microM), and p70s6-kinase inhibitor rapamycin (IC50=123 pM) but not by the p38 MAP-kinase inhibitor SB 203580 (10 microM) or the MEK-inhibitor PD 98059 (25 microM). Moreover, 5-MU (30 nM) but not CEC inhibited NA-induced activation of p70s6-kinase. We conclude that, in adult rat cardiomyocytes, alpha1A- and alpha1B-AR mediate NA-induced IP-formation but only alpha1A-ARs mediate increase in protein synthesis. Alpha1A-AR-mediated increase in protein synthesis involves activation of a PKC, PI 3-kinase and p70s6-kinase but not of ERK- or p38 MAP-kinase.
Pönicke
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Institute of Pharmacology and Toxicology, Martin Luther University of Halle, Magdeburger Strasse 4, 06097 Halle, Saale, Germany.
Schlüter
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KD
Heinroth-Hoffmann
I
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Seyfarth
T
T
Goldberg
M
M
Osten
B
B
Piper
H M
HM
Brodde
O E
OE
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D014176:Protein Biosynthesis; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007295:Inositol Phosphates; D018340:Receptors, Adrenergic, alpha-1; D019893:Ribosomal Protein S6 Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus; D009638:Norepinephrine