A mitogen-activated protein kinase is involved in the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1.
The activation of mitogen-activated protein kinase (MAPK) pathways in the heart, for instance by alpha(1)-adrenoceptor agonists and endothelin-1, has primarily been associated with cellular growth regulation. Here we have investigated a possible role of MAPK pathways in the inotropic and chronotropic effects of adrenoceptor agonists and endothelin-1 in isolated rat left and right atria. Inotropic and chronotropic responses of the isolated atria to methoxamine, isoprenaline and endothelin-1 were measured in the absence and presence of inhibitors of MAPK pathways. The MAPK kinase (MKK(mek)) inhibitors PD98059 (100 microM) and U0126 (10 microM) significantly inhibited the inotropic responses to the alpha(1)-adrenoceptor agonist methoxamine (300 microM) and endothelin-1 (50 nM), but not the chronotropic responses to these agonists. U0126 but not PD98059 inhibited the inotropic response to 3 microM isoprenaline. None of the aforementioned inotropic and chronotropic effects were inhibited by the MAPKP(p38) inhibitor SB203580 (2 microM). We conclude that activation of the PD98059/U0126-sensitive MAPK pathway is essential for the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1.
Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, The Netherlands. s.l.peters@amc.uva.nl
Stephan L M
SL
Peters
Carsten
C
Sand
Martin C
MC
Michel
Martin
M
Pfaffendorf
Pieter A
PA
Van Zwieten
D000322:Adrenergic Agonists / Q000494:pharmacology*; D058646:Adrenergic alpha-1 Receptor Agonists; D000704:Analysis of Variance; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism
D000322:Adrenergic Agonists; D058646:Adrenergic alpha-1 Receptor Agonists; D002070:Butadienes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008729:Methoxamine; D007545:Isoproterenol; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one