Altered signal transduction in cardiac ventricle overexpressing A(1)-adenosine receptors.
OBJECTIVE
The aim of the present study was to assess the effects of A(1)-adenosine receptor (A1-AR) stimulation in ventricle of A(1)-adenosine receptor overexpressing mice (transgenic mice, TG).


METHODS
Effects of the A(1)-adenosine receptor agonist R-PIA ((-)-N(6)-phenylisopropyladenosine) on phosphorylation of phospholamban (PLB), Ca(2+) transients, Ca(2+) currents and cell shortening were studied in isolated ventricular cardiomyocytes.


RESULTS
R-PIA alone did not affect contractility in isolated electrically stimulated cardiomyocytes from wild-type mice (WT) or TG. However, after pre-stimulation of beta-adrenoceptors by isoproterenol, R-PIA reduced contractility in cardiomyocytes from WT but increased contractility in TG. Under the same conditions, R-PIA reduced isoproterenol-stimulated currents through L-type Ca(2+) channels, Ca(2+) transients and phosphorylation of PLB in cardiomyocytes from WT. In contrast, R-PIA diminished phospholamban phosphorylation induced by isoproterenol but augmented isoproterenol-elevated currents through L-type Ca(2+) channels, and isoproterenol-heightened Ca(2+) transients in cardiomyocytes from TG.


CONCLUSIONS
We suggest that A(1)-adenosine receptor overexpression reverses the interaction of beta-adrenergic and A(1)-adenosine receptor stimulation, at least in part. Hence, the receptor/effector coupling is dependent on receptor density in this model.
Neumann
Joachim
J
Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Westfälische Wilhelms-Universität, Domagkstrasse 12, D-48129 Münster, Germany.
Boknik
Peter
P
Begrow
Frank
F
Hanske
Gabriela
G
Justus
Isabel
I
Mát'us
Marek
M
Reinke
Uta
U
Matherne
G Paul
GP
Schmitz
Wilhelm
W
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000235:genetics*; D015398:Signal Transduction; D013268:Stimulation, Chemical; D000099211:Phospholamban
D000241:Adenosine; D002118:Calcium; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D007545:Isoproterenol; D018047:Receptors, Purinergic P1; D000099211:Phospholamban; C047235:N-(1-methyl-2-phenylethyl)adenosine