TY - JOUR
T1 - Mechanisms of beta 3-adrenoceptor-induced eNOS activation in right atrial and left ventricular human myocardium
AU - Brixius, Klara
AU - Bloch, Wilhelm
AU - Pott, Christian
AU - Napp, Andreas
AU - Krahwinkel, Andreas
AU - Ziskoven, Christoph
AU - Koriller, Marco
AU - Mehlhorn, Uwe
AU - Hescheler, J
AU - Fleischmann, Bernd
AU - Schwinger, Robert H G
PY - 2004/12/1
Y1 - 2004/12/1
N2 - beta-Adrenoceptors are important modulators of cardiac function. The present study investigated beta(3)-adrenergic eNOS activation in human myocardium. We measured nitric oxide (NO) liberation (diaminofluorescence) and signal transduction (immunohistochemistry, phosphorylation of eNOS(Ser1177), eNOS(Thr495), eNOS(Ser114), Akt/protein kinase B (Akt/PKB), and eNOS translocation) in human right atrial (RA, aortocoronary-bypass OP) and left ventricular nonfailing (LV, rejected donor hearts) myocardium after application of BRL 37344 (BRL), a preferential beta(3)-adrenoceptor agonist. In both RA and LV, BRL (10 microl) induced a liberation of NO. An eNOS activation via translocation was only observed in RA after application of BRL (10 microM). Yet, the NO liberation in both LV and RA was accompanied by phosphorylation of eNOS(Ser1177) and Akt/PKB. BRL-induced eNOS phosphorylation was abolished by LY292004, a blocker of PI-3 kinase. eNOS-Ser(114) phosphorylation was unchanged in RA, but decreased in LV after beta(3)-adrenergic stimulation. BRL did not alter phosphorylation of eNOS(Thr495). In conclusion, receptor-dependent eNOS activation is differentially regulated in the human heart. In the left ventricle, eNOS activation via phosphorylation seems to be of major importance, whereas in human atrial myocardium eNOS translocation is the predominant mechanism induced by beta(3)-adrenergic activation.
AB - beta-Adrenoceptors are important modulators of cardiac function. The present study investigated beta(3)-adrenergic eNOS activation in human myocardium. We measured nitric oxide (NO) liberation (diaminofluorescence) and signal transduction (immunohistochemistry, phosphorylation of eNOS(Ser1177), eNOS(Thr495), eNOS(Ser114), Akt/protein kinase B (Akt/PKB), and eNOS translocation) in human right atrial (RA, aortocoronary-bypass OP) and left ventricular nonfailing (LV, rejected donor hearts) myocardium after application of BRL 37344 (BRL), a preferential beta(3)-adrenoceptor agonist. In both RA and LV, BRL (10 microl) induced a liberation of NO. An eNOS activation via translocation was only observed in RA after application of BRL (10 microM). Yet, the NO liberation in both LV and RA was accompanied by phosphorylation of eNOS(Ser1177) and Akt/PKB. BRL-induced eNOS phosphorylation was abolished by LY292004, a blocker of PI-3 kinase. eNOS-Ser(114) phosphorylation was unchanged in RA, but decreased in LV after beta(3)-adrenergic stimulation. BRL did not alter phosphorylation of eNOS(Thr495). In conclusion, receptor-dependent eNOS activation is differentially regulated in the human heart. In the left ventricle, eNOS activation via phosphorylation seems to be of major importance, whereas in human atrial myocardium eNOS translocation is the predominant mechanism induced by beta(3)-adrenergic activation.
KW - Adrenergic beta-3 Receptor Agonists
KW - Adult
KW - Enzyme Activation
KW - Ethanolamines
KW - Female
KW - Heart Atria
KW - Heart Ventricles
KW - Humans
KW - Male
KW - Middle Aged
KW - Myocardium
KW - Nitric Oxide Synthase
KW - Nitric Oxide Synthase Type III
KW - Receptors, Adrenergic, beta-3
U2 - 10.1038/sj.bjp.0705983
DO - 10.1038/sj.bjp.0705983
M3 - Journal articles
C2 - 15466444
SN - 0007-1188
VL - 143
SP - 1014
EP - 1022
JO - British journal of pharmacology
JF - British journal of pharmacology
IS - 8
ER -