ENOS is not activated by nebivolol in human failing myocardium.
Nebivolol is a highly selective beta(1)-adrenoceptor blocker with additional vasodilatory properties, which may be due to an endothelial-dependent beta(3)-adrenergic activation of the endothelial nitric oxide synthase (eNOS). beta(3)-adrenergic eNOS activation has been described in human myocardium and is increased in human heart failure. Therefore, this study investigated whether nebivolol may induce an eNOS activation in cardiac tissue. Immunohistochemical stainings were performed using specific antibodies against eNOS translocation and eNOS serine(1177) phosphorylation in rat isolated cardiomyocytes, human right atrial tissue (coronary bypass-operation), left ventricular non-failing (donor hearts) and failing myocardium after application of the beta-adrenoceptor blockers nebivolol, metoprolol and carvedilol, as well as after application of BRL 37344, a specific beta(3)-adrenoceptor agonist. BRL 37344 (10 microM) significantly increased eNOS activity in all investigated tissues (either via translocation or phosphorylation or both). None of the beta-blockers (each 10 microM), including nebivolol, increased either translocation or phosphorylation in any of the investigated tissues. In human failing myocardium, nebivolol (10 microM) decreased eNOS activity. In conclusion, nebivolol shows a tissue-specific eNOS activation. Nebivolol does not activate the endothelial eNOS in end-stage human heart failure and may thus reduce inhibitory effects of NO on myocardial contractility and on oxidative stress formation. This mode of action may be of advantage when treating heart failure patients.
Brixius
Klara
K
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Germany.
Song
Qiaofeng
Q
Malick
Alock
A
Boelck
Birgit
B
Addicks
Klaus
K
Bloch
Wilhelm
W
Mehlhorn
Uwe
U
Schwinger
Robert H G
RH
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002469:Cell Separation; D003720:Densitometry; D004983:Ethanolamines / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects / Q000201:enzymology; D006333:Heart Failure / Q000201:enzymology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D000068577:Nebivolol; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016707:Tissue Fixation; D014665:Vasodilator Agents / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000201:enzymology
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D014665:Vasodilator Agents; D000068577:Nebivolol; D052250:Nitric Oxide Synthase Type III