Effect of beta-blockers on free radical-induced cardiac contractile dysfunction.
BACKGROUND
We examined the effects of hydroxyl radicals (OH.) on human myocardial contractility and on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) activity and the effects of the beta-receptor antagonists metoprolol, carvedilol, and its metabolite BM-910228.


RESULTS
Isometric force of contraction was determined in isolated human myocardium. H(2)O(2) 1 mmol/L and Fe(3+)-nitrilotriacetic acid (Fe(3+)-NTA) 0.1 mmol/L used for generation of OH. induced a decrease in basal force of contraction and an increase in diastolic tension in atrial and left ventricular myocardial preparations. After challenge with OH., the maximum positive inotropic response to Ca(2+) 1.8 to 15 mmol/L was decreased by 60% and by 39%, respectively. The effects of OH. could be blocked by catalase. Carvedilol and its metabolite BM-910228 attenuated the OH.-induced impairment of the inotropic response to Ca(2+) in atrial myocardial preparations. Metoprolol had no significant effect. The stimulation frequency (0.5 to 3.0 Hz)-dependent increase in force of contraction and decrease in diastolic tension were abolished after exposure of atrial trabeculae to OH. In parallel, SERCA activity was decreased by OH. concentration-dependently, as determined in myocardial membrane preparations. BM-910228 partially restored the force-frequency relationship and preserved SERCA activity.


CONCLUSIONS
OH. radicals induce an impairment of contraction and relaxation and an attenuation of the force-frequency relationship in human myocardium accompanied by an inhibition of SERCA. Carvedilol and BM-910228 partly prevented OH.-induced contractile dysfunction. These observations could explain the improvement of ejection fraction in heart failure trials with carvedilol without a restoration of beta-adrenergic receptor density.
Klinik III für Innere Medizin and Klinik für Herz- und Thoraxchirurgie (M.S.) der Universität zu Köln, Cologne, Germany.
M
M
Flesch
C
C
Maack
B
B
Cremers
A T
AT
Bäumer
M
M
Südkamp
M
M
Böhm
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002118:Calcium / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D017665:Hydroxyl Radical / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology
D000319:Adrenergic beta-Antagonists; C103832:BM 910228; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D017665:Hydroxyl Radical; D000252:Calcium-Transporting ATPases; D008790:Metoprolol; D002118:Calcium