Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure.
OBJECTIVE
This study tested the hypothesis that metoprolol restores the reduction of the inotropic effect of the cyclic adenosine monophosphate (cAMP)-phosphodiesterase inhibitor milrinone, which is cAMP dependent but beta-adrenoceptor independent.


BACKGROUND
Treatment with beta-adrenergic blocking agents has been shown to lessen symptoms and improve submaximal exercise performance and left ventricular ejection fraction in patients with heart failure. Restoration of the number of down-regulated beta-adrenoceptors has been suggested to be one mechanism of beta-blocker effectiveness. However, the reversal of postreceptor events, namely, an increase in inhibitory G-protein alpha-subunit concentrations, could also play a role.


METHODS
Fifteen patients with heart failure due to dilated cardiomyopathy (left ventricular ejection fraction 24.6 +/- 1.5% [mean +/- SD], New York Heart Association functional class II or III) were treated with metoprolol (maximal dose 50 mg three times daily) for 6 months. Before and after metoprolol treatment, inotropic responses to milrinone (5 to 10 micrograms/kg body weight per min) were measured echocardiographically. For comparison, responses to milrinone were determined under control conditions and after accelerated application of 150 mg of metoprolol to inactivate beta-adrenoceptors in subjects with normal left ventricular function.


RESULTS
In subjects with normal left ventricular function, treatment with metoprolol did not alter the increase in fractional shortening or pressure/dimension ratio of circumferential fiber shortening after application of milrinone. In patients with heart failure, treatment with metoprolol significantly increased left ventricular ejection fraction, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations and functional class. After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blocker treatment.


CONCLUSIONS
Milrinone increases inotropic performance independently of beta-adrenoceptors in vivo. Metoprolol treatment restores the blunted inotropic response to milrinone in patients with heart failure, indicating that postreceptor events (e.g., increase in inhibitory G-protein) are favorably influenced. This mechanism could contribute to the beneficial effects observed in the study patients and represents an important mechanism of how beta-blocker treatment influences the performance of the failing heart.
Böhm
M
M
Klinik III für Innere Medizin, Universität zu Köln, Cologne, Germany. michael.boehm@medizin.univ.koeln.de
Deutsch
H J
HJ
Hartmann
D
D
Rosée
K L
KL
Stäblein
A
A
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000150:complications; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use*; D008875:Middle Aged; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011953:Receptors, Cyclic AMP / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D014463:Ultrasonography
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011943:Receptors, Adrenergic, beta; D011953:Receptors, Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008790:Metoprolol; D020105:Milrinone