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(Circulation. 2000;101:2103.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
ß-Adrenergic Blockade in Developing Heart Failure
Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling
From the Department of Medicine, University of Texas Health Science Center at San Antonio, and South Texas Veterans Health Care System, Audie Murphy Division, San Antonio, Tex.
Correspondence to Sumanth D. Prabhu, MD, Department of Medicine/Cardiology, University of Louisville, ACB, 3rd floor, 550 South Jackson St, Louisville, KY 40292. E-mail sprabhu{at}louiville.edu
Background—Whether ß-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear.
Methods and Results—We administered oral metoprolol or no therapy
to rats for 12 weeks after large myocardial infarction and subsequently
examined left ventricular (LV) remodeling; myocardial tumor
necrosis factor (TNF)-
, interleukin (IL)-1ß, and IL-6 expression;
and NO. In untreated rats, echocardiography
revealed significant (P<0.001) LV dilatation and
systolic dysfunction compared with sham. Papillary muscle
studies revealed isoproterenol hyporesponsiveness to be unaltered by NO
synthase (NOS) inhibition. Circulating NO metabolites were
undetectable. In noninfarcted myocardium, although
inducible NOS (iNOS) mRNA was absent, TNF-, IL-1ß, and IL-6 mRNA
and protein were markedly elevated compared with sham
(P<0.001), with 2-fold higher expression
(P<0.025) of IL-6 compared with TNF- or IL-1ß.
Metoprolol administration starting 48 hours after infarction (1)
attenuated (P<0.02) LV dilatation and systolic
dysfunction, (2) preserved isoproterenol responsiveness
(P<0.025) via NO-independent mechanisms, and (3)
reduced myocardial gene expression and protein production of
TNF- and IL-1ß (P<0.025) but not IL-6, which
remained high.
Conclusions—During heart failure development, adrenergic
activation contributes to increased myocardial expression of TNF-
and IL-1ß but not IL-6, and one mechanism underlying the beneficial
effects of ß-adrenergic blockade may involve attenuation of TNF-
and IL-1ß expression independent of iNOS and NO.
Key Words: heart failure • adrenergic beta antagonists • cytokines • nitric oxide • myocardial infarction
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