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Circulation. 2000;101:2103-2109

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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

Sumanth D. Prabhu, MD; Bysani Chandrasekar, PhD; David R. Murray, MD; Gregory L. Freeman, MD

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)-{alpha}, 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-{alpha}, 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-{alpha} 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-{alpha} 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-{alpha} and IL-1ß but not IL-6, and one mechanism underlying the beneficial effects of ß-adrenergic blockade may involve attenuation of TNF-{alpha} 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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