© 2000 American Heart Association, Inc.
Integrative Physiology |
ß-Blockade Prevents Sustained Metalloproteinase Activation and Diastolic Stiffening Induced by Angiotensin II Combined With Evolving Cardiac Dysfunction
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions (H.S., N.P., D.A.K.), and the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging (Y.A.G., M.T.C.), Baltimore, Md; the Section of Cardiovascular Science, DeBakey Heart Center, Department of Medicine, Methodist Hospital and Baylor College of Medicine, Houston, Tex (M.L.L.); and the Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, Ala (J.S.J.).
Correspondence to David A. Kass, MD, Halsted 500, Division of Cardiology, Johns Hopkins Medical Institutions, 600 N Wolfe St, Baltimore, MD 21287. E-mail dkass{at}bme.jhu.edu
Abstract—Angiotensin II (Ang II)–mediated sympathostimulation may worsen the progression of cardiac failure, although the nature and mechanisms of such interactions are largely unknown. We previously demonstrated that Ang II combined with evolving cardiodepression (48-hour tachycardia pacing, 48hP) induces marked chamber stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis that both abnormalities stem from sympathostimulatory effects of Ang II. Forty-eight dogs were instrumented to serially assess conscious ventricular mechanics, MMP abundance and activity, and myocardial histopathology. 48hP combined with 5 days of Ang II (15±5 ng · kg-1 · min-1 IV) more than doubled chamber stiffness (end-diastolic pressure >25 mm Hg, P<0.001), whereas stiffness was unchanged by Ang II or 48hP alone. In vitro and in situ zymography revealed increased MMP abundance and activity (principally 92-kDa gelatinase) from Ang II+48hP. Both stiffening and MMP changes were prevented by cotreatment with high-dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but not partial ß-blockade. Myocellular damage with fibroblast/neutrophil infiltration from Ang II+48hP was also inhibited by high- but not low-dose atenolol, whereas collagen content was not elevated with either dose. These data support a role of sympathostimulation by Ang II in modulating myocardial MMP abundance and activity and diastolic stiffening in evolving heart failure and suggest a novel mechanism by which ß-blockade may limit chamber remodeling and diastolic dysfunction.
Key Words: angiotensin II • heart failure • metalloproteinase • diastole • ß-receptor blocker
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