β-Blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction

Hideaki Senzaki, Nazareno Paolocci, Yehezkiel A. Gluzband, Merry L. Lindsey, Joseph S. Janicki, Michael T. Crow, David A. Kass

Research output: Contribution to journalArticlepeer-review

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 β-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 β-blockade may limit chamber remodeling and diastolic dysfunction.

Original languageEnglish (US)
Pages (from-to)807-815
Number of pages9
JournalCirculation research
Volume86
Issue number7
DOIs
StatePublished - Apr 14 2000

Keywords

  • Angiotensin II
  • Diastole
  • Heart failure
  • Metalloproteinase
  • β-receptor blocker

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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