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

Angiotensin II (Ang II)-mediated sympathostimulation may worsen the progres sion of cardiac failure, although the nature and mechanisms of such interac tions are largely unknown. We previously demonstrated that Ang II combined with evolving cardiodepression (48-hour tachycardia pacing, 48hP) induces m arked chamber stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis that both abnormalities stem from sympathostimulatory e ffects of Ang II. Forty-eight dogs were instrumented to serially assess con scious ventricular mechanics, MMP abundance and activity, and myocardial hi stopathology. 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+4XhP. Both stiffening and MMP c hanges were prevented by cotreatment with high-dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but not partial P-blockade. Myocellular damage with fibroblast/neutrophil infiltration from Ang II+48h P was also inhibited by high- but not low-dose atenolol, whereas collagen c ontent was not elevated with either dose. These data support a role of symp athostimulation by Ang II in modulating myocardial MMP abundance and activi ty and diastolic stiffening in evolving heart failure and suggest a novel m echanism by which beta-blockade may limit chamber remodeling and diastolic dysfunction.