A CALCIUM-STIMULATED CYSTEINE PROTEASE INVOLVED IN ISOPROTERENOL-INDUCED CARDIAC-HYPERTROPHY

The purpose of this study was to test the relationship between biochem ical and functional changes accompanying beta-agonist induced cardiac hypertrophy and the activation of a calcium stimulated cysteine protea se. Because the ultrastructural and ionic changes accompanying beta-ag onist induced cardiac hypertrophy are reminiscent of the actions of th e calcium activated neutral protease, calpain, it was hypothesized tha t lowering calpain activity (by the use of an exogenous inhibitor(s)) would reduce the extent of hypertrophy. Rats (275-300 g) were randomly assigned to either a control, beta-agonist (iso) or cysteine protease inhibitor (E64c) group. Isoproterenol administration(1 mg/kg) resulte d in changes for ventricular weight to body weight ratio (up arrow 19% ), ventricular [RNA] (up arrow 105.6%), rate of pressure development ( up arrow 22% for +dP/dt) and maximum developed left ventricular pressu re (up arrow 19%) (p < 0.05) after 3 days. Calpain-like activity (asse ssed by microplate method) increased by 45% (p < 0.05), while [cAMP] r eturned to control levels (following a transient rise at 1 day; 606.03 +/- 124.1 pmol/g/wet/wt to 937.9 +/- 225 (p < 0.05)). E64e (administe red 1 h prior to iso) reduced the extent of hypertrophy, from 19 to 12 %, and prevented the increases in; total [RNA], left ventricular funct ion, the initial [cAMP] increase and calpain-like activity. It is conc luded that a calcium stimulated cysteine protease(s), such as calpain, may be involved in the biochemical and functional changes associated with isoproterenol induced cardiac hypertrophy.