Abstract: A method is disclosed for inhibiting calpain by contacting calpain with one or more HIV protease inhibitors or analogs. Included are embodiments for identifying subjects at risk of suffering calpain-mediated physiological damage and administering to them the HIV protease inhibitors or analogs. Alternatively, a compound may be administered to a subject following an actual event implicating activation of calpain. Also included are methods of treating or preventing calpain-mediated physiological damage in a subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition which includes at least one HIV protease inhibitor or analog. The pharmaceutical compositions can be used in the treatment of a variety of conditions or diseases implicated by or associated with calpain activation, including cardiovascular diseases.