The present study evaluated the effects of indomethacin (INDO) on cardiovascular and lysosomal mechanisms during experimental myocardial ischemia (MI). INDO (5 mg/kg) was infused IV prior to MI, and the results were compared to vehicle-treated and sham-operated dogs. INDO induced a slight hypertension after MI. Additionally, INDO attenuated the decline in coronary blood flow in the non-ischemic myocardium after MI. Myocardial lysosomes (biopsied three hours post-MI) were more labile in ischemic than in nonischemic tissue, and INDO had a stabilizing effect on lysosomes from ischemic tissue. Plasma activity of cathepsin was increased following MI, and INDO attenuated this increase. In the myocardium (biopsies three hours post-MI) prostaglandin A + E levels were suppressed 60% in both ischemic and nonischemic tissue with INDO treatment; prostaglandin F2 alpha levels were lower with INDO treatment but not significantly so. These results suggest that INDO has a stabilizing effect on lysosomes in vivo, possibly involving an endogenous prostaglandin mechanism, and this protective effect may attenuate lysosomal damage to the cardiovascular system during MI.