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Ischemic heart disease (IHD) is the main cause of death and a major public health problem in the world. The traditional herbal medicinal formula Guan-Xin-Er-Hao (GXEH) has been used in China and East Asia for the treatment of coronary heart disease, however, the underlying cardioprotection mechanisms remain unclear. To make clear the antiischemic mechanism involved, GXEH was orally administered to 15 healthy volunteers. Heart rates (HR), blood pressure and coronary flow (CF) velocity before and 1 h after a single oral dose of GXEH were observed and compared. It was demonstrated that the oral administration of GXEH increased CF acutely in a dose-dependent manner without modification of systemic hemodynamic parameters. Moreover, the myocardial protection function of GXEH was also experimentally examined in ischemia-reperfusion (I/R) rat models. Apoptosis was measured quantitatively by the terminal transferase UTP nick end-labeling (TUNEL) method and confirmed by caspase-3 activity. The infarct size and TUNEL-positive cells of GXEH-treated group (20 g/kg) were reduced significantly, which was consistent with the decreased caspase-3 activity. These suggest that GXEH protects hearts from ischemia injury by increasing CF and reduces infarct size by inhibiting myocardial apoptosis.