Cariporide - a selective inhibitor of the sodium hydrogen exchanger isoform-1 -given during closed-chest resuscitation enables generation of viable perfusion pressures with less depth of compression. We hypothesized that such effect results from greater blood flows generated for a given depth of compression. Two series of 14 rats each underwent 10 minutes of untreated ventricular fibrillation followed by 8 minutes of chest compression before attempting defibrillation. Compression depth was adjusted to maintain an aortic diastolic pressure (ADP) between 26 and 28 mm Hg in the first series and between 36 and 38 mm Hg in the second series. Within each series, rats were randomized to receive cariporide (3-mg/kg) or NaCl 0.9% (control) before starting chest compression. Blood flow was measured using 15-µ fluorescent microspheres. Less depth of compression was required to maintain the target ADP when cariporide was present in both the first (13.6 ± 1.2 vs 16.6 ± 1.2 mm, p < 0.001) and the second series (15.3 ± 1.0 vs 18.9 ± 1.5 mm, p < 0.001). Despite less compression depth, the cardiac index in cariporide-treated rats was comparable to control rats in the first series (11.1 ± 0.7 vs 11.3 ± 1.4 ml/min/kg, NS) but higher in the second series (15.5 ± 2.3 vs 9.9 ± 1.4 ml/min/kg, p < 0.05). Increases in compression depth (first to second series) increased myocardial, cerebral, and adrenal blood flows in cariporide-treated rats. We conclude that cariporide enhances the efficacy of closed-chest resuscitation by leftward shift of the flow-depth relationship.