Recent evidence indicates that sodium glucose cotransporter‐2 inhibitors (SGLT2i) significantly reduce the incidence of major adverse cardiovascular events in high risk patients. However, the specific effects of SGLT2i on the cardiovascular system remain poorly defined. This study tested the hypothesis that SGLT2i improves cardiac function during acute regional myocardial ischemia and reperfusion. Lean domestic swine (~50 kg; control (n = 6), SGLT2i (n = 5)) were randomized to receive either placebo or oral doses of canagliflozin (300 mg) 24 hours prior to and the morning of a terminal experimental procedure. Measurements were obtained in open chest, anesthetized swine at baseline, during a 30 min complete occlusion of the circumflex coronary artery, and during a 2 hour reperfusion period. Blood pressure (85 ± 6 mmHg), heart rate (78 ± 7 beats/min), coronary flow (0.40 ± 0.05 mL/min/g), and myocardial oxygen consumption (43 ± 6 μL O2/min/g) were unaffected by canagliflozin treatment at rest and were not significantly altered by ischemia/reperfusion in either group. At the onset of ischemia, SGLT2i produced a significant parallel increase in both left ventricular end diastolic (85 ± 9 mL to 129 ± 10 mL; P < 0.05) and end systolic volumes (29 ± 8 mL to 78 ± 9 mL; P < 0.01) that was manifest ~30 to 90 sec post coronary artery occlusion. Left ventricular volumes remained elevated throughout the ischemic period and returned to baseline levels following ~30 min of reperfusion. Ventricular volumes remained unchanged in control swine throughout the entire protocol. Canagliflozin‐mediated increases in end diastolic volume were directly associated with significant increases in stroke volume (P < 0.05) and stroke work (P < 0.05) relative to untreated controls swine during ischemia. SGLT2i also increased cardiac efficiency (P < 0.05), as defined by stroke work/myocardial oxygen consumption. No differences in myocardial substrate uptake of glucose (P = 0.54) or lactate (P = 0.16) were noted between groups at any experimental time point. These data support the hypothesis that SGLT2i preserves cardiac contractile function during regional myocardial ischemia via activation of a Frank‐Starling mechanism and independent of alterations in myocardial substrate selection. Attached figure illustrates control responses (black) and SGLT2i responses (red). Support or Funding Information NIH HL117620 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.