Inhibition of Sodium Glucose Cotransporter‐2 Improves Cardiac Efficiency During Regional Myocardial Ischemia Independent of Sodium/Hydrogen Exchanger‐1

Abstract

Recent clinical outcome studies demonstrate that inhibitors of the type 2 sodium glucose cotransporters (SGLT2i) significantly reduce major adverse cardiovascular events and heart failure outcomes in type 2 diabetes mellitus. The mechanisms underlying these clinical benefits remain to be elucidated. We tested the hypothesis that SGLT2i improves cardiac function and efficiency during acute, regional ischemia/reperfusion injury via inhibition of cardiac sodium/hydrogen exchanger‐1 (NHE‐1). Lean swine (~50 kg) were anesthetized, a thoracotomy was performed, and perivascular flow transducers were placed around the left anterior descending and circumflex coronary arteries. A pressure‐volume catheter was then inserted into the left ventricle. Swine received a 15–30 min (0.05–0.1 mL/min) infusion of vehicle (DMSO), the SGLT2i canagliflozin (30 μM), or the NHE‐1 inhibitor (NHE‐1i) cariporide (1 μM) immediately prior to a 60 min occlusion of the left circumflex artery followed by a 2‐hour reperfusion period. Mean arterial pressure decreased from ~91 ± 3 mmHg at baseline to ~62 ± 3 mmHg following 60 min of myocardial ischemia in control, canagliflozin and cariporide treated swine. Heart rate averaged ~78 beats/min at baseline and throughout the ischemic period, however, SGLT2i significantly increased heart rate during reperfusion compared to control and NHE‐1i treated swine. SGLT2i was associated with a significant increase in left ventricular end diastolic volume (P = 0.02) that corresponded with a significant increase in stroke volume (P = 0.03) and cardiac efficiency (P < 0.001) relative to control animals. End diastolic volume, stroke volume, and efficiency were not significantly affected by ischemia/reperfusion injury in either the control or NHE‐1i treated animals. Additional fluorometric assays of antiport‐deficient Chinese hamster ovary (AP‐1) cells transfected with wild‐type NHE‐1 showed dose‐dependent inhibition of NHE‐1 activity by cariporide (IC50 = 0.11 mM), while canagliflozin had minimal effect on overall activity. This investigation demonstrates that SGLT2i improves cardiac function and efficiency during acute, regional ischemia in healthy swine. However, these data argue against an important role of NHE‐1 inhibition in mediating the beneficial cardiac effects of SGLT2i.Support or Funding InformationEli Lilly and Company