Lack of evidence for improved β-adrenoceptor-mediated papillary muscle contraction by low-dose empagliflozin treatment in a rat model of streptozotocin-induced diabetes

Diabetes mellitus leads to cardiovascular complications including impaired cardiac β-adrenoceptor (β-AR) function. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin (EMPA), improve outcomes in heart failure patients and animal models. Therefore, we have investigated the effects of EMPA on in vivo cardiac function and β-AR mediated contractile responses in streptozotocin (STZ)-induced diabetes in a design reflecting late-onset of treatment. Male Sprague Dawley rats were divided into 4 groups (control, EMPA-treated control, diabetic, and EMPA- treated diabetic). Diabetes was induced by STZ injection (40 mg/kg). 13-16 weeks after STZ injection, a low dose of EMPA (10 mg/kg/day, daily oral gavage) or vehicle was administered for another 8 weeks. At the end of the treatment period, in vivo cardiac function was evaluated by pressure-volume (PV) loop analysis and β-AR mediated contractile response was determined by isoprenaline on isolated papillary strips. The blood glucose-lowering effect of low-dose EMPA was confirmed. EMPA did not change cardiac function in control rats. Diabetic rats had a reduced heart rate, cardiac output, stroke work, rate of contraction and rate of relaxation and increased isovolumic relaxation, whereas in vitro responses were not markedly attenuated. Treatment with EMPA showed a trend for improvement of some (e.g., stroke volume, ejection fraction, cardiac index) but not all parameters. Our results indicate that low-dose EMPA treatment had limited effects on cardiac impairment despite reducing blood glucose when initiated after diabetes has manifested. Future studies using a preventive rather than therapeutic approach could help to clarify the possible benefits of EMPA on the diabetic heart.