Abstract
Background: High calcium levels in ischemia promote contractile dysfunction and cell death in myocytes from aged or ovariectomized female mice. This suggests that low estrogen levels alter myocyte calcium homeostasis promoting ischemia and reperfusion (I/R) injury. As I/R injury occurs during cardiac surgery, we propose to determine whether the G-protein coupled estrogen receptor (GPER) agonist, G1, enhances the benefits of a cardioplegic solution designed to protect hearts from ischemic damage. Methods: Hearts were isolated from adult female mice (7-9 mos, n=10) for Langendorff perfusion experiments and perfused with Krebs-Henseleit buffer (37°C; 80 mmHg) for 15 min. Perfusion was then interrupted and St. Thomas’ 2 cardioplegic solution was delivered (7-9°C) either with G1 (110 or 500 nM), or with vehicle alone for 6 min. This was followed by 90 mins global ischemia (22-24°C) and 30 min reperfusion (37°C). Results: Post-ischemic functional recovery in hearts perfused with cardioplegia + G1 (500 nM) was significantly better than cardioplegia alone. Left ventricular developed pressure (LVDP) recovered to 53.0 ± 21.5% for control vs. 78.5 ± 11.3% for G1 (p<0.05). There was, however, no significant difference compared to control with a lower concentration of G1 (110 nM; LVDP=62.0 ± 2.3%). Similar results were seen when the rates of pressure development (+dp/dt) and decay (-dp/dt) were assessed. Values for recovery of +dp/dt were 55.8 ± 22.5% vs. 84.2 ± 12% and for –dp/dt were 56.3 ± 22.3% vs. 86.3 ± 10.6% for control and G1 (500 nM), respectively. By contrast, lower concentrations of G1 had no effect on +dp/dt or –dp/dt. Conclusion: These results demonstrate that addition of 500 nM G1 enhances cardioprotective properties of a standard cardioplegic solution and significantly improves functional recovery after ischemia in female mouse hearts. These results have the potential to improve outcomes during cardiac surgery.
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