Effects of sex, gonadectomy, and oestrogen substitution on ischaemic preconditioning and ischaemia-reperfusion injury in mice.

Aim:  Ischaemic preconditioning (IPC) has been demonstrated to protect heart function and viability, but has been predominantly studied in male animals. Methods:  We studied a possible influence of sex and oestrogen for protection in IPC. Infarct size and heart function after 40 min global ischaemia and 60 min reperfusion with or without preceding classic IPC was investigated in Langendorff-perfused hearts. Hearts were harvested from 10-week-old male and female C57BL6 mice with or without gonadectomy 6 weeks earlier, or gonadectomy and substitution with 17β-oestradiol for 4 weeks (n = 104). Results:  Classic IPC reduced depression of left ventricular developed pressure (P < 0.01), attenuated the increase of end-diastolic pressure (P < 0.01), and reduced infarct size (P < 0.01) in hearts of untreated male mice, but failed to protect untreated females which had improved functional recovery and smaller infarctions than untreated males. After gonadectomy of female mice, developed pressure was reduced (P < 0.01) and infarct size increased (P < 0.01) compared with normal females, with no protection of preconditioning. The changes were not reversed by 17β-oestradiol substitution. In hearts of gonadectomized males, the post-ischaemic increase of end-diastolic pressure was attenuated (P < 0.01), and enhanced after substitution with 17β-oestradiol (P < 0.01). The preconditioning effect disappeared after gonadectomy and gonadectomy with substitution in male mice. Conclusion:  There is a sex difference in evoking preconditioning in male and female mice which is only partially dependent on sex hormones.