Introduction: 

Although the cardioprotective effects of female sex hormones are generally recognized, the possibility that estrogens' effects on myocardial Ca²⁺ homeostasis is a contributing factor has scarcely been investigated. The aim of our study was to elucidate the effects of estrogen deprivation on myocardial Ca²⁺ homeostasis and the ischemic tolerance of the heart.

Methods: 

The hearts of ovariectomized and sham-operated (control, C n=8) female rats were studied. A group of the ovariectomized animals received estrogen replacement therapy (ERT n=9) (estradiol propionate im., 450 micrograms/kg weekly) while the rest received no treatment (OVX n=10). Therapy was continued for 10 weeks, after which hearts were excised and perfused using a Langendorff preparation. Isolated hearts were subjected to 30 minutes of total ischemia followed by a 30 minute reperfusion period. Left ventricular pressure (LVP) was registered, and Ca²⁺ transients were recorded using Indo-1 surface fluorometry. Western blots were used to measure the expression of the key enzymes of Ca²⁺ transport.

Results: 

Pre-ischemic tests: resting hemodynamic performance was similar in every group. In the OVX group the rate of Ca²⁺ sequestration was decreased, in the ERT group this was normalized (-dCa_i²⁺/dt: C:9,7+/­2,1; OVX:7,4+/­2,3; ERT:9,6+/­1,9 x10^­3 nM/s, p<0,05). Ischemic period: we found marked ischemic contracture and significantly higher [Ca²⁺_i] in the OVX group (LVP: C:28+/­8; OVX:36+/­8; ERT:25+/­6 Hgmm, and [Ca²⁺_i]: C:481+/­44; OVX:580+/­57; ERT:456+/­45 nM by the end of 30 min of ischemia, p<0,05). Reperfusion: in the OVX group the rates of both release and sequestration of intracellular Ca²⁺ were decreased. In the ERT group the contractile and lusitropic function, as well as the Ca²⁺ transients were normalized to control levels (+dCa_i²⁺/dt: C:17,4+/­5,3; OVX:12,1+/­3,8; ERT:18,1+/­5,5; -dCa_i²⁺/dt: C: 6,6+/­2,1; OVX:4,3+/­1,7; ERT:6,3+/­1,8 x10^­3 nM/s by the end of 30 min of reperfusion, p<0,05). Protein expression studies indicated a decrement in the function of the Ca²⁺ ATPase of the Sarcoplasmic Reticulum (SERCA2a).

Conclusion: 

The estrogen deficient state elicits a decrease in the dynamics of myocardial Ca²⁺ transport and impaired SERCA2a function, which damages the ischemic tolerance of the heart. These effects are demonstrated by more significant ischemic contracture, and impaired restitution of hemodynamic function during reperfusion of the OVX animals' hearts. The substitution of estrogen inhibits these changes; one of the cardioprotective mechanisms effected by estrogens is protection of myocardial Ca²⁺ homeostasis.

Research supported by OTKA grant No. 68502.