Effect of ovariectomy on intracellular Ca2+ regulation in guinea pig cardiomyocytes

Abstract

<p class="first" id="d1718041e217">Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca ²⁺ waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca ²⁺ regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17β-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca ²⁺ regulation, potentially creating proarrhythmic substrates. </p><p class="first" id="d1718041e229">This study addressed the hypothesis that long-term deficiency of ovarian hormones after ovariectomy (OVx) alters cellular Ca ²⁺-handling mechanisms in the heart, resulting in the formation of a proarrhythmic substrate. It also tested whether estrogen supplementation to OVx animals reverses any alterations to cardiac Ca ²⁺ handling and rescues proarrhythmic behavior. OVx or sham operations were performed on female guinea pigs using appropriate anesthetic and analgesic regimes. Pellets containing 17β-estradiol (1 mg, 60-day release) were placed subcutaneously in selected OVx animals (OVx + E). Cardiac myocytes were enzymatically isolated, and electrophysiological measurements were conducted with a switch-clamp system. In fluo-4-loaded cells, Ca ²⁺ transients were 20% larger, and fractional sarcoplasmic reticulum (SR) Ca ²⁺ release was 7% greater in the OVx group compared with the sham group. Peak L-type Ca ²⁺ current was 16% larger in OVx myocytes with channel inactivation shifting to more positive membrane potentials, creating a larger “window” current. SR Ca ²⁺ stores were 22% greater in the OVx group, and these cells showed a higher frequency of Ca ²⁺ sparks and waves and shorter wave-free intervals. OVx myocytes showed higher frequencies of early afterdepolarizations, and a greater percentage of these cells showed delayed afterdepolarizations after exposure to isoprenaline compared with sham myocytes. The altered Ca ²⁺ regulation occurring in the OVx group was not observed in the OVx + E group. These findings suggest that long-term deprivation of ovarian hormones in guinea pigs lead to changes in myocyte Ca ²⁺-handling mechanisms that are considered proarrhythmogenic. 17β-Estradiol replacement prevented these adverse effects. </p><p id="d1718041e259"> <b>NEW &amp; NOTEWORTHY</b> Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca ²⁺ waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca ²⁺ regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17β-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca ²⁺ regulation, potentially creating proarrhythmic substrates. </p>