Role of Sex Hormones on Myocardial Ischemia Reperfusion Injury-Induced Calcium Overload: Possible Mechanisms
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- Category: Vol. 77, September 2009
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Role of Sex Hormones on Myocardial Ischemia Reperfusion Injury-Induced Calcium Overload:Possible Mechanisms,NAGAT Y. MINA, LOBNA A. KASSEM, WAFAA A. MATTAR and AYMAN S. SOLIMAN
Abstract
Background/Aim: The influence of sex on the response of the myocardium to ischemia-reperfusion (I/R) is under investigated. Sex hormones and their effects on intracellular calcium loading might be involved in gender difference. The aim of the present work is to study the effect of sex hormones on different mechanisms involved in calcium loading during myocardial I/R injury.
Methods: Rats were equally divided into male (gps 1~6) and female (gps 7~12) groups as follows: Sham groups (gps 1&7); gonadectomized groups (gps 2&8), gonadectomized with either testosterone (gp 3) or estrogen substitution (gp 9). Isolated Langendorff perfused hearts from all these groups were subjected to 45min. ischemia followed by 60min. reper-fusion. To test the effect of sex hormones on I/R-induced calcium loading, hearts from gonadectomized and hormone substituted rats were perfused 15 minutes prior to ischemia with Verapamil (gps 4&10); the L-type calcium channel blocker, Amiloride; the Na+/H+ exchanger inhibitor (gps 5&11) and Thapsigargin; the sarcoplasmic reticulum calcium ATPase pump inhibitor (gps 6&12). At 5 minutes of reperfu-sion, creatine Kinase activity was assessed. Then, left ventric-ular developed pressure, dp/dt, Fas Ligand, cytosolic calcium and infarct size were measured at the end of reperfusion period.
Results: The left ventricular functional parameters were significantly higher in female sham-operated rats and female ovariectomized rats with estrogen substitution than their corresponding values in male gps. Such improvement was associated with less myocardial damage as indicated by less CK release, smaller infarcts, decreased Fas ligand and less cytosolic calcium. We also noticed that gonadectomy was detrimental to the female rats and beneficial to the male rats, supporting the important beneficial role for endogenous estrogen to resist I/R injury. The addition of either Amiloride or Thapsigargin to hearts of male gps 5&6 resulted in signif-icantly greater left ventricular functional parameters and significantly lesser cytosolic calcium as compared to gp 3. Meanwhile, addition of Verapamil to the hearts of gp 4 caused insignificant change in any of the parameters measured. Concerning the female gender, Verapamil and Thapsigargin resulted in a more additional cardio-protective effects against I/R injury, while, Amiloride failed to cause any significant change as compared to gp 9.
Conclusions: Hearts of male rats have a higher vulnera-bility to I/R than hearts of female rats. The protective effect of estrogen is partly mediated via decreasing intracellular calcium accumulation through inhibition of Na+/H+ exchange mechanism. A supraphysiological dose of testosterone could afford a cardioprotective effect by inhibiting I/R-induced calcium load through L-type calcium channel blockade.