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Our previous study has demonstrated that ovariectomy (Ovx) significantly increased the left ventricular developed pressure (LVDP) and the maximal rate of developed pressure over time ([+ or -]dP/d[t.sub.max]) in the isolated perfused rat heart and the effects were reversed by female sex hormone replacement. In the present investigation, we studied the effects of Ovx for 6 wk on [Ca.sup.2+] homeostasis that determines the contractile function. Particular emphasis was given to [Ca.sup.2+] handling by ryanodine receptor (RyR) and [Na.sup.+]-[Ca.sup.2+] exchange (NCX). [sup.45][Ca.sup.2+] fluxes via the RyR, NCX, and [Ca.sup.2+]-ATPase (SERCA) were compared with their expression in myocytes from Ovx rats with and without estrogen replacement. Furthermore, we correlated the handling of [Ca.sup.2+] by these [Ca.sup.2+] handling proteins with the overall [Ca.sup.2+] homeostasis by determining the [Ca.sup.2+] transients induced by electrical stimulation and caffeine, which reveals the dynamic changes of cytosolic [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) in the heart. In addition, we determined the expression and contribution of protein kinase A (PKA) to the regulation of the aforementioned [Ca.sup.2+] handling proteins in Ovx rats. It was found that after Ovx there were 1) increased [Ca.sup.2+] fluxes via RyR and NCX, which were reversed not only by estrogen replacement, but more importantly by blockade of PKA; 2) an increased expression of PKA; and 3) no increase in expression of NCX and SERCA. We suggest that hyperactivities of RyR and NCX are a result of upregulation of PKA. The increased release of [Ca.sup.2+] through RyR and removal of [Ca.sup.2+] by NCX are believed to be responsible for the greater contractility and faster relaxation after Ovx. ovariectomy doi: 10.1152/ajpcell.00368.2006.