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Calcium (Ca 2+ ) is a key mediator of myocardial function. Calcium regulates contraction, and disruption of myocellular Ca 2+ handling plays a role in cardiac pathologies such as arrhythmias and heart failure. This investigation examines sex differences in sensitivity of the contractile proteins to Ca 2+ and myofibrillar Ca 2+ delivery in the ventricular myocardium. Sensitivity of contractile proteins to Ca 2+ was measured in weight-matched male and female SpragueDawley rats using the skinned ventricular papillary muscle fiber and Ca 2+ -stimulated Mg 2+ -dependent adenosine triphosphatase (ATPase) activity methodologies. Calcium delivery was examined by measuring the contractile response to a range of extracellular Ca 2+ concentrations in isolated ventricular myocytes, papillary muscle, and the isolated perfused whole heart. Findings from studies in the whole heart suggest that at a fixed preload, the male left ventricle generates more pressure than a female ventricle over a range of extracellular Ca 2+ concentrations. In contrast, results from myocyte and papillary muscle studies suggest that females require less extracellular Ca 2+ to elicit a similar contractile response. Results obtained from the 2 methods used to determine sex differences in Ca 2+ sensitivity were equivocal. Further studies are required to elucidate sex differences in myocardial Ca 2+ handling and the reasons for disparate results in different heart muscle preparations. The results of these studies will lead to the design of sex-optimized therapeutic interventions for cardiac disease.Calcium (Ca 2+ ) is a key mediator of myocardial cell function. Calcium initiates contraction and regulates contractile force on a beat-to-beat basis. Calcium also acts as a 2nd messenger for signal transduction pathways that modulate metabolism, hypertrophic cell growth, and apoptosis (del Monte and Hajjar 2002;Lynch and Michalak 2002). In the heart, the strength of contractile force is regulated in 2 ways. The 1st way is by altering the amount of Ca 2+ delivered to the contractile proteins. That is, an increase or decrease in the delivery of Ca 2+ to the contractile proteins results in a greater or reduced contractile force, respectively. The 2nd way is by altering the sensitivity of the myofibrils (contractile proteins) to Ca 2+ . Therefore, in the presence of the same concentration of intracellular Ca 2+ , an increase or decrease in the sensitivity of the myofibrils to Ca 2+ results in an increase or decrease in contractile force, respectively. Myofibrillar Ca 2+ sensitivity has been shown to be altered by the phosphorylation state of regulatory proteins (

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