It has long been recognised from whole heart preparations that intrinsic differences in cardiac function exist between males and females (Schaible & Sheuer, 1984). However, the precise subcellular mechanisms responsible remain poorly understood. Recent evidence suggests that sex hormones can alter the expression and function of key proteins involved in intracellular Ca²⁺ handling (e.g. Ren et al. 2003). We therefore tested the hypothesis that sex differences in cardiomyocyte function can be related to differences at the level of the sarcoplasmic reticulum (SR) and Na⁺-Ca²⁺ exchanger (NCX).

Weight-matched male and female guinea-pigs were humanely killed and left ventricular myocytes isolated by enzymatic dissociation. Ca²⁺ transients were recorded during field stimulation in a superfusion chamber (1 Hz, 37 °C) by loading cells with indo-1 AM. Electrophysiological recordings were performed using single electrode voltage-clamp.

There was no significant difference in Ca²⁺ transient amplitude between male and female myocytes (indo-1 ratios of 0.19 ± 0.01 and 0.18 ± 0.01; means ± S.E.M., n = 34 for both sexes). However, the peak L-type Ca²⁺ current (I_Ca,L) was greater in males (-6.3 ± 0.4 pA pF^-1 (n = 24) cf. -5.3 ± 0.3 pA pF^-1 (n = 27), Student’s unpaired t test, P < 0.05). In order to explain this apparent disparity, we measured SR Ca²⁺ contents by integrating the NCX current induced by rapid caffeine application. Female myocytes had a greater SR Ca²⁺ load (0.33 ± 0.02 pC pF^-1, n = 41) compared with males (0.27 ± 0.01 pC pF^-1, n = 42, P < 0.01). This could be related to differences in NCX function, as assessed by measuring the monoexponential time constant of the tail current (tau) following membrane depolarisation (-60 mV to 0 mV). Female myocytes exhibited longer tail tau compared with males (111 ± 31 ms (n = 22) cf. 37 ± 3 ms (n = 18), respectively, P < 0.05), implying a slower rate of Ca²⁺ extrusion via the NCX in females. In support of this, we found a longer time constant of decay of the Ca²⁺ transient in females compared with males following thapsigargin treatment (250 ± 6 ms (n = 24) cf. 202 ± 9 ms (n = 28), respectively, P < 0.001).

These data demonstrate important, intrinsic differences in intracellular Ca²⁺ handling between male and female myocytes. Although I_Ca,L is larger in males, SR Ca²⁺ load is greater in females, attributable to slower NCX activity. The end result is that of similar Ca²⁺ transient amplitudes in both sexes.

Financial support from the British Heart Foundation is gratefully acknowledged.