Sex-related decrease in [Ca ]i signaling and Ca -dependent contraction in inferior vena cava of female rat

Xia Y, Khalil RA. Sex-related decrease in [Ca ]i signaling and Ca -dependent contraction in inferior vena cava of female rat. Am J Physiol Regul Integr Comp Physiol 298: R15–R24, 2010. First published October 28, 2009; doi:10.1152/ajpregu.00465.2009.—Sex differences in the incidence of varicose veins have been suggested; however, the venous mechanisms involved are unclear. We hypothesized sex-related differences in venous function and underlying distinctions in intracellular free calcium, [Ca ]i, signaling and Ca dependent mechanisms of venous contraction. Circular segments of inferior vena cava (IVC) from male and female Sprague-Dawley rats were suspended between two hooks, labeled with fura-2, and placed in a cuvet inside a spectrofluorometer for simultaneous measurement of isometric contraction and the 340/380 fluorescence ratio (indicative of [Ca ]i). In male IVC, phenylephrine (PHE; 10 5 M) caused significant increase in contraction and [Ca ]i. In female IVC, PHEinduced contraction was significantly reduced, but [Ca ]i did not differ significantly from males. Membrane depolarization by KCl (96 mM), which stimulates Ca influx, caused parallel increases in contraction and [Ca ]i in male IVC, and the KCl-induced contraction was significantly reduced in parallel with [Ca ]i in female IVC. In male IVC stimulated with 0 Ca KCl solution, the addition of increasing concentrations of extracellular Ca ([Ca ]e) (0.1, 0.3, 0.6, 1, and 2.5 mM) caused stepwise increases in contraction and [Ca ]i, and both the KCl-induced [Ca ]e-contraction curve and the [Ca ]e-[Ca ]i curve were reduced in female IVC, suggesting reduced Ca entry via voltage-gated channels. The PHE-induced [Ca ]e-contraction curve was significantly reduced in females, but the [Ca ]e-[Ca ]i curve was similar in female and male IVC, suggesting the involvement of other mechanisms in addition to Ca entry. The [Ca ]e-contraction and [Ca ]e-[Ca ]i curves were used to construct the [Ca ]i-contraction relationship. The KCl-induced [Ca ]i-contraction relationship was superimposed in male and female IVC. In contrast, the PHE-induced [Ca ]i-contraction relationship was reduced and located to the right in female compared with male IVC, suggesting reduced [Ca ]i sensitivity of the venous contractile myofilaments. The reduced contraction, [Ca ]i, and [Ca ]i sensitivity in female veins render them more prone to dilation. These sex-specific reductions in venous function, if they also occur in human veins, may play a role in the greater incidence of varicose veins in females.