[No authors listed]
AIM:Corticosteroid binding globulin (CBG) is the high affinity plasma carrier protein for cortisol. It keeps the steroids inactive, prevents them from degradation and defines the amount of free hormone acting on target tissues. Previous findings have shown insufficient responsiveness of corticosterone in peripheral tissues in CBGâ»(/)â» mice despite elevated free plasma corticosterone. In the large intestine, glucocorticoids synergistically enhance the pro-absorptive effects of aldosterone. We therefore hypothesized that CBGâ»(/)â» mice have reduced responsiveness to aldosterone. METHODS:We used CBGâ»(/)â» and CBG(+/+) mice to investigate distal colonic electrogenic Na(+) absorption. An Ussing chamber was used to quantify amiloride-sensitive Na(+) transport in distal colonic mucosa (ÎI(sc) (amil)) as a measure of the physiological effect of aldosterone. RESULTS:No differences were observed in ÎI(sc) (amil) or aldosterone levels in animals on control diet. When Na(+) restricted, CBG(+/+) mice responded with a marked up-regulation of ÎI(sc) (amil) (25-fold). In CBGâ»(/)â» mice this up-regulation was greatly attenuated as seen in a markedly reduced amiloride-sensitive short circuit current (reduced by â¼50%), a reduced ability to lower faecal Na(+) excretion and a significantly attenuated up-regulation of the ENaC channel γ-subunit. Diet-induced increases of total plasma aldosterone were similar in both genotypes, but CBGâ»(/)â» mice had an increased free plasma aldosterone fraction. SUMMARY:This study defines the functional hyporesponsiveness and aldosterone resistance in distal colon of CBGâ»(/)â» mice. This resistance occurs despite sufficient free corticosterone plasma level. Thus, steroid actions require an intrinsic but unknown function of CBG, which allows the sufficient supply of the hormone/s to the target tissue.
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