Responses of blood pressure and catecholamine metabolism to high salt loading in endothelin-1 knockout mice

The molecular mechanism responsible for salt sensitivity is poorly understo od, Mice heterozygous for the null mutation of the endothelin-1 (ET-1) gene , Edn1, may be a potential tool for studying this mechanism, because they h ave elevated blood pressure and disturbances in central sympathetic nerve r egulation, In the present study, we used this mouse model to examine the de gree to which ET-1 contributes to the responses of blood pressure and catec holamine metabolism to high salt loading. Male Edn1+/- heterozygous mice an d Edn1+/+ wild-type littermates were given either a high salt (8%) or a nor mal salt (0.7%) diet for 4 wk, During the normal diet, renal ET-1 levels in Edn1+/- mice were approximately 50% lower than ET-1 levels in wild-type mi ce, whereas the high salt diet decreased renal ET-1 levels by about 50% in both Edn1+/- and wild-type mice. The high salt diet significantly increased urinary sodium excretion and fractional excretion of sodium (FENa) but did not affect circulating plasma volume, serum electrolytes, creatinine clear ance, or systemic blood pressure, In addition, urinary norepinephrine and n ormetanephrine excretion were significantly increased, indicating that salt loading can increase sympathetic nerve activity in normal mice. These resp onses to salt loading did not differ between Edn1+/- mice and their wild-ty pe littermates, We conclude that physiological changes in ET-1 production d o not affect the responses of blood pressure and catecholamine metabolism t o salt loading, although the renal ET-1 content is decreased by salt loadin g.