SIR-Kurihara et al.\in their paper on the production of mice deficient for the gene for endothelin-1 (ET-1), report one result of great interest to those in the field of human h~ ertension. In their heterozygote ET-1+~ mice, reductions in plasma and lung tissue levels of the mature peptide were confirmed, but this was accompanied by increased blood pressure. This hypertension was observed in both conscious and anaesthetized mice, and was not associated with any change in responsiveness to exogenous ET-1, or to inhibition of nitric oxide synthase. Some of the vascular mechanisms by which deficiency of ET-1 during ontogeny could cause hypertension have been discussed by Kurihara et al. 1 and by Vanhoutte in an accompanying News and Views article2• We would like to suggest a different mechanism based on the emerging role of the renal ET-1 system in blood pressure regulation. Kitamura et a/. 3 reported reduced tissue levels of ET-1 in kidneys of spontaneously hypertensive rats. Others4 have confirmed this observation. We recently reported markedly reduced urinary levels of ET-1 in patients with essential hypertension, especially in a subgroup whose blood pressure was sensitive to salt loading5. Decreased urinary levels of ET-1 are found in women with either pre-eclampsia or hypertension during pregnancy6• Because ET-1 is synthesized in the kidney, excreted in the urine, and not filtered from the plasma7, low urinary ET-1 could reflect a reduced rate of renal synthesis of ET-1.

The common denominator of all these studies, in both experimental animals and in humans, is an association between reduced renal ET-1 generation and elevated blood pressure. Because the accumulating evidence suggests that the physiological autocrine/paracrine function of ET-1 in the kidney is natriuresis and diuresis8, it is conceivable that renal deficiency of the peptide causes sodium and water retention and salt sensitivity, and thereby volume-overload hypertension. These observations suggest that either an absolute or relative deficiency of renal