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Objective: To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension.

Design: Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15).

Methods: Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion.

Results: Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 /- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 /- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 /- 0.5 fmol/ml compared with 3.7 /- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r2 = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r2 = 0.467).

Conclusions: Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.

(C) 2004 Lippincott Williams & Wilkins, Inc.