Abstract P642: Impact of Urinary Endothelin-1 on Derangements in Stress-Induced Pressure Natriuresis

Abstract

Sodium retention during stress (retainer) is known to increase the risk of hypertension and other diseases. Our group has previously shown that angiotensin II type I receptor blockade improves natriuresis in retainers. Since our pre-clinical studies demonstrate that angiotensin II inhibits endothelin-1 (ET-1) dependent natriuresis, we predict that ET-1 may be linked to the response. We hypothesize that reduction in urinary (renal) ET-1 accounts for derangements in sodium handling under stress, a link never before explored in a large human cohort. We evaluated urinary ET-1 and albumin excretion in 4 studies of stress-induced pressure natriuresis, of which 3 were observational studies with 776 healthy youth (15 - 19 years) enrolled in a 5 hr protocol (1 hr of mental stress before and after 2 hrs of rest). The 4th study involved 213 African American adults (18 - 54 years) in a double blind crossover trial comparing irbesartan (angiotensin II type I receptor antagonist) to placebo. The protocol entailed 7 days of vehicle (placebo or irbesartan 150 mg P.O.) followed by a 3 hr protocol (1 hr of rest before and after 1 hr of mental stress). In all studies, 60 min urine samples were obtained. Subjects were grouped as retainers or excreters if they retained or excreted sodium under stress. In the observational studies, mean change in ET-1 between stress and baseline was significant (p<0.001), being negative (mean= -0.0154 pmol/min) in retainers but positive (mean= 0.0194 pmol/min) in excreters. ET-1 excretion was significantly higher (p<0.028) in retainers than excreters at baseline but significantly lower in retainers under stress (p<0.0001). ET-1 excretion continued to decline in retainers during recovery but returned to pre-stress levels in excreters. Albumin excretion and albumin to creatinine ratio were significantly higher in retainers (p<0.046, p<0.008, respectively). During stress, the irbesartan group had significantly higher ET-1 excretion than placebo (p<0.001). Thus loss of ET-1-dependent natriuresis may account for sodium retention during stress and correction of sodium handling re-establishes ET-1-mediated natriuresis. Retainers have both lower ET-1 excretion and increased albuminuria, suggesting renal impairment and risk for future diseases.