Plasma endothelin-1 and -3 in cirrhosis: relationship with systemic hemodynamics, renal function and neurohumoral systems

The postural change from upright to supine is a physiological maneuvre which increases central blood volume. This model was used to investigate the effects of changes in effective volemia on plasma endothelin-1 and -3 concentrations in cirrhosis. Methods: Plasma endothelin concentrations, measured by radio-immunoassay, were determined in 20 patients with cirrhosis, 10 of whom had ascites, and nine healthy control subjects, in the upright posture and 30, 60 and 120 min after the assumption of the supine position. Results: In the upright posture, endothelin-1 was 8.9±0.4 pg/ml and endothelin-3 3.7±0.6 (mean±SEM) pg/ml in control subjects. Endothelin-1 was increased only in patients with ascites (12.7±1.4 pg/ml, p<0.05; patients without ascites: 9.7±0.7 pg/ml), while endothelin-3 was elevated in both patients with and without ascites (8.0±1.5 pg/ml, p<0.01; 5.9±0.5 pg/ml, p=0.01, respectively). In the supine position, no significant changes in endothelin-1 or -3 occurred either in patients with ascites or in controls throughout the observation period, while a reduction in endothelin-3 was found in compensated patients after 30 and 60 min. In patients, we found negative correlations between endothelin-3, but not endothelin-1, and mean arterial pressure, both in upright (r=−0.59; p<0.01) and supine (r=−0.56; p=0.01) positions, atrial natriuretic factor (r=0.50; p<0.05) and plasma renin activity (r=0.67; p-0.001) in the supine position alone. In patients with ascites, endothelin-1 was inversely correlated with both glomerular filtration rate (upright: R=−0.62; p=0.06; supine: R=−0.71, p<0.05) and renal sodium excretion (upright: R=−0.82; p<0.01; supine: R=−0.88; p<0.001). Conclusions: Plasma endothelin-1 and −3 were increased in cirrhosis with ascites, while, in pre-ascitic cirrhosis, only endothelin-3 was increased in the upright posture. Although increased endothelin-3 was associated with features suggesting a reduced effective volemia, it is likely that other mechanisms than hypovolemia were mainly responsible for high plasma endothelin levels. Increased endothelin production may play a role in circulatory and renal function abnormalities of advanced cirrhosis