Elevated endothelin-1 in heart failure and loss of normal response to postural change.

BACKGROUND: The possible contribution of endothelin-1, a potent endothelium-derived vasoconstrictor peptide, to neurohumoral compensation for hemodynamic stress was examined in nine normal volunteers and six patients with severe congestive heart failure. METHODS AND RESULTS: Plasma levels of endothelin-1 were measured with a sensitive and specific radioimmunoassay. Venous blood samples were obtained after 90 minutes of supine rest and serially during 30 minutes of 60 degrees upright tilt. Endothelin-1 levels were compared with those of known neurohumoral mediators of compensation. In normal subjects, the resting levels of endothelin-1 were low (0.74 +/- 0.11 pg/ml), and there was a rapid increase to 1.37 +/- 0.07 pg/ml at 5 minutes of upright tilting (p less than 0.05). This increase was not sustained at 10 and 15 minutes of tilt, but there was a trend toward a second rise at 30 minutes (1.14 +/- 0.17 pg/ml; p = 0.06). This biphasic pattern of response was shared by dopamine and reflected the response of systemic blood pressure to postural change. In contrast, slower and more sustained increases in circulating levels were observed for norepinephrine, epinephrine, aldosterone, plasma renin activity, and vasopressin, whereas atrial natriuretic peptide tended to decrease progressively. Patients with congestive heart failure had markedly higher basal levels of circulating endothelin-1 than normal subjects (3.7 +/- 0.5 pg/ml; p less than 0.01), and there was no further increase on postural change. Similar patterns were observed for the other neurohumoral mediators measured, with the degree of blunting of the response to upright tilting in heart failure being inversely related to the magnitude of increase in basal levels. CONCLUSIONS: Alterations in plasma levels of endothelin in congestive heart failure and in response to postural change were qualitatively and quantitatively similar to the alterations of known mediators of neurohumoral compensation. In addition, the increase in plasma endothelin-1 during upright tilting in normal subjects preceded the increases in circulating levels of the other vasoconstrictor mediators, consistent with a role of endothelin-1 in neurohumoral compensation for hemodynamic stress.