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For almost 50 years it has been known that hemolysed blood can increase blood pressure. Although preclinical studies suggest that this pressor response is due to an interaction of hemoglobin with endothelium-derived vasoactive substances, its mechanism in humans is unknown. We investigated the involvement of endothelin-1 in the blood pressure response to the oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) in stroke patients.In a randomized phase II study, increasing doses of DCLHb (25, 50 and 100 mg/kg, n = 8, 8 and 11, respectively) or placebo (n = 26) were infused intravenously every 6 h for 72 h to patients with an acute ischemic stroke. Blood pressure and heart rate were measured every 15 min and plasma concentrations of endothelin-1, catecholamines, renin, vasopressin and atrial natriuretic peptide were measured before and 24 and 66 h after the start of the infusions.In the placebo group, mean arterial pressure (MAP) was 112 (109–115) mmHg (mean and 95% confidence interval) at baseline and decreased spontaneously by 11.4 (5.4–17.5) and 12.5 (5.4–19.5) mmHg after 24 and 66 h, respectively. This decrease in MAP was attenuated in patients treated with DCLHb, reaching statistical significance in the highest dose group. The plasma endothelin-1 concentration decreased slightly in the placebo group, from 4.2 (3.1–5.3) pg/ml (median and range) at baseline to 2.4 (1.9–3.7) pg/ml after 24 h (P = 0.0044) and 2.8 (1.9–3.7) pg/ml after 66 h (P = 0.0042), but increased dose-dependently in response to DCLHb infusion. With the highest dose of DCLHb, the plasma endothelin-1 concentration rose from 4.8 (0.1–7.8) pg/ml at baseline to 21.2 (13.4–53.2) pg/ml after 24 h (P < 0.001) and to 27.6 (11.9–47.8) pg/ml after 66 h (P < 0.001). The increases in the plasma endothelin-1 concentration and in MAP were correlated (r = 0.30, P = 0.02). Other vasoactive hormones were not affected by the DCLHb infusion.Infusion of DCLHb in patients with acute ischemic stroke was associated with a dose-dependent increase in plasma endothelin-1 concentration. This may underlie the attenuation by DCLHb of the natural decrease in blood pressure that we observed in these patients.