L-arginine and endothelin receptor antagonist bosentan counteract hemodynamic effects of modified hemoglobin

Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), a nitric oxide scavenger, causes systemic and pulmonary vasoconstriction in normal and septic sheep. We studied the effect of L-arginine and the endothelin-1 (ET-1) antagonist bosentan on the PHP response to determine whether the PHP-induced vasoconstriction resulted predominantly from the action of ET-1 or solely from removal of NO. After 24 h of carrier solution (nonseptic sheep), sheep received PHP (20 mg/kg/h; n = 5), PHP plus L-arginine (at 28 h, 100 mg/kg bolus and 500 mg/kg for 1 h) plus bosentan (at 32 h, 10 mg/kg; n = 6), and only L-arginine and bosentan (n = 5). These protocols were repeated after 24 h of Pseudomonas aeruginosa (S, 6·10⁶ colony-forming units/kg/h). PHP induced vasoconstriction in septic and nonseptic sheep for the duration of its infusion. In nonseptic sheep, neither L-arginine nor bosentan significantly lowered systemic (SVRI) and pulmonary (PVRI) vascular resistance and did not antagonize the PHP-induced vasoconstriction. During sepsis, SVRI fell and cardiac index (Cl) rose. L-arginine and bosentan further decreased SVRI (L-arginine: 34 ± 2%*, p < .05; bosentan: 35 ± 5%*, p < .05) and PVRI (L-arginine: 28 ± 2%*, p < .05; bosentan: 33 ± 7%*, p < .05) and increased Cl (L-arginine: 29 ± 4%*, p < .05; bosentan: 11 ± 5%, NS). Both agents antagonized the PHP-induced vasoconstriction lowering SVRI (L-arginine: 29 ± 3%*, p < .05; bosentan: 26 ± 5%*, p < .05) and PVRI (L-arginine: 27 ± 4%*, p < .05; bosentan: 32 ± 4%*, p < .05) to levels before PHP administration. Plasma ET-1 levels increased during sepsis (from 9.8 ± .2 to 15.6 ±. 7* pg/mL, p < .05) and fell during PHP infusion (to 9.7 ± 1.6* pg/mL, p < .05). In nonseptic sheep, ET-1 levels decreased during PHP (from 8.5 ± .6 pg/mL to 5.9 ± .6*, p < .05). Bosentan increased ET-1 levels 2.7 times higher in septic than in nonseptic sheep. We conclude that during sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoconstriction, and its effect is antagonized by L-arginine and bosentan.