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

Pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), a nitric oxide sc avenger, causes systemic and pulmonary vasoconstriction in normal and septi c sheep. We studied the effect of L-arginine and the endothelin-1 (ET-1) an tagonist bosentan on the PHP response to determine whether the PHP-induced vasoconstriction resulted predominantly from the action of ET-1 or solely f rom 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 b olus and 500 mg/kg for 1 h) plus bosentan (at 32 h, 10 mg/kg; n = 6), and o nly L-arginine and bosentan (n = 5). These protocols were repeated after 24 h of Pseudomonas aeruginosa (S, 6 . 10(6) 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 significa ntly lowered systemic (SVRI) and pulmonary (PVRI) vascular resistance and d id not antagonize the PHP-induced vasoconstriction. During sepsis, SVRI fel l and cardiac index (CI) rose. L-arginine and bosentan further decreased SV RI (L-arginine: 34 +/- 2%*, p < .05; bosentan: 35 +/- 5%*, p < .05) and PVR I (L-arginine: 28 +/- 2%*, p < .05; bosentan: 33 +/- 7%*, p < .05) and incr eased CI (L-arginine: 29 +/- 4%*, p < .05; bosentan: 11 +/- 5%, NS). Both a gents antagonized the PHP-induced vasoconstriction lowering SVRI (L-arginin e: 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 a dministration. Plasma ET-1 levels increased during sepsis (from 9.8 +/- .2 to 15.6 +/- .7* pg/mL, p < .05) and fell during PHP infusion (10 9.7 +/- 1. 6* pg/mL, p < .05). In nonseptic sheep, ET-1 levels decreased during PHP (f rom 8.5 +/- .6 pg/mL to 5.9 +/- .6*, p < .05). Bosentan increased ET-1 leve ls 2.7 times higher in septic than in nonseptic sheep. We conclude that dur ing sepsis, the NO scavenger PHP unmasks an underlying ET-1 mediated vasoco nstriction, and its effect is antagonized by L-arginine and bosentan.