title: L-arginine and endothelin receptor antagonist bosentan counteract hemodynamic effects of modified hemoglobin.
abstract: 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, 6x10(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 significantly lowered systemic (SVRI) and pulmonary (PVRI) vascular resistance and did not antagonize the PHP-induced vasoconstriction. During sepsis, SVRI fell and cardiac index (CI) 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 CI (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.
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, and The Shriners Burns Institute, Galveston 77555-0833, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Fischer
authors.forename: D L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology*; D001802:Blood Substitutes / Q000494:pharmacology; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology*; D018805:Sepsis / Q000097:blood / Q000188:drug therapy; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D001802:Blood Substitutes; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006454:Hemoglobins; D013449:Sulfonamides; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001120:Arginine; D000077300:Bosentan