Fischer S R, Traber D L
Department of Anesthesiology, The University of Texas Medical Branch, and The Shriners Burns Institute, Galveston 77555-0833, USA.
Shock. 1999 Apr;11(4):283-90. doi: 10.1097/00024382-199904000-00010.
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.
吡哆醛化血红蛋白聚氧乙烯结合物（PHP）是一种一氧化氮清除剂，可引起正常和脓毒症绵羊的全身和肺血管收缩。我们研究了L-精氨酸和内皮素-1（ET-1）拮抗剂波生坦对PHP反应的影响，以确定PHP诱导的血管收缩主要是由ET-1的作用引起还是仅由一氧化氮的清除导致。在给予载体溶液24小时后（非脓毒症绵羊），绵羊接受PHP（20毫克/千克/小时；n = 5）、PHP加L-精氨酸（在28小时时，静脉推注100毫克/千克，随后1小时内输注500毫克/千克）加波生坦（在32小时时，10毫克/千克；n = 6），以及仅给予L-精氨酸和波生坦（n = 5）。在给予铜绿假单胞菌24小时后（脓毒症组，6×10⁶菌落形成单位/千克/小时）重复这些方案。在输注PHP期间，PHP在脓毒症和非脓毒症绵羊中均引起血管收缩。在非脓毒症绵羊中，L-精氨酸和波生坦均未显著降低全身血管阻力指数（SVRI）和肺血管阻力指数（PVRI），也未拮抗PHP诱导的血管收缩。在脓毒症期间，SVRI下降而心脏指数（CI）上升。L-精氨酸和波生坦进一步降低了SVRI（L-精氨酸：34±2%，p<0.05；波生坦：35±5%，p<0.05）和PVRI（L-精氨酸：28±2%，p<0.05；波生坦：33±7%，p<0.05），并增加了CI（L-精氨酸：29±4%，p<0.05；波生坦：11±5%，无统计学意义）。两种药物均拮抗了PHP诱导的血管收缩，使SVRI（L-精氨酸：29±3%，p<0.05；波生坦：26±5%，p<0.05）和PVRI（L-精氨酸：27±4%，p<0.05；波生坦：32±4%，p<0.05）降至PHP给药前的水平。脓毒症期间血浆ET-1水平升高（从9.8±0.2升至15.6±0.7皮克/毫升，p<0.05），而在PHP输注期间下降（至9.7±1.6皮克/毫升，p<0.05）。在非脓毒症绵羊中，PHP输注期间ET-1水平下降（从8.5±0.6皮克/毫升降至5.9±0.6，p<0.05）。在脓毒症绵羊中，波生坦使ET-1水平升高至非脓毒症绵羊的2.7倍。我们得出结论，在脓毒症期间，一氧化氮清除剂PHP揭示了潜在的ET-1介导的血管收缩，其作用可被L-精氨酸和波生坦拮抗。
