Role of ET and NO in resuscitative effect of diaspirin cross-linked hemoglobin after hemorrhage in rat.
Diaspirin cross-linked hemoglobin (DCLHb) is a hemoglobin-based therapeutic agent that produces significant cardiovascular effects, possibly due to its actions on vasoactive substances, such as endothelin (ET) and nitric oxide (NO). We have studied the modulation of cardiovascular effects of DCLHb by an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and an ETA-receptor antagonist, FR-139317, in hemorrhaged rats. Control rats resuscitated with vehicle [Ringer lactate (RL), 4 ml/kg iv] did not show any improvement in O2 consumption, base deficit, systemic hemodynamics, or regional blood flow after hemorrhage, and the rats survived for < 70 min. Administration of DCLHb (400 mg/kg iv) significantly improved O2 consumption, base deficit, systemic hemodynamics, and regional blood circulation after resuscitation, and the rats survived for > 120 min after hemorrhage. Plasma ET-1 and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations increased after hemorrhage. DCLHb produced an increase in ET-1 and decreased cGMP concentrations in plasma. Pretreatment with L-NAME (10 mg/kg iv) or FR-139317 (4 mg/kg iv) attenuated the DCLHb-induced improvement in survival time, base deficit, systemic hemodynamics, and regional blood circulation. L-NAME (10 mg/kg iv) per se did not produce any resuscitative effect; therefore the NO mechanism may not be contributing toward the efficacy of DCLHb in hemorrhaged rats. However, FR-139317 attenuated the efficacy of DCLHb; therefore an increase in plasma ET-1 concentration by DCLHb may be contributing toward the efficacy of DCLHb in hemorrhage. Hemorrhage-induced increase in cGMP levels could be attenuated by L-NAME, but L-NAME was not effective in resuscitation of hemorrhaged rats, indicating a lack of role of NO in resuscitation. It is concluded that the ET mechanism is more important in the beneficial effect of DCLHb than the NO mechanism in hemorrhage.
Gulati
A
A
Department of Phamaceutics, University of Illinois at Chicago Health Sciences Center 60612, USA.
Sen
A P
AP
Sharma
A C
AC
Singh
G
G
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001802:Blood Substitutes / Q000627:therapeutic use; D006152:Cyclic GMP / Q000097:blood; D019332:Endothelin-1 / Q000097:blood; D016232:Endothelins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005740:Gases / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000627:therapeutic use*; D006470:Hemorrhage / Q000401:mortality / Q000628:therapy*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D009569:Nitric Oxide / Q000502:physiology*; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012151:Resuscitation; D016019:Survival Analysis
D001802:Blood Substitutes; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D005740:Gases; D006454:Hemoglobins; D009569:Nitric Oxide; C083478:diaspirin-cross-linked hemoglobin; D006152:Cyclic GMP; D001241:Aspirin; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester