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.