Role of NO mechanism in cardiovascular effects of diaspirin cross-linked hemoglobin in anesthetized rats

Abstract

The role of nitric oxide (NO) in the cardiovascular actions of diaspirin cross-linked hemoglobin (DCLHb) was studied in anesthetized rats. The regional circulatory and systemic hemodynamic effects of DCLHb (400 mg/kg iv) were studied using a radioactive microsphere technique in control (untreated) and L-arginine (a NO precursor) pretreated rats. DCLHb produced a significant increase in blood pressure (75%), cardiac output (42%), stroke volume (36%), and total peripheral resistance (45%), without affecting heart rate, when administered to control rats. L-Arginine pretreatment significantly attenuated DCLHb-induced systemic hemodynamic effects. DCLHb-induced increase in blood flow to the skin and spleen was completely blocked, and that to the heart was partially blocked, by L-arginine pretreatment, suggesting that cardiovascular actions induced by DCLHb could be antagonized by the NO precursor L-arginine. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produced significant increases in regional vascular resistance, leading to a decrease in blood flow to all the organs except the heart, where an increase in blood flow and a decrease in vascular resistance was observed. DCLHb, when administered in L-NAME-pretreated rats, accentuated the decrease in blood flow to the gastrointestinal system, spleen, mesentery and pancreas, skin, and musculoskeletal system. These studies provide evidence that the NO precursor L-arginine can attenuate the effects of DCLHb and that DCLHb can potentiate the effect of the NOS inhibitor L-NAME. The role of NO in the mechanism of action of DCLHb was further studied by estimating plasma guanosine 3',5'-cyclic monophosphate (cGMP) in control, DCLHb-treated, L-NAME-treated, and L-NAME followed by DCLHb-treated rats. DCLHb and L-NAME significantly decreased the concentration of circulating cGMP in blood plasma. L-NAME pretreatment potentiated DCLHb-induced decrease in cGMP levels. Because the formation of cGMP is stimulated by NO, these studies provide additional evidence for the involvement of NO in the mechanism of action of DCLHb. It is concluded that NO plays an important role in the cardiovascular effects of DCLHb.

Glutaraldehyde Modification of Recombinant Human Hemoglobin Alters Its Hemodynamic Properties

“…Sharma and colleagues (16) reported that co-infusion of L-arginine diminishes the hemodynamic responses to diaspirin cross-linked hemoglobin, a monomeric hemoglobin. Similar results with L-arginine were reported by Katsuyama et al (43) who also showed that inhibition of NO synthesis by N -nitro-L-arginine attenuates the hypertensive response to diaspirin cross-linked hemoglobin.…”

“…Nitric oxide (NO), an important mediator of vasodilation and other physiological processes (13), is known to react rapidly with the oxyHb (14) forming metHb (Fe 3ϩ ) and NO 3 Ϫ or to bind to deoxyHb, essentially scavenging the NO and causing vasoconstriction. Scavenging of NO by hemoglobin is thought to contribute to the hypertensive response observed with many cell-free hemoglobin solutions in intact animals (15,16), perfused organs (17,18), and isolated vascular preparations (19,20). We have recently shown that genetic modification of the distal heme pocket to reduce the rate of NO scavenging, measured in vitro, can essentially eliminate the hemoglobin-induced pressor response (21).…”

Effects of S-Nitrosation and Cross-Linking of Hemoglobin on Hypoxic Pulmonary Vasoconstriction in Isolated Rat Lungs

“…[17][18][19][20] They are also consistent with the observed effect of free Hb products on systemic blood pressure (hypertension). 21,22 In addition to the oxidation and addition reactions of Hb with NO, a third, reversible reaction involving S-nitrosation of the ␤-cys93 residue to form SNO-Hb may be of physiological importance, thus making the relationship between Hb, NO, and vascular tone more complex than previously appreciated. The detection of an arterial-venous gradient in SNOHb 9 and evidence that administered SNO-Hb reduces systemic blood pressure 9,11 and increases cerebral blood flow 11 has led to the hypothesis that Hb is an active regulator of vascular tone.…”

“…1,21,22 These effects can be reduced by intra-and intermolecular cross-linking and conjugation of the Hb molecule to prevent abluminal movement. 28,29 The effects of modified HBOCs on the pulmonary circulation have not been rigorously studied, and there are no reports of the effects of these products on HPV to our knowledge.…”

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

“…The increased ability of cell-free Hb to scavenge NO has been widely attributed to the hypertension, increased systemic and pulmonary vascular resistance, and morbidity and mortality associated with administration of hemoglobin-based oxygen carriers (HBOCs or "blood substitutes") [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. More recently, the importance of intravascular hemolysis on NO bioavailability in diseased states including hemolytic anemias like sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and cardiopulmonary bypass has been elucidated [17][18][19][68][69][70][71][72][73].…”