Direct sGC Activation Bypasses NO Scavenging Reactions of Intravascular Free Oxy-Hemoglobin and Limits Vasoconstriction

Abstract

Aims: Hemoglobin-based oxygen carriers (HBOC) provide a potential alternative to red blood cell (RBC) transfusion. Their clinical application has been limited by adverse effects, in large part thought to be mediated by the intravascular scavenging of the vasodilator nitric oxide (NO) by cell-free plasma oxy-hemoglobin. Free hemoglobin may also cause endothelial dysfunction and platelet activation in hemolytic diseases and after transfusion of aged stored RBCs. The new soluble guanylate cyclase (sGC) stimulator Bay 41-8543 and sGC activator Bay 60-2770 directly modulate sGC, independent of NO bioavailability, providing a potential therapeutic mechanism to bypass hemoglobin-mediated NO inactivation. Results: Infusions of human hemoglobin solutions and the HBOC Oxyglobin into rats produced a severe hypertensive response, even at low plasma heme concentrations approaching 10 lM. These reactions were only observed for ferrous oxy-hemoglobin and not analogs that do not rapidly scavenge NO. Infusions of L-NG-Nitroarginine methyl ester (L-NAME), a competitive NO synthase inhibitor, after hemoglobin infusion did not produce additive vasoconstriction, suggesting that vasoconstriction is related to scavenging of vascular NO. Open-chest hemodynamic studies confirmed that hypertension occurred secondary to direct effects on increasing vascular resistance, with limited negative cardiac inotropic effects. Intravascular hemoglobin reduced the vasodilatory potency of sodium nitroprusside (SNP) and sildenafil, but had no effect on vasodilatation by direct NO-independent activation of sGC by BAY 41-8543 and BAY 60-2770. Innovation and Conclusion: These data suggest that both sGC stimulators and sGC activators could be used to restore cyclic guanosine monophosphate-dependent vasodilation in conditions where cell-free plasma hemoglobin is sufficient to inhibit endogenous NO signaling.

Strategies to increase nitric oxide signalling in cardiovascular disease

“…In atherosclerosis, antithrombotic and anti adhesive effects on platelets and leukocytes, respectively, has been observed with sGC stimulation 211,212 . The car dioprotective effects of sGC agonists in several disease models -such as hypertension, PAH, heart failure, haemolytic anaemia and I-R injury -are promising 67,213 . These findings support the prediction that we will prob ably see additional sGC stimulators and activators in the clinical management of different CVDs.…”

Nitric oxide functions in the heart

“…Inhibition of a negative regulator of cGMP, PDE5 is another therapeutic approach to stimulate cGMP/PKG signaling [95][96][97]. Stimulation of the PKG-dependent pathway has been demonstrated to exert potent protective effects in a broad range of cardiovascular disease models, including hypertension, PAH, heart failure, hemolytic anemia, and infarct-reperfusion injury [95][96][97][98][99].…”

Mechanisms underlying the antihypertensive effect of Alstonia scholaris

“…5). A number of direct sGC activators have been identified (Raat et al, 2013;Schmidt et al, 2003). sGC catalyzes the conversion of GTP into cGMP (Denninger and Marletta, 1999).…”