Nitric oxide formation versus scavenging: the red blood cell balancing act

Abstract

Nitric oxide (NO) is a key modulator of vascular homeostasis controlling critical functions related to blood flow, respiration, cell death and proliferation, and protecting the vasculature from pro‐inflammatory and coagulative stresses. Inhibition of NO formation, and/or diversion of NO away from its physiological signalling targets lead to dysregulated NO bioavailability, a hallmark of numerous vascular and pulmonary diseases. Current concepts suggest that the balance between NO formation and NO scavenging is critical in disease development, with the corollary being that redressing the balance offers a target for therapeutic intervention. Evidence presented over the last two decades has seen red blood cells (RBCs) and haemoglobin specifically emerge as prominent effectors in this paradigm. In this symposium review article, we discuss recent insights into the mechanisms by which RBCs may modulate the balance between NO‐formation and inhibition. We discuss how these mechanisms may become dysfunctional to cause disease, highlight key questions that remain, and discuss the potential impact of these insights on therapeutic opportunities.

CO2 Has no Therapeutic Effect on Early Micro Vasospasm after Experimental Subarachnoid Hemorrhage

“…Experiments by Iadecola and colleagues revealed that changes in CBF because of hypercapnia in the physiologic range are mediated primarily by nitric oxide (NO), 26,27 and these findings are supported by the fact that CO 2 elevates the classic NO-induced messenger molecule cyclic guanosine monophosphate in the smooth-muscle cells of cerebral vessels. 28 Because hemoglobin is a potent NO scavenger, 29 and because NO is required for both CO 2 -mediated vasodilatation and to maintain physiologic arteriolar diameter, we suggest that hemoglobin in the blood surrounding cerebral microvessels after SAH scavenges vascular (and/or perivascular) NO, thereby causing microvasospasm and a complete lack of CO 2 reactivity in these vessels. This hypothesis is supported, among others, by a recent nonhuman primate study that showed that replenishing vascular (or perivascular) NO by administering intravenously sodium nitrite-a strategy that is often used to deliver NO to endothelial cells-reversed SAHinduced macrovasospasm.…”

Is methemoglobin an inert bystander, biomarker or a mediator of oxidative stress—The example of anemia?

“…Blood flow is controlled by mechanism(s) that couple hemoglobin deoxygenation with the stimulation of NO-dependent vasodilation. The proposed mechanisms have been discussed previously [28] with nitrite-reduction being one. The latter occurs by DeoxyHb mediated reduction of nitrite, intermediate formation of reactive nitrogen species, and ultimate formation of NO and metHb [29].…”

Hemoglobin α in the blood vessel wall

“…Three general outcomes await NO once it is produced in EC: it can 1) diffuse into the blood stream where it is rapidly scavenged, first by cell free hemoglobin in the plasma and even further by hemoglobin in RBC 27 , 2) diffuse to neighboring VSMCs and cause vasorelaxation, 3) be scavenged by any number of molecules, such as reactive oxygen species (ROS) (for review, see Martinez et al, 2009 28 ). In the blood stream, most NO diffuses across its concentration gradient into RBC, where it is either scavenged or stored.…”