Intravascular flow decreases erythrocyte consumption of nitric oxide

Abstract

Nitric oxide (NO) produced by the endothelium diffuses both into the lumen and to the smooth muscle cells according to the concentration gradient in each direction. The extremely high reaction rate between NO and hemoglobin (Hb), k Hb ‫؍‬ 3-5 ؋ 10 7 M ؊1 ⅐s ؊1 , suggests that most of the NO produced would be consumed by Hb in the red blood cells (RBCs), which then would block the biological effect of NO. Therefore, specific mechanisms must exist under physiological conditions to reduce the NO consumption by RBCs, in which the Hb concentration is very high (24 mM heme). By using isolated microvessels as a bioassay, here we show that physiological concentrations of RBCs in the presence of intravascular f low does not inhibit NO-mediated vessel dilation, suggesting that RBCs under this condition are not an NO scavenger. On the other hand, RBCs (50% hematocrit) without intravascular f low reduce NO-mediated dilation to serotonin by 30%. In contrast, free Hb (10 M) completely inhibits NO-mediated dilation with or without intravascular f low. The effect of f low on NO consumption by RBCs may be attributed to the formation of an RBC-free zone near the vessel wall, which is caused by hydrodynamic forces on particles. Intravascular f low does not affect the reaction rate between NO and free Hb in the lumen, because the latter forms a homogeneous solution and is not subject to the hydrodynamic separation. However, intravascular f low only partially contributes to the reduced consumption of NO by RBCs, because without the f low, the NO consumption by RBCs is already about 3 orders of magnitude slower than free Hb.Nitric oxide (NO) is a biological messenger that participates in neurotransmission, vascular regulation, and immunological responses. It is produced in many cell types such as neurons, endothelial cells vascular smooth muscle cells, and macrophages. Since the discovery of its biological activity, the roles of NO in physiological and pathophysiological processes have been seen as increasingly important. In the cardiovascular system, NO has been documented to participate in the regulation of vascular tone and permeability (1, 2), platelet adhesion and aggregation (3, 4), smooth muscle proliferation (5, 6), and endothelial cell-leukocyte interactions (1, 7). The functions of NO in vivo have been clearly demonstrated by administration of L-arginine analogs that block NO production. For example, the administration of N G -monomethyl-L-arginine (L-NMMA) has been shown to cause hypertension in vivo (8) and abolish shear-induced, NO-mediated vessel dilation both in vivo (9) and in isolated intact vessel preparation (10).Despite the well-documented importance of NO, the transfer of NO from the producing cell to the target is poorly understood, because NO, as a free radical, can be degraded in a variety of reactions. In particular, NO reacts with deoxy-and oxy-hemoglobin (Hb) at a very high rate to form nitrosyl-Hb (HbNO), and metHb, respectively. The bimolecular reaction rate constants for these reactions are on th...

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

“…That NO is made in a compartment adjacent to the blood where there is about 10 mM Hb (heme concentration * ), led to questioning how it can function without being scavenged by the Hb [34]. In normal physiology, the reason that endothelial-derived NO is not scavenged to the extent predicted, based purely on kinetic calculations, is that red blood cell (RBC) encapsulated Hb in the blood reacts with NO much more slowly than does cell-free Hb [35][36][37][38][39][40][41][42][43][44][45]. Three mechanisms contribute to reduced NO scavenging by RBCs [46].…”

“…Three mechanisms contribute to reduced NO scavenging by RBCs [46]. : (1) the rate of the reaction is largely limited by external diffusion of NO through the plasma to the surface of the RBC [44], especially due to the presence of a red cell free zone adjacent to the vessel walls where NO is made [37][38][39]; (2) NO diffusion is partially blocked by a physical barrier across the RBC membrane [40,43,47]; and (3) RBC-encapsulated Hb is efficiently compartmentalized in the lumen; it does not extravasate into the endothelium and interstitium [44,[48][49][50][51][52].…”

Interactions of nitrosylhemoglobin and carboxyhemoglobin with erythrocyte

“…Ordinary differential equations (Eqns. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] describe the mass actions of chemical species. For the interaction of HbFe II CO and RBCs (Box 1), reactions in both the phase inside of RBCs and the extracellular solution were considered.…”

“…It is therefore necessary to preserve NO bioactivity in the proximity of a pool of hemoglobin (∼10 mM) in the lumen. Several solutions to this paradox have been proposed, including i) the diffusion and transport limitation arises from the encapsulation of hemoglobin (Hb) in erythrocyte [8,9,10,11,12,13,14,5,15,16,17,18], ii) the formation of S-nitroso-hemoglobin (SNO-Hb) from the intramolecular transfer of nitrosylhemoglobin (HbFe II NO) [19,20,21,22,23,24,5,25], and iii) the NO bioactivity transduced from nitrite [26,27,28,29]. In the latter two cases, the formation of HbFe II NO can be argued to play a role for preserving NO bioactivity.…”

Modelling Blood Flow Regulation by Nitric Oxide in Psoriatic Plaques

“…Like the production rate a, g 0 can be found by matching observation with simulation. The parameter ν is the product of haemoglobin concentration in the blood (typically 2 mM; Thibodeau and Patton, 1997), the proportion of the dermal papillae composed of blood vessels (about 10%; Auer et al, 1994), and the rate constant of NO binding to haemoglobin in flowing blood (5×10 4 M −1 s −1 ; Liao et al, 1999); this gives ν = 10 s −1 .…”