Plasma Nitrosothiols Contribute to the Systemic Vasodilator Effects of Intravenously Applied NO

Abstract

Abstract-Higher doses of inhaled NO exert effects beyond the pulmonary circulation. How such extrapulmonary effects can be reconciled with the presumed short half-life of NO in the blood is unclear. Whereas erythrocytes have been suggested to participate in NO transport, the exact role of plasma in NO delivery in humans is not clear. Therefore, we investigated potential routes of NO decomposition and transport in human plasma. NO consumption in plasma was accompanied by a concentration-dependent increase in nitrite and S-nitrosothiols (RSNOs), with no apparent saturation limit up to 200 mol/L. The supposedly rapid conversion of NO to biologically inactive metabolites in human blood formed the rationale for inhalation NO therapy, because the short half-life of NO should confine its effect to the pulmonary circulation. 4 However, recent evidence suggests that higher doses of inhaled NO may exert side effects beyond the pulmonary circulation. 5,6 Red blood cells (RBCs) are believed to be a major sink for NO by virtue of the rapid co-oxidation reaction of NO with oxyhemoglobin to form methemoglobin (metHb) and nitrate. Alternatively, NO may react with hemoglobin (Hb) to form either nitrosylhemoglobin (NOHb) or S-nitrosohemoglobin (SNOHb). 6,7 In addition to its reaction with RBCs, NO has to interact at some stage with plasma constituents, especially in view of the existence of an RBC-free zone close to the vessel wall. 8 A better knowledge of the fate of NO in plasma is an important prerequisite for a proper understanding of its physiology in blood and in the human circulation in general.Recently, we provided evidence that intra-arterially applied NO can be transported in a bioactive form over significant distances along the forearm circulation. 9 To date, no data have been reported on the systemic dilator effects of intravenously applied NO in the human peripheral vasculature, presumably because of its supposedly rapid clearance from blood. Our data challenge this current dogma. In the present study, we demonstrate that the intravenous infusion of NO solution results in the transport and delivery of NO as S-nitrosothiols (RSNOs), which are accompanied by systemic hemodynamic effects and vasodilation in conduit and resistance vessels.

Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration

“…Part of the NO released into the blood stream might be subjected to oxidative decomposition and to nitrosative chemistry as in the previous study on the systemic circulation (46). Nevertheless, a substantial portion of the NO produced in the coronary circulation was transported to the venous outflow tract, i.e., the coronary sinus.…”

Nitric Oxide Sensors for Biological Applications

“…While the assays can inform a researcher about the NO that is being produced in an entire system, they are not able to identify the specific areas of NO production and use throughout a cell or throughout a system of multiple cells. S-nitrosothiol (RSNO) is another upstream compound that is utilized to calculate NO concentration, since it is believed that RSNOs can act as reservoirs or carriers of NO within biological systems without altering NO's activity [52,68,69]. The Meyerhoff lab has shown the use of sensors that can reversibly detect RSNO within blood for a 10-day period, extending the timeframe for NO detection past most of the other sensor options [70].…”

Control of Plasma Nitric Oxide Bioactivity by Perfluorocarbons

“…34 Moreover, intravenous application of NO was shown to exert a systemic hemodynamic effect via RSNO in humans. 11 However, it has remained unclear whether intrinsic plasma NO or RSNO played any significant role in cardiovascular processes. In the present study, we addressed this important issue by devising an approach to specifically modulate the pool of plasma NO and RSNO without boosting NO production or delivering any exogenous NO into the system.…”

“…[3][4][5][6][7] Because RSNOs are relatively stable and can release NO when required on reaction with various reducing agents, 8,9 they may serve as a buffering system that magnifies the range of NO action along the vascular tree. 10,11 Although the pharmacological potential of RSNO is well appreciated, [12][13][14] the role of plasma NO and the mechanism of endogenous RSNO formation under physiological conditions are a source of considerable debate. 15 The apparent limitation for plasma NO to exert its biological function is the constant presence of abundant hemoglobin (10 mmol/L) from red blood cells that converts NO into inactive metabolites at near-diffusion-limited rates.…”