Short‐term hypoxic vasodilation in vivo is mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin‐mediated nitrite reduction

Abstract

Short-term hypoxic vasodilation in vivo isr In a short-term rodent model, hypoxaemia was associated with hypotension and lower plasma nitrite levels suggestive of nitrite bioactivation; this was only partially reversed by NO synthase inhibition. Administration of sodium nitrite produced marked vasodilation and increased nitrosylation. Scavenging of NO had little effect.r Early hypoxic vasodilation is mediated by a complex interaction of multiple NO-related species, rather than by NO from haemoglobin-mediated reduction of nitrite per se.r NO and its metabolites play a pivotal role in the body's initial adaptation to an acute decrease in oxygen supply, probably offering protection against a supply-demand mismatch.Abstract Local increases in blood flow -'hypoxic vasodilation' -confer cellular protection in the face of reduced oxygen delivery. The physiological relevance of this response is well established, yet ongoing controversy surrounds its underlying mechanisms. We sought to confirm that early hypoxic vasodilation is a nitric oxide (NO)-mediated phenomenon and to study putative pathways for increased levels of NO, namely production from NO synthases, intravascular nitrite reduction, release from preformed stores and reduced deactivation by cytochrome c oxidase. Experiments were performed on spontaneously breathing, anaesthetized, male Wistar rats undergoing short-term systemic hypoxaemia, who received pharmacological inhibitors and activators of the various NO pathways. Arterial blood pressure, cardiac output, tissue oxygen tension and the circulating pool of NO metabolites (oxidation, nitrosation and nitrosylation products) were measured in plasma and erythrocytes. Hypoxaemia caused a rapid and sustained vasodilation, which was only partially reversed by non-selective NO synthase inhibition. This was associated with significantly lower plasma nitrite, and marginally elevated nitrate levels, suggestive of nitrite bioinactivation. Administration of sodium nitrite had little effect in normoxia, but produced significant vasodilation and increased nitrosylation during hypoxaemia that could not be reversed by NO scavenging. Methodological issues prevented assessment of the contribution, if any, of reduced deactivation of NO by cytochrome c oxidase. In conclusion, acute hypoxic vasodilation is an adaptive NO-mediated response conferred through bioactive metabolites rather than free NO from haemoglobin-mediated reduction of nitrite.

Hydrogen Sulfide as an Oxygen Sensor

“…Recently, Miljkovic et al (106) showed that H 2 S is a rapid mediator of nitrite reduction by providing reducing equivalents to Fe 3 + , thereby generating both NO and its reduced congener, nitroxyl (HNO). Vasodilation produced by acute hypoxia in mice in vivo appears to be independent of NO production, and it is associated with reduced plasma nitrite concentration and increased RSNOs (174). This is consistent with H 2 S, as the initial hypoxic signal that mediates downstream increases in both H 2 S 2 and HNO as shown in Figure 7.…”

Sepsis impairs microvascular autoregulation and delays capillary response within hypoxic capillaries

“…Changes in capillary O 2 supply rate are due in part to upstream changes in arteriolar tone distant from sites where RBC O 2 saturation is lowest (the venular ends of capillary networks) indicating that conducted microvascular responses [ 16 , 25 , 45 ] are integral to microvascular autoregulation. The other important distinctions to be made are: 1) the septic injury in this study does not involve systemic hypoxia, as arterial O 2 saturations were normal; rather, altered functional capillary density and micro-regions within capillary networks with stopped-flow or decreased capillary O 2 supply cause local hypoxia and thus a different mechanism is likely involved than that of hypoxic vasodilation [ 23 , 46 , 52 ]; 2) the skeletal muscle NO environment in this model is known to be due to an upregulation of iNOS [ 2 ]; 3) microvascular derangements exist in the face of hypotensive [ 2 ], “relatively preserved” [ 7 ] and even normotensive blood pressure [ 3 , 4 ] with fluid resuscitation, normal arterial O 2 concentration and cardiac output [ 3 , 4 ]. Thus microvascular dysfunction is apparently independent of mean arterial pressure and may be masked by seemingly normal cardiovascular parameters.…”

The Effect of Sepsis on the Erythrocyte

“…Blood flow into the capillaries is controlled by the upstream arteriolar tone feeding the capillary network. Vasoactive molecules released from the RBC in response to hypoxic conditions, including ATP [ 135 , 136 ], nitric oxide (generated by deoxy-hemoglobin acting as a nitrite reducatse) [ 137 , 138 , 139 ] and nitrosothiols [ 140 ] have been proposed as possible mediators of hypoxic vasodilation; though, the role of nitric oxide vis-à-vis nitrosothiols and reaction with the hemoglobin βCys93 residue is somewhat controversial [ 141 , 142 , 143 ]. As RBCs travel through the microcirculation, ATP may be released in hypoxic regions from ATP compartments [ 144 ] via the RBC Pannexin-1 channel [ 145 ].…”