The fundamental, yet poorly understood, physiological mechanism known as 'acidic-metabolic' vasodilation, contributes to local blood flow regulation during hypoxia/ischaemia and increased metabolic activity. The vasodilator nitric oxide (NO) has been suggested to be involved in this event. Besides enzymatic production by NO synthases, a novel mechanism for generation of this gas in vivo was recently described. This involves non-enzymatic reduction of inorganic nitrite to NO, a reaction that takes place predominantly during acidic/reducing conditions. We have studied the effects of physiological amounts of nitrite on NO generation and relaxation of rat aorta in vitro in a situation where environmental pH was reduced to levels seen in tissues during hypoxia/ischaemia. The relaxatory effect of nitrite was increased in an acidic buffer solution (pH 6.6) compared with neutral pH; EC50 for nitrite was reduced from 200 to 40 microM. Nitrite-evoked relaxation was effectively prevented by coadministration of an inhibitor of soluble guanylyl cyclase. The relaxation was further potentiated by the addition of ascorbic acid. In parallel, NO was generated from nitrite in a pH dependent manner with even larger amounts seen after addition of ascorbic acid. NO generation from nitrite correlated to the the degree of relaxation of rat aorta. These results illustrate non-enzymatic release of NO from nitrite at physiological concentrations. This may be an important auto-regulated physiological mechanism involved in the regulation of vascular tone during hypoxia/ischaemia.

The fundamental, yet poorly understood, physiological mechanism known as 'acidic-metabolic' vasodilation, contributes to local blood flow regulation during hypoxia/ischaemia and increased metabolic activity. The vasodilator nitric oxide (NO) has been suggested to be involved in this event. Besides enzymatic production by NO synthases, a novel mechanism for generation of this gas in vivo was recently described. This involves non-enzymatic reduction of inorganic nitrite to NO, a reaction that takes place predominantly during acidic/reducing conditions. We have studied the effects of physiological amounts of nitrite on NO generation and relaxation of rat aorta in vitro in a situation where environmental pH was reduced to levels seen in tissues during hypoxia/ischaemia. The relaxatory effect of nitrite was increased in an acidic buffer solution (pH 6.6) compared with neutral pH; EC50 for nitrite was reduced from 200 to 40 microM. Nitrite-evoked relaxation was effectively prevented by coadministration of an inhibitor of soluble guanylyl cyclase. The relaxation was further potentiated by the addition of ascorbic acid. In parallel, NO was generated from nitrite in a pH dependent manner with even larger amounts seen after addition of ascorbic acid. NO generation from nitrite correlated to the the degree of relaxation of rat aorta. These results illustrate non-enzymatic release of NO from nitrite at physiological concentrations. This may be an important auto-regulated physiological mechanism involved in the regulation of vascular tone during hypoxia/ischaemia.

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BACKGROUND: Albumin may persist intravascularly for a shorter time in patients after major surgery than in healthy volunteers due to a surgery-induced breakdown (shedding) of the endothelial glycocalyx layer. METHODS: In this nonrandomized clinical trial, an IV infusion of 3 mL/kg of 20% albumin was given at a constant rate during 30 minutes to 15 patients on the first day after major open abdominal surgery (mean operating time 5.9 h) and to 15 conscious volunteers. Blood samples and urine were collected during 5 h and mass balance calculations used to estimate the half-lives of the administered albumin molecules and the induced plasma volume expansion, based on measurements of hemodilution and the plasma albumin concentration. RESULTS: At the end of the infusions, albumin had diluted the plasma volume by 13.3% ± 4.9% (mean ± SD) in the postoperative patients and by 14.2% ± 4.8% in the volunteers (mean difference −0.9, 95% CI, −4.7 to 2.9; 1-way ANOVA P = .61), which amounted to twice the infused volume. The intravascular half-life of the infused albumin molecules was 9.1 (5.7–11.2) h in the surgical patients and 6.0 (5.1–9.0) h in the volunteers (Mann-Whitney U test, P = .26; geometric mean difference 1.2, 95% CI, 0.8–2.0). The half-life of the plasma volume expansion was 10.3 (5.3–17.6; median and interquartile range) h in the surgical patients and 7.6 (3.5–9.0) h in the volunteers (P = .10; geometric mean difference 1.5, 95% CI, 0.8–2.8). All of these parameters correlated positively with the body mass index (correlation coefficients being 0.42–0.47) while age and sex did not affect the results. CONCLUSIONS: Twenty percent albumin caused a long-lasting plasma volume expansion of similar magnitude in postoperative patients and volunteers.

Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to NO and related compounds, which have potential biological activity. We used an in vivo rat model as a bioassay to test effects of human saliva on gastric mucosal blood flow and mucus thickness. Gastric mucosal blood flow and mucus thickness were measured after topical administration of human saliva in HCl. The saliva was collected either after fasting (low in nitrite) or after ingestion of sodium nitrate (high in nitrite). In additional experiments, saliva was exchanged for sodium nitrite at different doses. Mucosal blood flow was increased after luminal application of nitrite-rich saliva, whereas fasting saliva had no effects. Also, mucus thickness increased in response to nitrite-rich saliva. The effects of nitrite-rich saliva were similar to those of topically applied sodium nitrite. Nitrite-mediated effects were associated with generation of NO and S-nitrosothiols. In addition, pretreatment with an inhibitor of guanylyl cyclase markedly inhibited nitrite-mediated effects on blood flow. We conclude that nitrite-containing human saliva given luminally increases gastric mucosal blood flow and mucus thickness in the rat. These effects are likely mediated through nonenzymatic generation of NO via activation of guanylyl cyclase. This supports a gastroprotective role of salivary nitrate/nitrite.

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Figure 3(a and b) Correlation between MSI and AAG (a) or APE1 (b) activity. Bar graphs represent means ± SEM. There was a significant trend for MSI and AAG activity (robust regression analysis, P = 0.0012). Although this trend was not observed between MSI and APE1, there was a significant increase in APE1 activity in the MSI-High group (n = 5; one-way ANOVA with Scheffe multiple comparison test, P = 0.0004). *, AAG activity is significantly higher in the MSI-Low group (n = 10) than in the microsatellite stable group (n = 15). **, AAG activity is significantly higher in the MSI-High group (n = 5) than in the MSI-Low group (n = 10). ***, APE1 activity is significantly higher in the MSI-High group (n = 5) than in the MSI-Low (n = 10) and microsatellite stable (n = 15) groups. (c-e) Number of samples belonging to a specific AAG and APE1 activity category. AAG and APE1 activities were ranked in order, then placed into tertiles as samples with activity belonging to the Lower 1/3, Middle 1/3, or Top 1/3. (c) Of the 60 samples, 43 did not have a band shift and were characterized as microsatellite stable samples. (d) Of the 60 samples, 11 had a band shift in one of the markers examined (including TGFβRII and BLM) and were characterized as MSI-Low samples. (e) Of the 60 samples, six had a band shift in two or more of the markers examined (including TGFβRII and BLM) and were characterized as MSI-High samples. Shaded boxes represent activities where there is an imbalance of AAG and APE1 activities. The simple κ statistic indicates a trend for imbalance between AAG and APE1 as MSI levels increase. The simple κ statistic of 1.0 indicates no imbalance. A simple κ statistic moving toward zero indicates greater imbalance between the two enzymes.

Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to NO and related compounds, which have potential biological activity. We used an in vivo rat model as a bioassay to test effects of human saliva on gastric mucosal blood flow and mucus thickness. Gastric mucosal blood flow and mucus thickness were measured after topical administration of human saliva in HCl. The saliva was collected either after fasting (low in nitrite) or after ingestion of sodium nitrate (high in nitrite). In additional experiments, saliva was exchanged for sodium nitrite at different doses. Mucosal blood flow was increased after luminal application of nitrite-rich saliva, whereas fasting saliva had no effects. Also, mucus thickness increased in response to nitrite-rich saliva. The effects of nitrite-rich saliva were similar to those of topically applied sodium nitrite. Nitrite-mediated effects were associated with generation of NO and S-nitrosothiols. In addition, pretreatment with an inhibitor of guanylyl cyclase markedly inhibited nitrite-mediated effects on blood flow. We conclude that nitrite-containing human saliva given luminally increases gastric mucosal blood flow and mucus thickness in the rat. These effects are likely mediated through nonenzymatic generation of NO via activation of guanylyl cyclase. This supports a gastroprotective role of salivary nitrate/nitrite.