Effects of Nitric Oxide Donor SIN-1 on Oxygen Availability and Regional Blood Flow During Endotoxic Shock

Rats were exposed to hypobaric hypoxia (0.5 atm) for up to 3 wk. Hypoxic rats failed to gain weight but maintained normal brain water and ion content. Blood hematocrit was increased by 48% to a level of 71% after 3 wk of hypoxia compared with littermate controls. Brain blood flow was increased by an average of 38% in rats exposed to 15 min of 10% normobaric oxygen and by 23% after 3 h but was not different from normobaric normoxic rats after 3 wk of hypoxia. Sucrose space, as a measure of brain plasma volume, was not changed under any hypoxic conditions. The mean brain microvessel density was increased by 76% in the frontopolar cerebral cortex, 46% in the frontal motor cortex, 54% in the frontal sensory cortex, 65% in the parietal motor cortex, 68% in the parietal sensory cortex, 68% in the hippocampal CA1 region, 57% in the hippocampal CA3 region, 26% in the striatum, and 56% in the cerebellum. The results indicate that hypoxia elicits three main responses that affect brain oxygen availability. The acute effect of hypoxia is an increase in regional blood flow, which returns to control levels on continued hypoxic exposure. Longer-term effects of continued moderate hypoxic exposure are erythropoiesis and a decrease in intercapillary distance as a result of angiogenesis. The rise in hematocrit and the increase in microvessel density together increase oxygen availability to the brain to within normal limits, although this does not imply that tissue PO2 is restored to normal.

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Purinergic Receptors, Nitric Oxide, and Regional Blood Flow

Nitric Oxide and the Regulation of the Peripheral Circulation ◽

10.1007/978-1-4612-1326-0_5 ◽

2000 ◽

pp. 65-84

Author(s):

Vera Ralevic ◽

Geoffrey Burnstock

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Purinergic Receptors ◽

Regional Blood Flow

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Nitric oxide production duringVibrio choleraeinfection

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1997.273.5.g1160 ◽

1997 ◽

Vol 273 (5) ◽

pp. G1160-G1167 ◽

Cited By ~ 10

Author(s):

Edward N. Janoff ◽

Hiroshi Hayakawa ◽

David N. Taylor ◽

Claudine E. Fasching ◽

Julie R. Kenner ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Epithelial Cells ◽

Regional Blood Flow ◽

Fluid Secretion ◽

The United States ◽

No Production ◽

Loop Model ◽

Ileal Loop

Vibrio cholerae induces massive intestinal fluid secretion that continues for the life of the stimulated epithelial cells. Enhanced regional blood flow and peristalsis are required to adapt to this obligatory intestinal secretory challenge. Nitric oxide (NO) is a multifunctional molecule that modulates blood flow and peristalsis and possesses both cytotoxic and antibacterial activity. We demonstrate that, compared with those in asymptomatic control subjects, levels of stable NO metabolites ([Formula: see text]/[Formula: see text]) are significantly increased in sera from acutely ill Peruvian patients with natural cholera infection as well as from symptomatic volunteers from the United States infected experimentally with V. cholerae. In a rabbit ileal loop model in vivo, cholera toxin (CT) elicited fluid secretion and dose-dependent increases in levels of[Formula: see text]/[Formula: see text]in the fluid ( P < 0.01). In contrast, lipopolysaccharide (LPS) elicited no such effects when applied to the intact mucosa. NO synthase (NOS) catalytic activity also increased in toxin-exposed tissues ( P< 0.05), predominantly in epithelial cells. The CT-induced NOS activity was Ca2+dependent and was not suppressed by dexamethasone. In conclusion, symptomatic V. cholerae infection induces NO production in humans. In the related animal model, CT, but not LPS, stimulated significant production of NO in association with increases in local Ca2+-dependent NOS activity in the tissues.

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Role of nitric oxide in the regulation of regional blood flow and metabolism in anaesthetized pigs

Acta Physiologica Scandinavica ◽

10.1046/j.1365-201x.1998.t01-1-00396.x ◽

1998 ◽

Vol 163 (4) ◽

pp. 339-348 ◽

Cited By ~ 4

Author(s):

M. Licker ◽

H. Boussairi ◽

L. Hohn ◽

D.R. Morel

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Regional Blood Flow

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Sodium Nitrite Increases Regional Blood Flow in Patients with Sickle Cell Disease.

Blood ◽

10.1182/blood.v106.11.2328.2328 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2328-2328

Author(s):

A. Kyle Mack ◽

Roberto F. Machado ◽

Vandana Sachdev ◽

Mark T. Gladwin ◽

Gregory J. Kato

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Forearm Blood Flow ◽

Regional Blood Flow ◽

Cell Disease ◽

No Donor ◽

No Donors ◽

Before And After

Abstract Patients with sickle cell disease have decreased nitric oxide bioavailability, and studies from several groups have confirmed a blunted response to various NO donors in humans and mice with sickle cell disease. Recently published studies show that nitrite induces vasodilation in humans, apparently mediated by conversion of nitrite to NO. This study is designed to determine the potential therapeutic effect of intra-arterial nitrite infusion to restore nitric oxide dependent blood flow in the forearms of patients with sickle cell disease. Venous occlusion strain gauge plethysmography is used to measure the change of forearm blood flow in patients with sickle cell disease, before and after sequential brachial artery infusions of increasing doses of sodium nitrite. In addition, NO responsiveness before and after nitrite infusion is measured by test doses of the NO donor sodium nitroprusside (SNP). Six patients have completed the study and enrollment is continuing. These data indicate that nitrite promotes regional blood flow in patients with sickle cell disease, albeit with a blunted response compared to our healthy control subjects, in whom we previously have found increased blood flow up to 187% with comparable dosing. The significant but blunted response is consistent with the state of nitric oxide resistance to NO donors that has been seen by several groups in patients and mice with SCD. Additionally, we find in these patients that nitrite partially restores SNP responsiveness, with baseline maximal SNP responses more than doubling on average following nitrite infusion, although this finding is preliminary. No adverse effects of nitrite were seen in these six patients. Our early results support a role for nitrite as an NO donor effective in restoring NO-dependent blood flow in patients with sickle cell disease. Additional translational studies are warranted to evaluate the therapeutic effects of systemic nitrite dosing. Table 1. Forearm Blood Flow Response to Nitrite Infusion Nitrite Dose (micromole/min) Sickle Cell Disease Historical Controls P< .0001 (ANOVA) 0.4 5 +/−7.2% N=6 22 +/−3.2% N=10 4 15 +/− 11% N=6 Not infused 40 49 +/− 8.9% N=6 187 +/− 16%N=18 Table 2. Nitrite Effect on Nitroprusside Responsiveness SNP Dose (micrograms/min) Pre-Nitrite Post-Nitrite P= .02 (RM-ANOVA) N=6 0.8 +21 +/− 5.6% +33 +/− 8.3% 1.6 +15 +/− 5.9% +62 +/− 15.1% 3.2 +29 +/− 6.3% +67 +/− 11.5%

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