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Endogenous Nitric Oxide Production and Pulmonary Blood Flow: during different experimental lung conditions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nitric oxide (NO) is an important regulator of pulmonary blood flow and attenuates hypoxic pulmonary vasoconstriction (HPV). Nitric oxide is synthesized enzymatically in a number of tissues, including the lungs, and can also be generated from reduction of nitrite during hypoxia and acidosis. Inhaled nitric oxide (INO) is a selective pulmonary vasodilator, with no effects on systemic arterial blood pressure due to inactivation by hemoglobin in the blood. INO has distant effects both within the lungs and in other organs, since NO can be transported to remote tissues bound to proteins, or as more stable molecules of nitrite and nitrate. In healthy pigs, INO causes vasoconstriction and down regulation of endogenous NO production in lung regions not reached by INO, and predominantly so in hypoxic lung regions, i.e. augmentation of HPV. In this thesis, distant effects of INO in pigs with endotoxemic- and lavage-induced lung injuries were studied. INO increased the NO production in lung regions not reached by INO in endotoxemic pigs, whereas endogenous NO production was unaffected in pigs with lavage-induced injury.

Metabolic and/or hypercapnic acidosis frequently occurs in critically ill patients, but whether acidosis affects the endogenous pulmonary NO production is unclear. The regional NO production and blood flow in hyperoxic and hypoxic lung regions, were studied during metabolic and hypercapnic acidosis. Neither metabolic, nor hypercapnic acidosis changed the endogenous NO production in hyperoxic or hypoxic lung regions. Metabolic acidosis potentiated HPV, whereas hypercapnic acidosis transiently attenuated HPV.

In conclusion, the present thesis has demonstrated that INO in experimental sepsis increases the endogenous NO production in lung regions not reached by INO, which may cause increased shunt and poor response to INO. This distant effect is not seen in lavage injuried lungs, an experimental model with less inflammation. Acidosis does not affect the endogenous pulmonary NO production in hyperoxic or hypoxic lung regions. Whereas metabolic acidosis potentiates HPV, hypercapnic acidosis transiently attenuates HPV, due to a combination of hypercapnia-induced increase in cardiac output and a probable vasodilating effect of the CO2-molecule.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 694
Keyword [en]
Nitric oxide, pulmonary blood flow, endotoxin, nitric oxide inhalation, endothelin, hypercapnia, acidosis, lavage-induced lung injury
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-157162ISBN: 978-91-554-8132-2 (print)OAI: oai:DiVA.org:uu-157162DiVA: diva2:435424
Public defence
2011-09-30, Hedstrandsalen, Akademiska sjukhuset,ing 70, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2011-09-09 Created: 2011-08-18 Last updated: 2011-11-03Bibliographically approved
List of papers
1. Distant effects of nitric oxide inhalation in endotoxemic pigs
Open this publication in new window or tab >>Distant effects of nitric oxide inhalation in endotoxemic pigs
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2010 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 1, 242-248 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Inhalation of nitric oxide (INO) has distant effects. By a blood- borne factor, INO down-regulates endogenous nitric oxide production in healthy pig lungs, resulting in vasoconstriction in lung regions not directly reached by INO. The aim of this study was to investigate whether INO has distant effects in endotoxemic pig lungs. The hypothesis was that INO down-regulates endogenous NO production in lung regions not reached by INO. DESIGN: Prospective, randomized animal study. SETTING: University hospital research laboratory. SUBJECTS: Twenty-two pairs of domestic pigs. INTERVENTIONS: Cross-circulation was established in 22 pairs of anesthetized pigs. Nine pairs received endotoxin (control group) and 13 pairs received endotoxin, with one pig inhaling NO (80 ppm) and one pig receiving blood from that pig (NO-blood recipient group). MEASUREMENTS AND MAIN RESULTS: NO in exhaled air, NO synthase activity in lung tissue, endothelin-1 in the blood, ETA and ETB receptor immunoreactivity in lung tissue, vital parameters, and blood gases were measured. Endotoxin per se increased NO in exhaled air by 100% compared to baseline (control group). In the NO-blood recipient group, i.e., pigs receiving blood from the NO-inhaling pigs, NO in exhaled air increased by 300% (p = .03). The Ca-dependent NO synthase activity was higher in these pigs (p = .02), indicating increased endogenous NO production. The ET B receptor immunoreactivity was higher in the NO-blood recipient group (p = .004). CONCLUSIONS: As opposed to findings in healthy pigs, INO in endotoxemic pigs causes an increase in endogenous NO production in lung regions not reached by INO. Increased NO production in nonventilated lung regions may cause vasodilatation, counteracting the INO-induced increase in blood flow to the ventilated lung regions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-113072 (URN)10.1097/CCM.0b013e3181b4a4fc (DOI)000273224800033 ()19730256 (PubMedID)
Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2017-12-12Bibliographically approved
2. Distant effects of nitric oxide inhalation in lavage induced lung injury in anaesthetised pigs
Open this publication in new window or tab >>Distant effects of nitric oxide inhalation in lavage induced lung injury in anaesthetised pigs
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2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 3, 326-333 p.Article in journal (Refereed) Published
Abstract [en]

Background Inhalation of nitric oxide (INO) exerts both local and distanteffects. INO in healthy pigs causes down-regulation of endogenous nitric oxide(NO) production and vasoconstriction in lung regions not reached by INO, especially in hypoxic regions, which augments hypoxic pulmonary vasoconstriction. In contrast, in pigs with endotoxemia-induced lung injury, INO causes increased NO production in lung regions not reached by INO. The aim ofthis study was to investigate whether INO exerts distant effects in surfactant-depleted lungs. Methods Twelve pigs were anaesthetised, and the left lower lobe (LLL) was separately ventilated. Lavage injury was induced in all lung regions, except the LLL. In six pigs, 40 ppm INO was given to the LLL (INO group), and theeffects on endogenous NO production and blood flow in the lavage-injured lungregions were studied. Six pigs served as a control group. NO concentration inexhaled air (ENO), NO synthase (NOS) activity and cyclic guanosine monophosphate (cGMP) in lung tissue, and regional pulmonary blood flow were measured. Results The calcium (Ca2+)-dependent NOS activity was lower (P<0.05) in the lavage-injured lung regions in the INO group than in the control group. There were no measurable differences between the groups for Ca2+-independent NOS activity, cGMP, ENO, or regional pulmonary blood flow. Conclusions Regional INO did not increase endogenous NO production in lavage-injured lung regions not directly reached by INO, but instead down-regulated the constitutive calcium-dependent nitric oxide synthase activity, indicating that NO may inhibit its own synthesis.

Keyword
Nitric oxide, Nitric oxide synthase, Lavage induced lung injury, pulmonary blood flow, exhaled nitric oxide, cyclic guanosine monophosphate
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-157085 (URN)10.1111/aas.12030 (DOI)000314652400009 ()
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2017-12-08Bibliographically approved
3. No effect of metabolic acidosis on nitric oxide production in hypoxic and hyperoxic lung regions in pigs
Open this publication in new window or tab >>No effect of metabolic acidosis on nitric oxide production in hypoxic and hyperoxic lung regions in pigs
2011 (English)In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 1, 59-68 p.Article in journal (Refereed) Published
Abstract [en]

Aim: In the severely ill intensive care patients metabolic acidosis and hypoxia often co-exist. We studied the effects of metabolic acidosis on nitric oxide synthase (NOS) dependent and NOS independent nitric oxide (NO) production in hypoxic and hyperoxic lung (HL) regions in a pig model. Methods: Eighteen healthy anaesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (LLL) and hyperoxic gas to the rest of the lung. Six pigs received HCl infusion (HCl group), six pigs received the non-specific NOS inhibitor N omega-nitro-l-arginine methyl ester (l-NAME) and HCl infusions (l-NAME + HCl group) and six pigs received buffered Ringer's solution (control group). NO concentration in exhaled air (ENO), NOS activity in lung tissue, and regional pulmonary blood flow were measured. Results: Metabolic acidosis, induced by infusion of HCl, decreased the relative perfusion to the hypoxic LLL from 7 (3) [mean (SD)] to 3 (1) % in the HCl group (P < 0.01), and from 4 (1) to 1 (1) % in the l-NAME + HCl group (P < 0.05), without any measurable significant changes in ENO from hypoxic or HL regions There were no significant differences between the HCl and control groups for Ca2+-dependent (cNOS) or Ca2+-independent NOS (iNOS) activity in hypoxic or HL regions. Conclusions: Metabolic acidosis augmented the hypoxic pulmonary vasoconstriction, without any changes in pulmonary NOS dependent or NOS independent NO production. When acidosis was induced during ongoing NOS blockade, the perfusion of hypoxic lung regions was almost abolished, indicating acidosis-induced pulmonary vasoconstriction was not NO dependent.

Keyword
acidosis, exhaled nitric oxide, hypoxic pulmonary vasoconstriction, nitric oxide, nitric oxide synthase blockade
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-152868 (URN)10.1111/j.1748-1716.2011.02250.x (DOI)000289250500007 ()21251235 (PubMedID)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
4. Hypercapnic acidosis transiently weakens hypoxic pulmonary vasoconstriction in anesthetized pigs, without affecting the endogenous pulmonary nitric oxide production.
Open this publication in new window or tab >>Hypercapnic acidosis transiently weakens hypoxic pulmonary vasoconstriction in anesthetized pigs, without affecting the endogenous pulmonary nitric oxide production.
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2012 (English)In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 38, no 3, 509-517 p.Article in journal (Refereed) Published
Abstract [en]

Purpose  Hypercapnic acidosis often occurs in critically ill patients and during protective mechanical ventilation; however, the effect of hypercapnic acidosis on endogenous nitric oxide (NO) production and hypoxic pulmonary vasoconstriction (HPV) presents conflicting results. The aim of this study is to test the hypothesis that hypercapnic acidosis augments HPV without changing endogenous NO production in both hyperoxic and hypoxic lung regions in pigs.

Methods  Sixteen healthy anesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (LLL) and hyperoxic gas to the rest of the lung. Eight pigs received 10% carbon dioxide (CO2) inhalation to both lung regions (hypercapnia group), and eight pigs formed the control group. NO concentration in exhaled air (ENO), nitric oxide synthase (NOS) activity, cyclic guanosine monophosphate (cGMP) in lung tissue, and regional pulmonary blood flow were measured.

Results  There were no differences between the groups for ENO, Ca2+-independent or Ca2+-dependent NOS activity, or cGMP in hypoxic or hyperoxic lung regions. Relative perfusion to LLL (Q LLL/Q T) was reduced similarly in both groups when LLL hypoxia was induced. During the first 90 min of hypercapnia, Q LLL/Q T increased from 6% (1%) [mean (standard deviation, SD)] to 9% (2%) (p < 0.01), and then decreased to the same level as the control group, where Q LLL/Q T remained unchanged. Cardiac output increased during hypercapnia (p < 0.01), resulting in increased oxygen delivery (p < 0.01), despite decreased PaO2 (p < 0.01).

Conclusions  Hypercapnic acidosis does not potentiate HPV, but rather transiently weakens HPV, and does not affect endogenous NO production in either hypoxic or hyperoxic lung regions.

Keyword
Nitric oxide, hypercapnic acidosis, hypoxic pulmonary vasoconstriction, exhaled nitric oxide, cyclic guanosine monophosphate, pulmonary blood flow.
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-157084 (URN)10.1007/s00134-012-2482-7 (DOI)000300776300020 ()
Available from: 2011-08-15 Created: 2011-08-15 Last updated: 2017-12-08Bibliographically approved

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