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| 2. |
- Hambraeus Jonzon, Kristina
(author)
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Hypoxic pulmonary vasoconstriction and nitric oxide
- 2000
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Doctoral thesis (other academic/artistic)abstract
- Hypoxia causes pulmonary vasoconstriction (HPV), improving oxygenation by redistribution of the pulmonary blood flow to better oxygenated lung regions. HPV is intrinsic to the pulmonary vascular smooth muscle cell, but can be modulated by several vasoactive substances, as for example endothelium derived nitric oxide (NO) and endothelin-1 (ET-1). A stimulus-response relationship between alveolar oxygen tension and pulmonary vascular resistance (PVR) has been observed in animals. The degree of hypoxia has also been shown to be of importance for endogenous NO production in the lung, but results are conflicting. We hypothesized that the fraction of inhaled oxygen (FIO2) is of importance for the active regulation of pulmonary vascular tone by hypoxia, NO and ET-1. We tested whether the strength of HPV in human lungs is related to FIO2 and if regional hypoxia influences the endogenous enzymatic and non-enzymatic production of NO in pig lungs, and circulating ETI levels in plasma in humans and pigs. We also studied the mechanism of action for inhaled NO (INO) in relation to hyperoxic and hypoxic lung regions in humans and pigs. The studies were conducted in anesthetized, lung-healthy patients or pigs, which were double-lumen intubated, enabling separate and synchronous mechanical ventilation of the right and left lung (Patients), or the left lower lobe (LLL) and the other lung regions (Pigs). Regional pulmonary blood flow was measured by inert gas elimination technique (Patients), or by ultrasonic flow probes (Pigs). We found a stimulus-response relationship between F102 and blood flow diversion, in the normal human lung. Exhaled NO concentration (NOE) from, and NO synthase (NOS) activity in hypoxic lung regions were significantly higher, than in hyperoxic lung regions. No significant changes were detected in plasma levels of ET-1-like immunoreactivity (ET-1-LI) during acute global or regional hypoxia. NOE was very low during NOS-blockade, but consistently higher in hypoxic than in hyperoxic lung regions. Infusion of nitrite during ongoing NOS-blockade increased NOE in a concentration-dependent manner, and much more in hypoxic than in hyperoxic lung regions. F102 was also shown to be of importance for the mechanism of action for NO. INO to hyperoxic lung regions, augmented the vaso-constriction in hypoxic lung regions, causing a further redistribution of pulmonary blood flow to hyperoxic lung regions in both Patients and Pigs. No such redistribution of pulmonary blood flow was observed in the absence of regional hypoxia. INO to hyperoxic lung regions, significantly decreased NOE from, and NOS activity in hypoxic lung regions, indicating a decreased endogenous enzymatic NO production in hypoxic lung regions. The mediator, or mediators causing this distant down-regulation of NO production was shown to be bloodborne, in a cross-circulation pig model. PVR increased and NOE decreased, predominantly in hypoxic lung regions, when pigs with regional LLL hypoxia received blood from pigs with INO, but not when they received blood from pigs without INO. Conclusions: A stimulus-response relationship exists between F102 and blood flow diversion in the healthy human lung. Acute hypoxia increases endogenous enzymatic NO production, but not ET- I -LI in plasma. Non-enzymatic NO production from nitrite can occur in hypoxic lung regions. INO has dual effects, dilating vessels in lung regions directly reached by INO, and constricting vessels in lung regions not directly reached by INO. This distant effect is blood-borne, and more prominent in hypoxic, than in hyperoxic lung regions.
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| 3. |
- Hambraeus-Jonzon, Kristina, et al.
(author)
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Pulmonary Vasoconstriction during Regional Nitric Oxide Inhalation : Evidence of a Blood-borne Regulator of Nitric Oxide Synthase Activity
- 2001
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In: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 95:1, s. 102-112
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Journal article (peer-reviewed)abstract
- BACKGROUND: Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect. METHODS: Nitric oxide concentration was measured in exhaled air (NO(E)), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [FIO2] = 0.05), with and without INO to HL (FIO2 = 0.8), and during cross-circulation of blood from pigs with and without INO. RESULTS: Left lower lobar hypoxia increased exhaled NO from the LLL (NO(E)LLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca2+-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol x g(-1) x min(-1), P < 0.05). INO to HL decreased the Ca2+-dependent NOS activity in hypoxic tissue to 49 [56] pmol x g(-1) x min(-1) (P < 0.01), and NO(E)LLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO(E)LLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca2+-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol x g(-1) x min(-1) (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions. CONCLUSIONS: Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.
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- Nilsson, Manja C. A., 1966-, et al.
(author)
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Hypercapnic acidosis transiently weakens hypoxic pulmonary vasoconstriction in anesthetized pigs, without affecting the endogenous pulmonary nitric oxide production.
- 2012
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In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 38:3, s. 509-517
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Nilsson, Manja, et al.
(author)
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Distant effects of nitric oxide inhalation in lavage induced lung injury in anaesthetised pigs
- 2013
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 57:3, s. 326-333
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Journal article (peer-reviewed)abstract
- 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.
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| 6. |
- Nilsson, Manja
(author)
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Endogenous Nitric Oxide Production and Pulmonary Blood Flow : during different experimental lung conditions
- 2011
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 7. |
- Trachsel, Sebastien, et al.
(author)
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No redistribution of lung blood flow by inhaled nitric oxide in endotoxemic piglets pretreated with an endothelin receptor antagonist
- 2015
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 118:6, s. 768-775
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Journal article (peer-reviewed)abstract
- Inhaled nitric oxide (INO) improves ventilation-perfusion matching and alleviates pulmonary hypertension in patients with acute respiratory distress syndrome. However, outcome has not yet been shown to improve, and non-response is common. A better understanding of the mechanisms by which INO acts, may guide in improving treatment with INO in patients with severe respiratory failure. We hypothesized that INO may act not only by vasodilation in ventilated lung regions, but also by causing vasoconstriction via endothelin (ET-1) in atelectatic, non-ventilated lung regions. This was studied in 30 anesthetized, mechanically ventilated piglets. The fall in oxygenation and rise in pulmonary artery pressure during a sepsis-like condition (infusion of endotoxin) were blunted by INO 40ppm. Endotoxin infusion increased serum ET-1, and INO almost doubled the ratio between mRNA expression of endothelin receptor A (mediating vasoconstriction) and B (mediating vasodilation and clearance of ET-1) (ET-A/ET-B) in atelectatic lung regions. INO caused a shift in blood flow away from atelectatic lung regions in the endotoxemic piglets, but not during ET receptor antagonism. We conclude that INO in short term experiments, in addition to causing selective pulmonary vasodilation in ventilated lung regions, also increases the ET-A/ET-B mRNA expression ratio in lung tissue. This might augment the vasoconstriction in atelectatic lung regions, enhancing the redistribution of pulmonary blood flow to ventilated lung regions which are reached by INO. Such vasoconstriction may be an important additional factor explaining the effect of INO.
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