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Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.

Ketabchi F, Ghofrani HA, Schermuly RT, Seeger W, Grimminger F, Egemnazarov B, Shid-Moosavi SM, Dehghani GA, Weissmann N, Sommer N - Respir. Res. (2012)

Bottom Line: This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units.L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared.In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Justus-Liebig-University Giessen, University of Giessen & Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Medical Clinic II/IV/V, Aulweg 130, 35392 Giessen, Germany.

ABSTRACT

Background: Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined.

Method: We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability.

Results: In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W.

Conclusion: Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.

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Effects of L-NNA on lung weight during normocapnia and hypercapnia. Lung weight changes of the respective experiments of figure 5. Data are mean ± SEM. ‡', significant difference (P < 0.05) between hypoxic normocapnia and normoxic normocapnia. ‡'', significant difference (P < 0.05) between hypoxic hypercapnia with or without acidosis and normoxic normocapnia.
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Figure 6: Effects of L-NNA on lung weight during normocapnia and hypercapnia. Lung weight changes of the respective experiments of figure 5. Data are mean ± SEM. ‡', significant difference (P < 0.05) between hypoxic normocapnia and normoxic normocapnia. ‡'', significant difference (P < 0.05) between hypoxic hypercapnia with or without acidosis and normoxic normocapnia.

Mentions: For better visualization of the effect of hypercapnia on HPV in the presence of L-NNA or 1400 W, ΔPAP values of the normocapnic and hypercapnic groups from Figure 3 and 4 are displayed in Figure 5A/B and 7A/B in a direct comparison. In the presence of L-NNA the effects of hypercapnia on acute HPV were similar (Figure 5A) as in the absence of L-NNA (Figure 1A) but the increase in sustained hypoxia was no longer significant, compared to hypoxic normocapnia. Normoxic values were not different between the groups in presence of L-NNA (Figure 5B). Moreover, during L-NNA treatment the lung weights showed no difference between hypoxic groups (Figure 6). In presence of 1400 W, ΔPAP was increased in sustained hypoxic hypercapnic acidosis at 150-182 min, but not in hypercapnia without acidosis compared to hypoxic normocapnia. Acute HPV was still increased (minutes 4-16) during hypoxic hypercapnia without acidosis compared to hypoxic normocapnia, similar to the effect in the absence of 1400 W (Figure 7A). Normoxic values were not different between the groups in presence of 1400 W (Figure 7B). Moreover, during 1400 W treatment the lung weights showed no difference between hypoxic groups (Figure 8).


Effects of hypercapnia and NO synthase inhibition in sustained hypoxic pulmonary vasoconstriction.

Ketabchi F, Ghofrani HA, Schermuly RT, Seeger W, Grimminger F, Egemnazarov B, Shid-Moosavi SM, Dehghani GA, Weissmann N, Sommer N - Respir. Res. (2012)

Effects of L-NNA on lung weight during normocapnia and hypercapnia. Lung weight changes of the respective experiments of figure 5. Data are mean ± SEM. ‡', significant difference (P < 0.05) between hypoxic normocapnia and normoxic normocapnia. ‡'', significant difference (P < 0.05) between hypoxic hypercapnia with or without acidosis and normoxic normocapnia.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306743&req=5

Figure 6: Effects of L-NNA on lung weight during normocapnia and hypercapnia. Lung weight changes of the respective experiments of figure 5. Data are mean ± SEM. ‡', significant difference (P < 0.05) between hypoxic normocapnia and normoxic normocapnia. ‡'', significant difference (P < 0.05) between hypoxic hypercapnia with or without acidosis and normoxic normocapnia.
Mentions: For better visualization of the effect of hypercapnia on HPV in the presence of L-NNA or 1400 W, ΔPAP values of the normocapnic and hypercapnic groups from Figure 3 and 4 are displayed in Figure 5A/B and 7A/B in a direct comparison. In the presence of L-NNA the effects of hypercapnia on acute HPV were similar (Figure 5A) as in the absence of L-NNA (Figure 1A) but the increase in sustained hypoxia was no longer significant, compared to hypoxic normocapnia. Normoxic values were not different between the groups in presence of L-NNA (Figure 5B). Moreover, during L-NNA treatment the lung weights showed no difference between hypoxic groups (Figure 6). In presence of 1400 W, ΔPAP was increased in sustained hypoxic hypercapnic acidosis at 150-182 min, but not in hypercapnia without acidosis compared to hypoxic normocapnia. Acute HPV was still increased (minutes 4-16) during hypoxic hypercapnia without acidosis compared to hypoxic normocapnia, similar to the effect in the absence of 1400 W (Figure 7A). Normoxic values were not different between the groups in presence of 1400 W (Figure 7B). Moreover, during 1400 W treatment the lung weights showed no difference between hypoxic groups (Figure 8).

Bottom Line: This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units.L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared.In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Justus-Liebig-University Giessen, University of Giessen & Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary System (ECCPS), Medical Clinic II/IV/V, Aulweg 130, 35392 Giessen, Germany.

ABSTRACT

Background: Acute respiratory disorders may lead to sustained alveolar hypoxia with hypercapnia resulting in impaired pulmonary gas exchange. Hypoxic pulmonary vasoconstriction (HPV) optimizes gas exchange during local acute (0-30 min), as well as sustained (> 30 min) hypoxia by matching blood perfusion to alveolar ventilation. Hypercapnia with acidosis improves pulmonary gas exchange in repetitive conditions of acute hypoxia by potentiating HPV and preventing pulmonary endothelial dysfunction. This study investigated, if the beneficial effects of hypercapnia with acidosis are preserved during sustained hypoxia as it occurs, e.g in permissive hypercapnic ventilation in intensive care units. Furthermore, the effects of NO synthase inhibitors under such conditions were examined.

Method: We employed isolated perfused and ventilated rabbit lungs to determine the influence of hypercapnia with or without acidosis (pH corrected with sodium bicarbonate), and inhibitors of endothelial as well as inducible NO synthase on acute or sustained HPV (180 min) and endothelial permeability.

Results: In hypercapnic acidosis, HPV was intensified in sustained hypoxia, in contrast to hypercapnia without acidosis when HPV was amplified during both phases. L-NG-Nitroarginine (L-NNA), a non-selective NO synthase inhibitor, enhanced acute as well as sustained HPV under all conditions, however, the amplification of sustained HPV induced by hypercapnia with or without acidosis compared to normocapnia disappeared. In contrast 1400 W, a selective inhibitor of inducible NO synthase (iNOS), decreased HPV in normocapnia and hypercapnia without acidosis at late time points of sustained HPV and selectively reversed the amplification of sustained HPV during hypercapnia without acidosis. Hypoxic hypercapnia without acidosis increased capillary filtration coefficient (Kfc). This increase disappeared after administration of 1400 W.

Conclusion: Hypercapnia with and without acidosis increased HPV during conditions of sustained hypoxia. The increase of sustained HPV and endothelial permeability in hypoxic hypercapnia without acidosis was iNOS dependent.

Show MeSH
Related in: MedlinePlus