Limits...
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.

Show MeSH

Related in: MedlinePlus

Effects of L-NG-Nitroarginine (L-NNA) and N-([3-(Aminomethyl) phenyl] methyl) ethanimidamide dihydrochloride (1400 W) on pulmonary vascular tone during normoxic ventilation. Normoxic ΔPAP values in the absence of L-NNA and 1400 W are identical to those depicted in Figure 1. A. L-NNA-treated normoxic normocapnia (n = 5), B. L-NNA-treated normoxic hypercapnic acidosis (n = 5), C. L-NNA-treated normoxic hypercapnia without acidosis (n = 4), D. 1400 W-treated normoxic normocapnia (n = 6), E. 1400 W-treated normoxic hypercapnic acidosis (n = 4), F. 1400 W-treated normoxic hypercapnia without acidosis (n = 6) compared to ΔPAP from lungs in the absence of L-NNA or 1400 W during 190 min of normoxic ventilation. ΔPAP: change of PAP referenced to the value at time set at zero. Data are mean ± SEM. *, significant difference (P < 0.05) between treated and untreated groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3306743&req=5

Figure 3: Effects of L-NG-Nitroarginine (L-NNA) and N-([3-(Aminomethyl) phenyl] methyl) ethanimidamide dihydrochloride (1400 W) on pulmonary vascular tone during normoxic ventilation. Normoxic ΔPAP values in the absence of L-NNA and 1400 W are identical to those depicted in Figure 1. A. L-NNA-treated normoxic normocapnia (n = 5), B. L-NNA-treated normoxic hypercapnic acidosis (n = 5), C. L-NNA-treated normoxic hypercapnia without acidosis (n = 4), D. 1400 W-treated normoxic normocapnia (n = 6), E. 1400 W-treated normoxic hypercapnic acidosis (n = 4), F. 1400 W-treated normoxic hypercapnia without acidosis (n = 6) compared to ΔPAP from lungs in the absence of L-NNA or 1400 W during 190 min of normoxic ventilation. ΔPAP: change of PAP referenced to the value at time set at zero. Data are mean ± SEM. *, significant difference (P < 0.05) between treated and untreated groups.

Mentions: In the presence of L-NNA, no significant changes of pulmonary artery pressure were detectable under normoxic ventilation, although a tendency towards higher values at later time points was evident (Figure 3A, B, C). Treatment with 1400 W did neither change normoxic normocapnic PAP nor PAP during normoxic hypercapnic acidosis compared to the untreated group (Figure 3D, E). However, during normoxic hypercapnia without acidosis 1400 W induced a significant PAP decrease at min 4-6 and an increase at min 55-65 compared to lungs in the absence of 1400 W (Figure 3F).


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-NG-Nitroarginine (L-NNA) and N-([3-(Aminomethyl) phenyl] methyl) ethanimidamide dihydrochloride (1400 W) on pulmonary vascular tone during normoxic ventilation. Normoxic ΔPAP values in the absence of L-NNA and 1400 W are identical to those depicted in Figure 1. A. L-NNA-treated normoxic normocapnia (n = 5), B. L-NNA-treated normoxic hypercapnic acidosis (n = 5), C. L-NNA-treated normoxic hypercapnia without acidosis (n = 4), D. 1400 W-treated normoxic normocapnia (n = 6), E. 1400 W-treated normoxic hypercapnic acidosis (n = 4), F. 1400 W-treated normoxic hypercapnia without acidosis (n = 6) compared to ΔPAP from lungs in the absence of L-NNA or 1400 W during 190 min of normoxic ventilation. ΔPAP: change of PAP referenced to the value at time set at zero. Data are mean ± SEM. *, significant difference (P < 0.05) between treated and untreated groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Effects of L-NG-Nitroarginine (L-NNA) and N-([3-(Aminomethyl) phenyl] methyl) ethanimidamide dihydrochloride (1400 W) on pulmonary vascular tone during normoxic ventilation. Normoxic ΔPAP values in the absence of L-NNA and 1400 W are identical to those depicted in Figure 1. A. L-NNA-treated normoxic normocapnia (n = 5), B. L-NNA-treated normoxic hypercapnic acidosis (n = 5), C. L-NNA-treated normoxic hypercapnia without acidosis (n = 4), D. 1400 W-treated normoxic normocapnia (n = 6), E. 1400 W-treated normoxic hypercapnic acidosis (n = 4), F. 1400 W-treated normoxic hypercapnia without acidosis (n = 6) compared to ΔPAP from lungs in the absence of L-NNA or 1400 W during 190 min of normoxic ventilation. ΔPAP: change of PAP referenced to the value at time set at zero. Data are mean ± SEM. *, significant difference (P < 0.05) between treated and untreated groups.
Mentions: In the presence of L-NNA, no significant changes of pulmonary artery pressure were detectable under normoxic ventilation, although a tendency towards higher values at later time points was evident (Figure 3A, B, C). Treatment with 1400 W did neither change normoxic normocapnic PAP nor PAP during normoxic hypercapnic acidosis compared to the untreated group (Figure 3D, E). However, during normoxic hypercapnia without acidosis 1400 W induced a significant PAP decrease at min 4-6 and an increase at min 55-65 compared to lungs in the absence of 1400 W (Figure 3F).

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