J Korean Med Sci.  2010 Oct;25(10):1411-1417. 10.3346/jkms.2010.25.10.1411.

Inhibition of Hypoxic Pulmonary Vasoconstriction of Rats by Carbon Monoxide

• Yoo HY
• Park SJ
• Bahk JH
• Kim SJ

• KMID: 2157842
• DOI: http://doi.org/10.3346/jkms.2010.25.10.1411

Abstract

Hypoxic pulmonary vasoconstriction (HPV), a unique response of pulmonary circulation, is critical to prevent hypoxemia under local hypoventilation. Hypoxic inhibition of K+ channel is known as an important O2-sensing mechanism in HPV. Carbon monoxide (CO) is suggested as a positive regulator of Ca2+-activated K+ channel (BK(Ca)), a stimulator of guanylate cyclase, and an O2-mimetic agent in heme moiety-dependent O2 sensing mechanisms. Here we compared the effects of CO on the HPV (Po2, 3%) in isolated pulmonary artery (HPV(PA)) and in blood-perfused/ventilated lungs (HPV(lung)) of rats. A pretreatment with CO (3%) abolished the HPV(PA) in a reversible manner. The inhibition of HPV(PA) was completely reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. In contrast, the HPV(lung) was only partly decreased by CO. Moreover, the partial inhibition of HPV(lung) by CO was affected neither by the pretreatment with ODQ nor by NO synthase inhibitor (L-NAME). The CO-induced inhibitions of HPV(PA) and HPV(lung) were commonly unaffected by tetraethylammonium (TEA, 2 mM), a blocker of BK(Ca). As a whole, CO inhibits HPV(PA) via activating guanylate cyclase. The inconsistent effects of ODQ on HPV(PA) and HPV(lung) suggest that ODQ may lose its sGC inhibitory action when applied to the blood-containing perfusate.

Keyword

Anoxia; Pulmonary Artery; Carbon Monoxide; Guanylate Cyclase; Oxygen

MeSH Terms

Animals
Anoxia/*physiopathology
Carbon Monoxide/*pharmacology
Guanylate Cyclase/antagonists & inhibitors/metabolism
NG-Nitroarginine Methyl Ester/chemistry/pharmacology
Nitric Oxide Synthase/antagonists & inhibitors/metabolism
Oxadiazoles/chemistry/pharmacology
Pulmonary Artery/*physiopathology
Quinoxalines/chemistry/pharmacology
Rats
Tetraethylammonium/chemistry/pharmacology
Vasoconstriction/*drug effects/physiology

Figure

• 

  Fig. 1 Abolishment of HPVPA by exogenous CO. (A) After confirming maximum contraction of PA by 80 mM KCl (80 K), 10 nM U46619 was applied as a pretone agent to induce a partial contraction. In the presence of U46619, hypoxia (Po2 3%) increased the tone of PA similar to the level of 80 K contraction. (B) CO pretreatment almost completely abolished the HPV in a reversible manner. Isometric tone of PA is normalized to the 80 K contraction, and averaged values are shown as bar graphs (mean±SEM) in right panels.

• 

  Fig. 2 Effects of TEA and ODQ on the CO-induced inhibition of HPVPA. (A) Under the inhibition of HPVPA by 3% CO treatment, an additive application of 2 mM TEA induced a partial increase of basal tone. Only after the removal of CO, a full HPVPA was observed. (B) Under the inhibition of HPVPA by 3% CO treatment, an additive application of 30 µM ODQ induced a strong contraction that was equivalent to the full HPVPA. Isometric tone of PA is normalized to the 80 K contraction, and averaged values are shown as bar graphs (mean±SEM) in right panels. *P<0.05; †P<0.01.

• 

  Fig. 3 Partial inhibition of HPV in V/P lungs by CO applied to the ventilating gas. (A) A representative trace of pulmonary artery pressure (PAP) and its increase by hypoxic ventilation (HPVlung). Both basal PAP and HPVlung are decreased by CO in a dose-dependent manner (0.3%, 1% and 3%). (B) Summaries of the HPVlung normalized to the initial control are shown as a bar graph (mean±SEM). *P<0.05.

• 

  Fig. 4 Effects of ODQ, TEA and L-NAME on the HPV in V/P lungs. (A, C) The pretreatment with ODQ did not prevent the inhibition of HPVlung by CO. (B) The partial inhibition of HPVlung is also unaffected by 2 mM TEA. The treatment with TEA alone increases the basal PAP and HPVlung. Summaries of the HPVlung normalized to the initial control (%) are shown as bar graphs (mean±SEM, right panels). *P<0.05; †P<0.01. (C) The inhibition of HPV by CO is observed after the treatment with ODQ and 10 µM L-NAME. Note the large increase of basal PAP and HPVlung.

• 

  Fig. 5 Effects of ZnPP on HPV in V/P lungs. (A) A representative trace of pulmonary artery pressure (PAP) and its changes in response to hypoxia and 30 µM ZnPP, a heme oxygenase inhibitor. (B) Summaries of the ΔHPV changes (%) are shown as bar graphs (mean±SEM, n=3).

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