β2-adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats

Hisashi Nagai, Ichiro Kuwahira, Daryl O. Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Tadakatsu Inagaki, Sayoko Ogura, Yutaka Fujii, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, James T. Pearson, Koichi Uemura, Mikiyasu Shirai

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

In sleep apnea syndrome (SAS), intermittent hypoxia (IH) induces repeated episodes of hypoxic pulmonary vasoconstriction (HPV) during sleep, which presumably contribute to pulmonary arterial hypertension (PAH). However, the prevalence of PAH was low and severity is mostly mild in SAS patients, and mild or no right ventricular hypertrophy (RVH) was reported in IH-exposed animals. The question then arises as to why PAH is not a universal finding in SAS if repeated hypoxia of sufficient duration causes cycling HPV. In the present study, rats underwent IH at a rate of 3 min cycles of 4-21% O2 for 8 h/d for 6w. Assessment of diameter changes in small pulmonary arteries in response to acute hypoxia and drugs were performed using synchrotron radiation microangiography on anesthetized rats. In IH-rats, neither PAH nor RVH was observed and HPV was strongly reversed. Nadolol (a hydrophilic β1,2-blocker) augmented the attenuated HPV to almost the same level as that in Nrats, but atenolol (a hydrophilic β1-blocker) had no effect on the HPV in IH. These b-blockers had almost no effect on the HPV in N-rats. Chronic administration of nadolol during 6 weeks of IH exposure induced PAH and RVH in IH-rats, but did not in N-rats. Meanwhile, atenolol had no effect on morphometric and hemodynamic changes in N and IH-rats. Protein expression of the β1-adrenergic receptor (AR) was down-regulated while that of β2AR was preserved in pulmonary arteries of IH-rats. Phosphorylation of p85 (chief component of phosphoinositide 3-kinase (PI3K)), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) were abrogated by chronic administration of nadolol in the lung tissue of IH-rats. We conclude that IH-derived activation of β2AR in the pulmonary arteries attenuates the HPV, thereby preventing progression of IH-induced PAH. This protective effect may depend on the β2AR-Gi mediated PI3K/Akt/eNOS signaling pathway.

Original languageEnglish
Article numbere110693
JournalPLoS One
Volume9
Issue number10
DOIs
Publication statusPublished - 2014 Oct 28
Externally publishedYes

Fingerprint

vasoconstriction
adrenergic receptors
Vasoconstriction
Pulmonary Hypertension
Adrenergic Receptors
hypertension
Rats
hypoxia
lungs
Lung
rats
Nadolol
sleep apnea
Right Ventricular Hypertrophy
Atenolol
Nitric Oxide Synthase Type III
pulmonary artery
Sleep Apnea Syndromes
Phosphatidylinositols
hypertrophy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

β2-adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats. / Nagai, Hisashi; Kuwahira, Ichiro; Schwenke, Daryl O.; Tsuchimochi, Hirotsugu; Nara, Akina; Inagaki, Tadakatsu; Ogura, Sayoko; Fujii, Yutaka; Umetani, Keiji; Shimosawa, Tatsuo; Yoshida, Kenichi; Pearson, James T.; Uemura, Koichi; Shirai, Mikiyasu.

In: PLoS One, Vol. 9, No. 10, e110693, 28.10.2014.

Research output: Contribution to journalArticle

Nagai, H, Kuwahira, I, Schwenke, DO, Tsuchimochi, H, Nara, A, Inagaki, T, Ogura, S, Fujii, Y, Umetani, K, Shimosawa, T, Yoshida, K, Pearson, JT, Uemura, K & Shirai, M 2014, 'β2-adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats', PLoS One, vol. 9, no. 10, e110693. https://doi.org/10.1371/journal.pone.0110693
Nagai, Hisashi ; Kuwahira, Ichiro ; Schwenke, Daryl O. ; Tsuchimochi, Hirotsugu ; Nara, Akina ; Inagaki, Tadakatsu ; Ogura, Sayoko ; Fujii, Yutaka ; Umetani, Keiji ; Shimosawa, Tatsuo ; Yoshida, Kenichi ; Pearson, James T. ; Uemura, Koichi ; Shirai, Mikiyasu. / β2-adrenergic receptor-dependent attenuation of hypoxic pulmonary vasoconstriction prevents progression of pulmonary arterial hypertension in intermittent hypoxic rats. In: PLoS One. 2014 ; Vol. 9, No. 10.
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AU - Nagai, Hisashi

AU - Kuwahira, Ichiro

AU - Schwenke, Daryl O.

AU - Tsuchimochi, Hirotsugu

AU - Nara, Akina

AU - Inagaki, Tadakatsu

AU - Ogura, Sayoko

AU - Fujii, Yutaka

AU - Umetani, Keiji

AU - Shimosawa, Tatsuo

AU - Yoshida, Kenichi

AU - Pearson, James T.

AU - Uemura, Koichi

AU - Shirai, Mikiyasu

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