Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

Mariko Tanaka, Kohtaro Abe, Masahiko Oka, Keita Saku, Keimei Yoshida, Tomohito Ishikawa, Ivan F. McMurtry, Kenji Sunagawa, Sumio Hoka, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿学術誌査読

7 被引用数 (Scopus)


It is widely accepted that impaired bioavailability of endothelial nitric oxide (NO) plays a critical role in the pathophysiology of pulmonary arterial hypertension (PAH). However, there are published data that show that relatively many PAH patients respond favorably to acetylcholine-induced pulmonary vasodilation during their follow-up period, when diverse stages of the disorder are included. We hypothesized that NO bioavailability varies depending on the progression of PAH. Adult rats were exposed to the VEGF receptor blocker Sugen5416 and 3 weeks of hypoxia followed by return to normoxia for various additional weeks. All rats developed increased right ventricular systolic pressure (RVSP) and occlusive lesion formation at 1, 3, 5, and 8 weeks after the Sugen5416 injection. Acute NO synthase blockade did not change the elevated RVSP at the 1-week time point, while it further increased RVSP markedly at the 3-, 5-, and 8-week time points, leading to death in all rats tested at 8 weeks. Acetylcholine caused significant reduction in RVSP at the 8-week but not the 1-week time point, whereas sodium nitroprusside decreased the pressure similarly at both time points. Increased NO-mediated cGMP production was found in lungs from the 8-week but not the 1-week time point. In conclusion, despite its initial impairment, NO bioavailability is restored and endogenous NO plays a critical protective role by counteracting severe pulmonary vasoconstriction in established stages of PAH in the Sugen5416/hy-poxia/normoxia-exposed rats. Our results provide solid pharmacological evidence for a major contribution of a NO-suppressed vasoconstrictor component in the pathophysiology of established PAH.

ジャーナルPhysiological Reports
出版ステータス出版済み - 12月 2017

!!!All Science Journal Classification (ASJC) codes

  • 生理学
  • 生理学(医学)


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