Vol. 284, Issue 3, H931-H938, March 2003
Downregulation of hypoxic vasoconstriction by chronic hypoxia
in rabbits: effects of nitric oxide
Norbert
Weissmann,
Matthias
Nollen,
Boris
Gerigk,
Hossein Ardeschir
Ghofrani,
Ralph Theo
Schermuly,
Andreas
Günther,
Karin
Quanz,
Ludger
Fink,
Jörg
Hänze,
Frank
Rose,
Werner
Seeger, and
Friedrich
Grimminger
Department of Internal Medicine, Justus-Liebig-University
Giessen, 35392 Giessen, Germany
Hypoxic
pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation
for optimizing pulmonary gas exchange. Chronic alveolar hypoxia results
in vascular remodeling and pulmonary hypertension. Previous studies
have reported conflicting results of the effect of chronic alveolar
hypoxia on pulmonary vasoreactivity and the contribution of nitric
oxide (NO), which may be related to species and strain differences as
well as to the duration of chronic hypoxia. Therefore, we
investigated the impact of chronic hypoxia on HPV in rabbits, with a
focus on lung NO synthesis. After exposure of the animals to normobaric
hypoxia (10% O2) for 1 day to 10 wk, vascular reactivity
was investigated in ex vivo perfused normoxic ventilated lungs. Chronic
hypoxia induced right heart hypertrophy and increased normoxic vascular
tone within weeks. The vasoconstrictor response to an acute hypoxic
challenge was strongly downregulated within 5 days, whereas the
vasoconstrictor response to the thromboxane mimetic U-46619 was
maintained. The rapid downregulation of HPV was apparently not linked
to changes in the lung vascular NO system, detectable in the exhaled
gas and by pharmacological blockage of NO synthesis. Treatment of the
animals with long-term inhaled NO reduced right heart hypertrophy and
partially maintained the reactivity to acute hypoxia, without any
impact on the endogenous NO system being noted. We conclude that
chronic hypoxia causes rapid downregulation of acute HPV as a specific
event, preceding the development of major pulmonary hypertension and
being independent of the lung vascular NO system. Long-term NO
inhalation partially maintains the strength of the hypoxic
vasoconstrictor response.
isolated lung; pulmonary hypertension; right heart failure; inhaled
nitric oxide