Downregulation of hypoxic vasoconstriction by chronic hypoxia in rabbits: effects of nitric oxide

Abstract

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% O(2)) 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.

Reversal of experimental pulmonary hypertension by PDGF inhibition

“…In addition, hypoxia is the main stimulus for the induction of pulmonary hypertension accompanying chronic ventilatory disorders such as chronic obstructive pulmonary disease and interstitial lung disease. While acute hypoxia causes selective pulmonary arteriolar vasoconstriction, chronic exposure to hypoxia results in morphological and functional changes in the pulmonary vascular bed (24,25,38,39). Hypoxia may also be an activator of the PDGF-related pathway, as previously shown in HT1080 cells (40).…”

“…Hypoxic pulmonary vascular remodeling was induced by exposure of mice (8-week-old C57BL/6) to chronic hypoxia (10% O2) in a ventilated chamber, as described previously (39). The chronic effects of STI571 were assessed in mice exposed to hypoxia for 35 days.…”

Exogenous nitric oxide centrally enhances pulmonary reactivity in the normal and hypertensive rat

“…26 However, there are conflicting reports as to whether the HPV response is accentuated or attenuated by pulmonary hypertension. 6,27 Therefore, a second aim of the present study was to assess the acute HPV before and after chronic hypoxia and to determine whether central NO has a role in modulating this response.…”

Sildenafil Acutely Reverses the Hypoxic Pulmonary Vasoconstriction Response of the Newborn Pig

“…Exposure to hypoxia for at least 3 hours selectively suppresses the HPV response and animals living at high altitude exhibit a weak or absent response (34). The HPV response has also been shown to markedly decrease after 5 days in adult rabbits exposed to chronic hypoxia, (35) possibly secondary to an increase in NO production that abrogates the HPV response (36).…”