Effects of dimethylthiourea on chronic hypoxia-induced pulmonary arterial remodelling and ventricular hypertrophy in rats.
Ischemia, followed by reperfusion and restoration of oxygen to tissues, generates hydrogen peroxide which in turn generates injurious free radicals, particularly hydroxyl. Chronic hypoxia may also result in liberation of free radicals. In rats, chronic hypoxia causes pulmonary hypertension, associated with structural remodelling of pulmonary arteries, polycythemia, and vasoconstriction. We studied in rats the effects of dimethylthiourea (DMTU), a hydroxyl and hydrogen peroxide scavenger, on acute hypoxic vasoconstriction, and on the arterial structure and development of polycythemia after chronic hypoxia (FIO2 0.10 for 10 days, daily DMTU). DMTU did not affect acute vasoconstriction nor polycythemia. It significantly reduced muscularization of alveolar wall and alveolar duct arteries, medial thickening of alveolar wall and preacinar arteries, and right ventricular hypertrophy, suggesting reduction of pulmonary hypertension. However, DMTU caused marked growth retardation in both control and hypoxic rats, an effect not previously described. In other rats a similar degree of growth retardation due to reduced food intake failed to prevent the effects of hypoxia, suggesting that DMTU's effect is not through this mechanism. The results of this study support but do not confirm the hypothesis that free radicals may have a role in the pathogenesis of the arterial structural changes in the microcirculation contributing to chronic hypoxic pulmonary hypertension. However, in view of DMTU's effects on growth, definitive testing of the hypothesis will not be possible until other, less toxic, chronic hydroxyl scavengers become available.
Langleben
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Division of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Québec.
Fox
R B
RB
Jones
R C
RC
Reid
L M
LM
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology*; D002908:Chronic Disease; D016166:Free Radical Scavengers; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000473:pathology; D008297:Male; D011086:Polycythemia / Q000209:etiology; D011651:Pulmonary Artery / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
D016166:Free Radical Scavengers; C038983:1,3-dimethylthiourea; D013890:Thiourea