1 The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2 Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3 Treatment with tempol (86 mg kg À1 day À1 in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4 Treatment with molsidomine (15 mg kg À1 day À1 in drinking water) had the same effects as tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining tempol and molsidomine did not have additional effects compared to tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5 The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with tempol, molsidomine, or the combination of tempol and molsidomine. 6 We conclude that tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.

1 The present study was designed to investigate the eects and mechanisms of relaxation induced by the nitric oxide (NO) donor, GEA 3175 (a 3-aryl-substituted oxatriazole derivative) on bovine bronchioles (eective lumen diameter 200 ± 800 mm) suspended in microvascular myographs for isometric tension recording. 2 In segments of bovine bronchioles contracted to 5-hydroxytryptamine, GEA 3175 (10 78 ± 10induced concentration-dependent reproducible relaxations. These relaxations were slow in onset compared to other NO-donors such as 3-morpholinosydonimine-hydrochloride (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP).3 In 5-hydroxytryptamine-contracted preparations the order of relaxant potency (pD 2 ) was: salbutamol (7.80)4GEA 3175 (6.18)4SIN-1 (4.90)4SNAP (3.55). In segments contracted to acetylcholine, the relaxant responses were reduced and GEA 3175 relaxed the bronchioles with pD 2 =4.41+0.12 and relaxations of 66+10% (n=4), while SNAP and salbutamol caused relaxations of 19+6% (n=4) and 27+6% (n=8) at the highest concentration used, respectively. and iberiotoxin (10 78 M), did inhibit the relaxations to GEA 3175. The combination of apamin and charybdotoxin did not induce an additional inhibitory eect on the relaxations to GEA 3175 compared to charybdotoxin alone. 6 In preparations where a concentration-response curve to GEA 3175 or NO was ®rst obtained in the presence of LY 83583, incubation with charybdotoxin (10 77 M) did produce an additional inhibitory eect of the relaxations. However, in the presence of ODQ (3610 76 M), iberiotoxin (10 78 M) did not produce additional reduction of the NO-or GEA 3175-induced relaxations. 7 The present results suggest that the slow-releasing NO-donor GEA 3175 is more potent than the traditional NO donors in inducing relaxations of bovine bronchioles. GEA 3175, as for exogenously added NO, elicits relaxations through a cyclic GMP-dependent mechanism followed by opening of large conductance Ca 2+ -activated K + -channels.

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