The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats

Abstract

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.

Superoxide dismutase: Master and Commander?

“…The latter spontaneously develop pulmonary hypertension. The use of an SOD mimetic in rats exposed to chronic hypoxia prevents pulmonary hypertension and reduces right ventricular hypertrophy, suggesting that the observed decrease in SOD in IPAH patients may play a role in the aetiology [27]. These findings are supported by observations made in PPHN lambs, which have decreased SOD.…”

Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

“…Pups received either Allopurinol (5 l/g body wt of 10 mg/ml suspended in 0.9% saline vehicle ϭ 50 mg/kg), U74389G [5 l/g body wt of 2 mg/ml solution in CS4 vehicle (20 mM citric acid monohydrate, 3.2 mM sodium citrate dihydrate, 77 mM NaCl, pH 3.0) ϭ 10 mg/kg], Tempol (5 l/g body wt of 20 mg/ml solution in 0.9% saline vehicle ϭ 100 mg/kg), or vehicle alone by daily intraperitoneal injection. The doses of the above compounds used were similar to those previously reported to be effective in vivo by our group and others (16,25,30). At the end of each exposure period, pups were either killed by pentobarbital overdose or exsanguinated after anesthesia.…”

Chronic hypoxia augments depolarization-induced Ca2+sensitization in pulmonary vascular smooth muscle through superoxide-dependent stimulation of RhoA

“…Although ROS generation has been reported to be reduced in isolated lungs from CH rats (37), substantial evidence supports a contribution of ROS to enhanced agonist-mediated pulmonary vasoconstriction and pulmonary hypertension following CH (8,11,15,20,27). However, few studies have investigated a potential link between ROS and VSM Ca 2ϩ sensitivity in this response.…”