Preventive Effects of trans-4-Methoxy-β-nitrostyrene on Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.

Abstract

BACKGROUND: The soluble guanylate cyclase (sGC)/GMPc pathway plays an important in pulmonary arterial hypertension (PAH). OBJECTIVE: We investigated whether trans-4-methoxy-β-nitrostyrene (T4MN), a novel sGC stimulator, prevents development of monocrotaline (MCT)-induced HAP in rats. METHODS: At Day 0 (D0), rats were injected with MCT (60 mg/kg, sc). Control (CNT) rats received an equal volume of MCT vehicle only. MCT-injected rats were divided into four groups, which were treated orally once a day from D1 to D28 with one of the following: T4MN vehicle (MCT-V group), T4MN at 18.75 mg/kg (MCT-T4MN1 group), T4MN at 37.50 mg/kg (MCT-T4MN2 group), or sildenafil (SIL; 10 mg/kg) (MCT-SIL group). RESULTS: Compared to the CNT group, MCT treatment induced a significant increase in heart weight to body weight, lung weight to body weight, and right ventricular systolic pressure but significantly reduced the maximum vasorelaxation (Rmax) induced by acetylcholine in aortic ring preparations. Indeed, MCT treatment increased the wall thickness of small pulmonary arterioles and reduced the mRNA levels of BMPR2, eNOS, and VEGF-A while it increased that of IL-6 in pulmonary tissue. All these effects of MCT, except those on mRNA expression levels in the lungs, were significantly reduced by preventive treatment with T4MN or SIL. CONCLUSION: Taken together, the present study provided the first evidence that T4MN prevents the development of MCT-induced HAP in rats. Further mechanistic studies of these protective effects of T4MN are warranted.