Fosinopril Prevents the Pulmonary Arterial Remodeling in Sinoaortic-denervated Rats by Regulating Phosphodiesterase

Abstract

To study the effects of fosinopril on sinoaortic denervation (SAD)-induced pulmonary vascular remodeling and on phosphodiesterases (PDE) 1 in rats. SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. The experiment included sham-operated (Sham), SAD, and fosinopril-treated SAD groups. Fosinopril (15 mg/kg/d) was given in rat chow. After 16 weeks of treatment, the pulmonary arteries were taken for investigations, including pharmacological study, measurement of cGMP, light microscopy, immunohistochemistry, Western blotting, and quantitative real-time RT-PCR. Compared with Sham rats, blood pressure variability (BPV) was significantly increased in the SAD group. However, the mean pulmonary artery pressure (mPAP) was not significant change among 3 groups. After SAD, maximal contraction of pulmonary artery rings to phenylephrine was markedly decreased; the most prominent morphological change in the lung included thickening vascular walls, increasing number of smooth muscle cells, and greater wall-to-lumen ratio; the tissue concentrations of cGMP was reduced significantly; PDE1A or PDE1C expression was upregulated significantly, and endothelial nitric oxide synthase (eNOS) expression was downregulated significantly. Fosinopril treatment prevented these changes induced by SAD. Pulmonary artery remodeling (structural and functional abnormalities) was induced by SAD. Fosinopril, an angiotensin-converting enzyme inhibitor, mainly via potentiating eNOS pathway and inhibiting AngII formation, effectively prevented increased blood pressure variability and vascular remodeling of the pulmonary artery after SAD by regulating the activity levels or expression of eNOS, cGMP, and PDE1s.