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LUNG

Effects of Sildenafil on Pulmonary Hypertension and Levels of ET-1, eNOS, and cGMP in Aorta-Banded Rats

Zen-Kong Dai^*,,, Mian-Shin Tan, Chee-Yin Chai^||, Shah-Hwa Chou^¶, Pei-Chin Lin, Jwu-Lai Yeh^#, Arco Y. Jeng^**, Chung-I Chang, Ing-Jun Chen^# and Jiunn-Ren Wu^*,1

^* Division of Cardiology and Pulmonology, Department of Pediatrics, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan; Faculty of Graduate Institute of Medicine, Faculty of Biomedical Science and Environmental Biology, ^|| Department of Pathology, ^¶ Department of Chest Surgery, and ^# Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; ^** Cardiovascular Diseases Research, Novartis Institute of Biomedical Research, East Hanover, New Jersey 07936-1080; and Department of Surgery, National Taiwan University Hospital, Taipei 104, Taiwan

To whom requests for reprints should be addressed at ¹ Division of Pediatric Pulmonology and Cardiology, Department of Pediatrics, Kaohsiung Medical University Hospital, 100, Shih-Chuan 1st Road, San-Ming District, Kaohsiung 817, Taiwan. E-mail: zenkong{at}kmu.edu.tw

Abstract

Sildenafil, an oral phosphodiesterase Type 5 inhibitor, has vasodilatory effects through a cGMP-dependent mechanism. We previously showed that aortic banding could result in left ventricular overloading and pulmonary hypertension (PH). In this study, we investigated whether early administration of sildenafil, either immediately after or 2 weeks after aortic banding, could ameliorate the development of PH and alter gene expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS), and alter the levels of cGMP in rats undergoing an ascending aortic banding. Rats (n = 32) were divided into sham-operated and banding groups with or without treatment. The banded rats were further divided into three groups: (i) receiving saline on Days 1–28 (AOB₂₈; n = 8), (ii) receiving saline on Days 1–14 followed by treatment with 50 mg/kg/day sildenafil on Days 15–28 (AOB₂₈/Sil_15–28; n = 8), and (iii) receiving 50 mg/kg/day sildenafil on days 1–28 (AOB₂₈/Sil_1–28; n = 8). The sham-operated rats were administrated saline on Days 1–28 (n = 8).

Four weeks after banding, there was a significant development of PH with pulmonary vascular remodeling. Although both sildenafil-treatment groups had significant increases in cGMP and had reductions in the thickening in the medial layer of pulmonary arteriole, notable attenuation of PH occurred only in the AOB₂₈/Sil_1–28 group. PreproET-1 and eNOS messenger RNA (mRNA) expressions were measured by competitive reverse transcription polymerase chain reaction, and eNOS protein was determined by Western blotting. Sildenafil did not alter the elevated ET-1 or preproET-1 mRNA in banded rats. Interestingly, pulmonary eNOS increased in the AOB₂₈/Sil_1–28 group. In conclusion, early treatment with sildenafil inhibited the rise in pulmonary arterial pressure and pulmonary vascular remodeling in PH secondary to heart failure, and cGMP, but not ET-1, might be involved. Clinically, early repeated administration of sildenafil may offer an alternative in protecting against PH in heart failure.

Key Words: endothelial nitric oxide synthase • endothelin-1 • pulmonary vascular remodeling • pulmonary hypertension • aortic banding • sildenafil