Dai Zen-Kong, Tan Mian-Shin, Chai Chee-Yin, Chou Shah-Hwa, Lin Pei-Chin, Yeh Jwu-Lai, Jeng Arco Y, Chang Chung-I, Chen Ing-Jun, Wu Jiunn-Ren
Division of Pediatric Pulmonology and Cardiology, Department of Pediatrics, Kaohsiung Medical University, Kaohsiung, Taiwan.
Exp Biol Med (Maywood). 2006 Jun;231(6):942-7.
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.
西地那非是一种口服的5型磷酸二酯酶抑制剂，通过环磷酸鸟苷（cGMP）依赖机制发挥血管舒张作用。我们之前的研究表明，主动脉缩窄可导致左心室负荷过重和肺动脉高压（PH）。在本研究中，我们调查了在主动脉缩窄后立即或2周后早期给予西地那非，是否能改善PH的发展，并改变内皮素（ET）-1和内皮型一氧化氮合酶（eNOS）的基因表达，以及改变升主动脉缩窄大鼠体内cGMP的水平。将大鼠（n = 32）分为假手术组和带环组，每组再分为给药组和不给药组。带环大鼠进一步分为三组：（i）在第1 - 28天接受生理盐水（AOB28；n = 8）；（ii）在第1 - 14天接受生理盐水，随后在第15 - 28天接受50 mg/kg/天的西地那非治疗（AOB28/Sil(15 - 28)；n = 8）；（iii）在第1 - 28天接受50 mg/kg/天的西地那非治疗（AOB28/Sil(1 - 28)；n = 8）。假手术组大鼠在第1 - 28天接受生理盐水（n = 8）。缩窄4周后，出现了伴有肺血管重塑的显著PH发展。虽然两个西地那非治疗组的cGMP均显著增加，且肺小动脉中层增厚有所减轻，但仅在AOB28/Sil(1 - 28)组出现了显著的PH减轻。通过竞争性逆转录聚合酶链反应测量前ET-1和eNOS信使核糖核酸（mRNA）表达，通过蛋白质免疫印迹法测定eNOS蛋白。西地那非并未改变带环大鼠中升高的ET-1或前ET-1 mRNA水平。有趣的是，AOB28/Sil(1 - 28)组的肺eNOS增加。总之，早期使用西地那非治疗可抑制继发于心力衰竭的PH中肺动脉压升高和肺血管重塑，可能涉及cGMP，但不涉及ET-1。临床上，早期重复给予西地那非可能为预防心力衰竭中的PH提供一种替代方法。
