Choi Dae Eun, Jeong Jin Young, Lim Beom Jin, Chung Sarah, Chang Yoon Kyung, Lee Sang Ju, Na Ki Ryang, Kim Seok Young, Shin Young Tai, Lee Kang Wook
Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.
Am J Physiol Renal Physiol. 2009 Aug;297(2):F362-70. doi: 10.1152/ajprenal.90609.2008. Epub 2009 May 27.
Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
西地那非是首个被广泛用于治疗勃起功能障碍的磷酸二酯酶-5（PDE5）选择性抑制剂。最近许多研究在动物模型中探究了西地那非的心脏保护作用。我们在两项研究中评估了西地那非对实验性肾缺血再灌注（IR）损伤的保护作用。在研究1中，雄性Sprague-Dawley大鼠被分为四组：假手术组、西地那非处理的假手术组、溶剂处理的IR组和西地那非处理的IR组。在研究2中，我们将大鼠分为两组：西地那非处理的IR大鼠组和PD98059（ERK抑制剂）+西地那非处理的IR大鼠组。在分子和结构水平评估肾脏的功能参数。西地那非处理的IR大鼠的血尿素氮（BUN）和血清肌酐水平低于溶剂处理的IR大鼠。西地那非处理的IR大鼠中诱导型（iNOS）和内皮型一氧化氮合酶（eNOS）蛋白的表达显著高于溶剂处理的IR大鼠。IR大鼠中西地那非预处理增加了ERK磷酸化，并降低了肾Bax/Bcl-2比值、肾caspase-3活性和末端脱氧核苷酸转移酶介导的缺口末端标记阳性凋亡细胞。相反，PD98059处理增加了BUN和血清肌酐水平，并减弱了西地那非诱导的pERK、iNOS、eNOS和Bcl-2的表达。PD98059还增加了caspase-3活性，但并未降低西地那非诱导的cGMP积累。总之，本研究表明西地那非在实验性IR肾损伤中通过ERK磷酸化、诱导iNOS和eNOS产生以及降低Bax/Bcl-2比值发挥抗凋亡作用。
