Ballester C, Sarriá B, García-Granero E, Morcillo E J, Lledó S, Cortijo J
Department of Surgery, University of Valencia, Valencia, Spain.
Br J Surg. 2007 Jul;94(7):894-902. doi: 10.1002/bjs.5724.
Hypertonicity of the internal anal sphincter (IAS) appears to be involved in the pathogenesis of anal fissure. The relaxant effects of sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, on isolated human IAS were investigated.
The efficacy (maximal effect, E(max)) and potency (-log IC(50), where IC(50) is half-maximal inhibitory concentration) of the PDE5 inhibitors, sildenafil and zaprinast, and of nitric oxide donors, sodium nitroprusside and glyceryl trinitrate, as relaxants of histamine (0.1 mmol/l)-induced tone were examined in IAS strips under isometric contraction. The presence of PDE5 isoenzymes and changes in intracellular calcium and cyclic nucleotide levels in IAS muscle were tested by real-time reverse transcriptase-polymerase chain reaction, epifluorescence microscopy and enzyme immunoassay respectively.
Sildenafil produced a concentration-related inhibition of the mean(s.e.m.) histamine-induced tone (E(max) 83(2) per cent, - log IC(50) 7.04(0.05); n = 12). Zaprinast produced relaxation to similar degree, but with lower potency. Nitric oxide donors also relaxed IAS. Sildenafil (1 micromol/l) produced a 1.8-fold increase in guanosine 3',5'-cyclic monophosphate content, with no change in adenosine 3',5'-cyclic monophosphate levels. Sildenafil markedly depressed the peak intracellular calcium increase evoked by histamine. PDE5A1, PDE5A2 and PDE5A3 transcripts were expressed in IAS muscle.
Sildenafil relaxes the augmented tone of human IAS in vitro. These results support the potential use of this PDE5 inhibitor in the treatment of chronic anal fissure.
肛门内括约肌（IAS）的高张性似乎参与肛裂的发病机制。研究了选择性磷酸二酯酶5（PDE5）抑制剂西地那非对离体人IAS的松弛作用。
在等长收缩条件下，检测PDE5抑制剂西地那非和扎普司特以及一氧化氮供体硝普钠和硝酸甘油作为组胺（0.1 mmol/l）诱导张力松弛剂的效能（最大效应，E(max)）和效价（-log IC(50)，其中IC(50)是半数最大抑制浓度）。分别通过实时逆转录聚合酶链反应、落射荧光显微镜和酶免疫测定法检测IAS肌肉中PDE5同工酶的存在以及细胞内钙和环核苷酸水平的变化。
西地那非产生了与浓度相关的对平均（标准误）组胺诱导张力的抑制作用（E(max) 83(2)%，-log IC(50) 7.04(0.05)；n = 12）。扎普司特产生了相似程度的松弛，但效价较低。一氧化氮供体也使IAS松弛。西地那非（1 μmol/l）使3',5'-环磷酸鸟苷含量增加了1.8倍，而3',5'-环磷酸腺苷水平没有变化。西地那非显著抑制了组胺引起的细胞内钙峰值增加。PDE5A1、PDE5A2和PDE5A3转录本在IAS肌肉中表达。
西地那非在体外可松弛人IAS增强的张力。这些结果支持这种PDE5抑制剂在慢性肛裂治疗中的潜在应用。
