Paula Vasconcelos Araújo, Cristiano Magalhães Clemente, José Ronaldo Vasconcelos da Graça, Francisco Hélio Rola, Ricardo Brandt de Oliveira, Armênio Aguiar dos Santos, Pedro Jorge Caldas Magalhães
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Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC(50) of 16.2 micromol/L (95% CI 9.5-27.6 micromol/L). Sildenafil produced significant additional relaxation of 25.2 +/- 8.1% of the CCh-induced contraction, beyond basal tone. 4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 micromol/L (95% CI 5.7-16.2 micromol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 micromol/L (95% CI 46.0-182.2 micromol/L) and 78.5 micromol/L (95% CI 37.1-166.3 micromol/L), respectively. 5. In preparations treated previously with methylene blue (10 micromol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 micromol/L (95% CI 23.9-63.4 micromol/L) and 43.8 micromol/L (95% CI 24.5-78.3 micromol/L), respectively. These values were significantly greater than those obtained with sildenafil alone. 6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segments in vitro. The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation.</p>","PeriodicalId":10259,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"32 3","pages":"191-5"},"PeriodicalIF":2.4000,"publicationDate":"2005-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1440-1681.2005.04170.x","citationCount":"9","resultStr":"{\"title\":\"Inhibitory effect of sildenafil on rat duodenal contractility in vitro: putative cGMP involvement.\",\"authors\":\"Paula Vasconcelos Araújo, Cristiano Magalhães Clemente, José Ronaldo Vasconcelos da Graça, Francisco Hélio Rola, Ricardo Brandt de Oliveira, Armênio Aguiar dos Santos, Pedro Jorge Caldas Magalhães\",\"doi\":\"10.1111/j.1440-1681.2005.04170.x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>1. Sildenafil citrate (Viagratrade mark; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activity in vitro. 2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 micromol/L (95% confidence interval (CI) 2.0-55.3 micromol/L). 3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC(50) of 16.2 micromol/L (95% CI 9.5-27.6 micromol/L). Sildenafil produced significant additional relaxation of 25.2 +/- 8.1% of the CCh-induced contraction, beyond basal tone. 4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 micromol/L (95% CI 5.7-16.2 micromol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 micromol/L (95% CI 46.0-182.2 micromol/L) and 78.5 micromol/L (95% CI 37.1-166.3 micromol/L), respectively. 5. In preparations treated previously with methylene blue (10 micromol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 micromol/L (95% CI 23.9-63.4 micromol/L) and 43.8 micromol/L (95% CI 24.5-78.3 micromol/L), respectively. These values were significantly greater than those obtained with sildenafil alone. 6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segments in vitro. 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引用次数: 9
摘要
1. 枸橼酸西地那非(伟哥商标;一种磷酸二酯酶5抑制剂,可提高平滑肌细胞中的cGMP水平。它能放松血管和内脏平滑肌。为了评估西地那非的肠道作用,我们决定在体外研究其对大鼠十二指肠运动活性的影响。2. 在Tyrode溶液中保存的离体十二指肠段中,西地那非对乙酰胆碱(ACh)诱导的相性收缩表现出浓度依赖性的抗痉挛作用,IC50值为26.7微mol/L(95%置信区间(CI) 2.0-55.3微mol/L)。3.西地那非还能缓解氨甲酰胆碱(CCh)诱导的持续收缩,其IC(50)为16.2微mol/L (95% CI 9.5 ~ 27.6微mol/L)。西地那非产生了cch诱导收缩的25.2 +/- 8.1%的显著额外松弛,超出了基底张力。4. 西地那非降低了自发性十二指肠收缩的幅度,EC50为9.6微mol/L (95% CI为5.7-16.2微mol/L)。这一作用明显比zaprinast和罂粟碱的作用更有效,后者也能减少十二指肠收缩,EC50值分别为91.6微mol/L (95% CI 46.0-182.2微mol/L)和78.5微mol/L (95% CI 37.1-166.3微mol/L)。5. 在先前用亚甲基蓝(10微mol/L)或1H-[1,2,4]恶二唑(4,3-a)喹诺沙林-1- 1 (ODQ;10微mol/L),西地那非效应的EC50值分别显著提高至39.0微mol/L (95% CI 23.9 ~ 63.4微mol/L)和43.8微mol/L (95% CI 24.5 ~ 78.3微mol/L)。这些值明显大于单独使用西地那非获得的值。6. 综上所述,西地那非对大鼠十二指肠段具有肌松弛和抗痉挛作用。西地那非对大鼠离体十二指肠的收缩抑制作用可能是由于其降解减少导致细胞内cGMP积累所致。
Inhibitory effect of sildenafil on rat duodenal contractility in vitro: putative cGMP involvement.
1. Sildenafil citrate (Viagratrade mark; Pfizer, Sandwich, Kent, UK), a phosphodiesterase 5 inhibitor, rises cGMP levels in smooth muscle cells. It relaxes both vascular and visceral smooth muscle. In order to assess the intestinal effects of sildenafil, we decided to investigate its actions on rat duodenal motor activity in vitro. 2. In isolated duodenal segments maintained in Tyrode's solution, sildenafil exhibited a concentration-dependent antispasmodic effect on acetylcholine (ACh)-induced phasic contractions, with an IC50 value of 26.7 micromol/L (95% confidence interval (CI) 2.0-55.3 micromol/L). 3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC(50) of 16.2 micromol/L (95% CI 9.5-27.6 micromol/L). Sildenafil produced significant additional relaxation of 25.2 +/- 8.1% of the CCh-induced contraction, beyond basal tone. 4. Sildenafil reduced the amplitude of spontaneous duodenal contractions with an EC50 of 9.6 micromol/L (95% CI 5.7-16.2 micromol/L). This effect was significantly more potent than the effects of zaprinast and papaverine, which also reduced duodenal contractions with EC50 values of 91.6 micromol/L (95% CI 46.0-182.2 micromol/L) and 78.5 micromol/L (95% CI 37.1-166.3 micromol/L), respectively. 5. In preparations treated previously with methylene blue (10 micromol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 micromol/L (95% CI 23.9-63.4 micromol/L) and 43.8 micromol/L (95% CI 24.5-78.3 micromol/L), respectively. These values were significantly greater than those obtained with sildenafil alone. 6. In conclusion, sildenafil has myorelaxant and antispasmodic effects on rat duodenal segments in vitro. The contractile inhibitory effect of sildenafil on rat isolated duodenum is probably due to intracellular cGMP accumulation as a result of its decreased degradation.
期刊介绍:
Clinical and Experimental Pharmacology and Physiology is an international journal founded in 1974 by Mike Rand, Austin Doyle, John Coghlan and Paul Korner. Our focus is new frontiers in physiology and pharmacology, emphasizing the translation of basic research to clinical practice. We publish original articles, invited reviews and our exciting, cutting-edge Frontiers-in-Research series’.