Inhibitory effect of sildenafil on rat duodenal contractility in vitro:: Putative cGMP involvement

被引:9
作者
Araújo, PV
Clemente, CM
da Graça, JRV
Rola, FH
de Oliveira, RB
dos Santos, AA
Magalhaes, PJC
机构
[1] Univ Fed Ceara, Sch Med, Dept Physiol & Pharmacol, Fortaleza, Ceara, Brazil
[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Med, BR-14049 Ribeirao Preto, SP, Brazil
关键词
guanylate cyclase; intestinal motility; peristalsis; phosphodiesterase inhibitors; sildenafil citrate;
D O I
10.1111/j.1440-1681.2005.04170.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1. Sildenafil citrate (Viagra(TM); 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 mumol/L (95% confidence interval (CI) 2.0-55.3 mumol/L). 3. Sildenafil also relaxed the carbamylcholine (CCh)-induced sustained contraction with an IC50 of 16.2 mumol/L (95% CI 9.5-27.6 mumol/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 mumol/L (95% CI 5.7-16.2 mumol/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 mumol/L (95% CI 46.0-182.2 mumol/L) and 78.5 mumol/L (95% CI 37.1-166.3 mumol/L), respectively. 5. In preparations treated previously with methylene blue (10 mumol/L) or 1H-[1,2,4]oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 mumol/L), the EC50 values for the sildenafil effect were significantly increased to 39.0 mumol/L (95% CI 23.9-63.4 mumol/L) and 43.8 mumol/L (95% CI 24.5-78.3 mumol/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.
引用
收藏
页码:191 / 195
页数:5
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