Sildenafil inhibits duodenal contractility via activation of the NO-K+ channel pathway

Phosphodiesterase type‐5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well‐known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenaf...

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Published in:	Fundamental & clinical pharmacology Vol. 22; no. 1; pp. 61 - 67
Main Authors:	Clemente, Cristiano M., Araújo, Paula V., Palheta Jr, Raimundo C., Ratts, Zoélia M. L., Fernandes, Geórgea H., Rola, Francisco H., De Oliveira, Ricardo B., Dos Santos, Armênio A., Magalhães, Pedro J. C.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-02-2008
Subjects:	Animals Colforsin - pharmacology contractility Diazoxide - pharmacology duodenum Duodenum - drug effects Duodenum - physiology In Vitro Techniques Male Muscle Contraction - drug effects NG-Nitroarginine Methyl Ester - pharmacology Nitric Oxide - physiology Nitric Oxide Donors - pharmacology Nitric Oxide Synthase Type II - antagonists & inhibitors Nitric Oxide Synthase Type III Nitroprusside - pharmacology phosphodiesterase Phosphodiesterase Inhibitors - pharmacology Piperazines - pharmacology Potassium Channel Blockers - pharmacology Potassium Channels - physiology Purines - pharmacology rat Rats Rats, Wistar sildenafil Sildenafil Citrate smooth muscle Sulfones - pharmacology Vasodilator Agents - pharmacology
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Summary:	Phosphodiesterase type‐5 (PDE5) specifically cleaves cyclic guanosine monophosphate (cGMP), a key intracellular secondary messenger. The PDE5 inhibitor sildenafil is a well‐known vasodilator that also has gastrointestinal myorelaxant properties. In the present study, we further investigated sildenafil‐induced myorelaxation in rat isolated duodenum, assessing its interaction with nitric oxide (NO) synthase and K+ channel opening. The spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil (0.1–300 μm) in a concentration‐dependent manner [mean (95% confidence interval); EC50 = 6.8 (2.7–17.3) μm]. The sildenafil‐induced myorelaxation was significantly decreased by the NO synthase inhibitor N‐nitro‐l‐arginine methyl ester [increasing the EC50 value to 41.9 (26.1–67.3) μm]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil‐induced myorelaxation. In isolated strips pretreated with BaCl2 (0.2 mm), 4‐aminopyridine (4‐AP, 3 mm), or glybenclamide (1 μm), the sildenafil‐induced EC50 value was significantly increased to 32.8 (19.1–56.4), 27.1 (15.2–48.3) and 20.1 (16.4–24.7) μm, respectively. Minoxidil (50 μm) or diazoxide (100 μm) also significantly attenuated the sildenafil‐induced potency. In conclusion, the NO synthase/cyclic nucleotide pathway activation is involved in sildenafil‐induced inhibition of spontaneous duodenal contractions. Its pharmacological action seems to be influenced by K+ channel opening, especially the voltage‐sensitive ones, being inhibited by 4‐AP and KATP channels, sensitive to glybenclamide.
Bibliography:	ark:/67375/WNG-T3PGW4R0-D ArticleID:FCP549 istex:E3D4596C0A8E7081DB177C50E76F2770CC1DABFD ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0767-3981 1472-8206
DOI:	10.1111/j.1472-8206.2007.00549.x