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 2008-02, Vol.22 (1), p.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: Article
Language:English
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.
ISSN:0767-3981
1472-8206
DOI:10.1111/j.1472-8206.2007.00549.x