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Sildenafil inhibits duodenal contractility via activation of the NO–K + channel pathway
Author(s) -
Clemente Cristiano M.,
Araújo Paula V.,
Palheta Raimundo C.,
Ratts Zoélia M. L.,
Fernandes Geórgea H.,
Rola Francisco H.,
De Oliveira Ricardo B.,
Dos Santos Armênio A.,
Magalhães Pedro J. C.
Publication year - 2008
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2007.00549.x
Subject(s) - sildenafil , chemistry , sodium nitroprusside , cyclic guanosine monophosphate , endocrinology , cgmp specific phosphodiesterase type 5 , medicine , nitric oxide , pharmacology , potassium channel , nitric oxide synthase
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 μ m ) in a concentration‐dependent manner [mean (95% confidence interval); EC 50 = 6.8 (2.7–17.3) μ m ]. The sildenafil‐induced myorelaxation was significantly decreased by the NO synthase inhibitor N ‐nitro‐ l ‐arginine methyl ester [increasing the EC 50 value to 41.9 (26.1–67.3) μ m ]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil‐induced myorelaxation. In isolated strips pretreated with BaCl 2 (0.2 m m ), 4‐aminopyridine (4‐AP, 3 m m ), or glybenclamide (1 μ m ), the sildenafil‐induced EC 50 value was significantly increased to 32.8 (19.1–56.4), 27.1 (15.2–48.3) and 20.1 (16.4–24.7) μ m , respectively. Minoxidil (50 μ m ) or diazoxide (100 μ m ) 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 K ATP channels, sensitive to glybenclamide.