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

Abstract

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 microM) in a concentration-dependent manner [mean (95% confidence interval); EC(50) = 6.8 (2.7-17.3) microM]. 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) microM]. Sodium nitroprusside or forskolin pretreatments enhanced the sildenafil-induced myorelaxation. In isolated strips pretreated with BaCl(2) (0.2 mM), 4-aminopyridine (4-AP, 3 mM), or glybenclamide (1 microM), 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) microM, respectively. Minoxidil (50 microM) or diazoxide (100 microM) 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.

Black Tea Extract and its Thearubigins Relieve the Sildenafil‐Induced Delayed Gut Motility in Mice: A Possible Role of Nitric Oxide

“…In addition to the peripheral gut activation of NOS/cyclic nucleotide pathway, SLD can cross the blood brain barrier, and thus central sympathetic stimulation may also play a role in delaying gut motility (de Rosalmeida et al ., ). The delayed gut motility could occur through activation of NO–K + channel pathway, and its reversal by l ‐NAME indicates involvement of the NOS/cyclic nucleotide pathway (Clemente et al ., ).…”

Oral Phosphodiesterase Type 5 Inhibitors: Nonerectogenic Beneficial Uses

“…Clemente et al. [70] investigated sildenafil‐induced myorelaxation in rat isolated duodenum to assess its interaction with NOS and potassium (K+) channel opening. Spontaneous contractions of duodenal strips were reversibly inhibited by sildenafil in a concentration‐dependent manner that was significantly decreased by NOS inhibition.…”

Effect of a crude sulfated polysaccharide from Halymenia floresia (Rhodophyta) on gastrointestinal smooth muscle contractility

“…The barostat liquid level was set at 4.0 cm above the animal's xiphoid appendix. The gastric tonus that changed the gastric balloon volume was electronically sensored and continuously displayed by a digital plethysmometer (LE 7500-PanLab ® ) (Clemente et al, 2008). Following a basal period of 20 min, the animals received (i.v.)…”

“…As the extracellular Ca 2+ influx through the voltage-gated Ca 2+ channels played an important role in gastrointestinal smooth muscle contraction (Clemente et al, 2008), the duodenal strips were pretreated with verapamil (1 µM), an inhibitor of voltage-gated Ca2+ channels. In addition, the response of this muscle to Hf2s in a Ca 2+ -free medium was investigated.…”

“…In order to evaluate the possible role of extracellular Ca 2+ effect on the polysaccharide responses, verapamil (10 −6 M), a voltage-gated Ca 2+ channel blocker, or a Ca 2+ -free medium was used. To verify tissue vitality, the duodenal spontaneous contractile were tested 30 min after the polysaccharide removal (Clemente et al, 2008).…”