Inhibitory effect of sildenafil on gastrointestinal smooth muscle: role of NO-cGMP transduction pathway.
Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.
Patil
Chandrashekhar S
CS
Pharmacology Division, University Institute of Pharmaceutical Sciences Panjab University, Chandigarh, India.
Singh
Vijay Pal
VP
Jain
Naveen K
NK
Kulkarni
Shrinivas K
SK
D000284:Administration, Oral; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester