Sildenafil, an inhibitor of phosphodiesterase subtype 5, prevents indomethacin-induced small-intestinal ulceration in rats via a NO/cGMP-dependent mechanism.
We examined the effect of sildenafil, an inhibitor of phosphodiesterase subtype 5, that catalyzes hydrolysis of 3',5'-cyclic guanosine monophosphate (cGMP), on indomethacin-induced small-intestinal ulceration in rats and investigated the mechanism of this action, especially in relation to endogenous nitric oxide (NO). Animals without fasting were given indomethacin (10 mg/kg) s.c. and then killed 24 h later. Indomethacin produced hemorrhagic lesions in the small intestine, accompanied by a promotion of enterobacterial invasion and the expression of inducible NO synthase (iNOS) as well as myeloperoxidase (MPO) activity in the mucosa. Sildenafil (3-20 mg/kg), given p.o. 30 min before indomethacin, dose-dependently reduced the severity of these lesions, with concomitant suppression of the increase in MPO activity, iNOS expression and bacterial invasion. These effects were attenuated by the prior administration of the nonselective NOS inhibitor, N (G)-nitro-L-arginine methyl ester, in an L-arginine-reversible manner. Indomethacin also decreased the secretion of mucus and fluid (enteropooling) and enhanced intestinal motility, but these responses were all prevented by the prior administration of sildenafil. Likewise, pretreatment of the animals with NOR-3, a NO donor, also reversed the functional changes caused by indomethacin, followed by suppression of bacterial invasion and iNOS expression, and prevented the development of intestinal lesions. These results suggest that sildenafil prevents indomethacin-induced small-intestinal ulceration in rats, via a NO/cGMP-dependent mechanism, and this effect is functionally associated with an increase in the secretion of mucus/fluid and a decrease of hypermotility, resulting in the suppression of bacterial invasion and iNOS expression following indomethacin treatment.
Kato
Naho
N
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Mashita
Yuji
Y
Kato
Shinichi
S
Mitsufuji
Shoji
S
Yoshikawa
Toshikazu
T
Takeuchi
Koji
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D006152:Cyclic GMP / Q000378:metabolism; D004755:Enterobacteriaceae / Q000502:physiology; D005766:Gastrointestinal Contents / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000009:adverse effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D007421:Intestine, Small / Q000201:enzymology / Q000382:microbiology; D008297:Male; D009093:Mucus / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009574:Nitro Compounds; D010437:Peptic Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D009569:Nitric Oxide; C061872:FK 409; D000068677:Sildenafil Citrate; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP; D007213:Indomethacin