Sildenafil prevents indomethacin-induced gastropathy in rats: role of leukocyte adherence and gastric blood flow

1 Nitric oxide (NO) is an important mediator of gastric mucosal defense. Sildenafil (SILD), a cyclic GMP-specific phosphodiesterase inhibitor, promotes an increase in cGMP concentrations in the gastrointestinal tract. cGMP mediates many of the biological actions of NO. 2 We tested the hypothesis that SILD could increase mucosal defense against indomethacin-induced gastropathy in rats. 3 SILD (1, 4 or 10 mg kg(-1), p.o.) pretreatment significantly reduced (P<0.01) the gastric damage and the increase in gastric myeloperoxidase (MPO) activity elicited by indomethacin (20 mg kg(-1) p.o.), with the maximal effect at the dose of 10 ing kg(-1). 4 L-NAME (3, 10 or 20 mg kg(-1), i.p.) dose dependently reversed the protective effects of SILD, an effect not seen when L-arginine (L-ARG) (200 mg kg(-1), i.p.) was co-administered with L-NAME. 5 Indomethacin-induced leukocyte adhesion, assessed by intravital microscopy, was decreased (P<0.01) by SILD, and this effect was reversed by L-NAME cotreatment. 6 Indomethacin elicited a decrease in gastric blood flow and in gastric PGE(2) levels. SILD was able to prevent the decrease in gastric blood flow (P<0.01), without diminishing the inhibitory effect of indomethacin on prostaglandin synthesis. 7 These results indicate that SILD, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy, possibly through a reduction of leukocyte adhesion and maintenance of gastric blood flow.