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

Abstract

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 mg 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. © 2005 Nature Publishing Group All rights reserved.