misoprostol and Ischemia

Recent studies have shown that flunixin prevented recovery of equine jejunum post ischaemia. However, the use of a purported cyclooxygenase (COX)-2 preferential inhibitor, etodolac, also prevented recovery. These findings may have implications for the use of nonsteroidal anti-inflammatory drugs in colic patients.. To compare the effects of deracoxib, a highly selective canine COX-2 inhibitor, with flunixin on in vitro recovery of ischaemic-injured equine jejunum.. Six horses underwent 2 h jejunal ischaemia, after which mucosa was mounted in Ussing chambers and recovered for 240 mins. Transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol were monitored as indices of barrier function in the presence of flunixin or deracoxib.. The TER of ischaemic-injured tissue recovered significantly over 240 mins in the presence of no treatment, but not in the presence of flunixin or deracoxib. In addition, flunixin-treated ischaemic jejunum was significantly more permeable to mannitol when compared with untreated tissue by the end of the recovery period, whereas deracoxib treatment did not increase permeability. Addition of the PGE1 analogue misoprostol to flunixin-treated tissue restored recovery of TER.. Treatment of horses with ischaemic jejunal disease with flunixin may result in a prolonged permeability defect in recovering mucosa. Addition of misoprostol or replacement of flunixin with deracoxib may ameliorate effects of COX inhibitors on recovering mucosa.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Transport; Clonixin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Electric Impedance; Histological Techniques; Horse Diseases; Horses; Intestinal Mucosa; Ischemia; Jejunum; Mannitol; Misoprostol; Permeability; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Reperfusion; Sulfonamides; Tritium

Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage.. Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 microg/kg/min) and for 3 hours after reperfusion (0.5 microg/kg/min). Animals were divided into five groups: untreated control group (n=10); high-dose misoprostol (total 100 microg/kg) group (MP-H, n=5); middle-dose misoprostol (50 microg/kg) group (MP-M, n=5); low-dose misoprostol (25 microg/kg) group (MP-L, n=5); and OP-41483 group (OP, n=5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed.. Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension.. These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects.

Topics: Analysis of Variance; Animals; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Female; Ischemia; Liver; Liver Function Tests; Misoprostol; Platelet Aggregation Inhibitors; Prostaglandins, Synthetic; Reperfusion Injury

The ability of prostaglandins to protect the kidney against ischemic and toxic renal injury was evaluated by in vivo and in vitro models of renal ischemia. The prostaglandin E1 analogue, misoprostol, was found to provide significant protection against ischemia-induced renal dysfunction in rats subjected to 40 minutes of renal artery occlusion. Misoprostol-treated rats had glomerular filtration rates almost threefold greater than control animals, although renal blood flow and renal vascular resistance were not significantly different. Improved tubular function was reflected in a lower fractional excretion of sodium and a higher urine-to-plasma creatinine ratio. Misoprostol also provided similar protection in a model of toxic renal injury produced by mercuric chloride. In an in vitro model employing primary cultures of proximal tubule epithelial cells subjected to hypoxia and reoxygenation, misoprostol limited cell death. Posthypoxic cells had apical membrane disruption and loss of microvilli when examined by transmission electron microscopy. These changes were not seen in misoprostol-treated cells. The "cytoprotective" effect was also produced by prostaglandin E2 and prostacyclin. The ability of prostaglandin E to protect against toxic and ischemic renal injury did not appear to be due to an antioxidant effect because misoprostol did not limit lipid peroxidation in vivo and did not protect against oxidant injury by tert-butyl hydroperoxide in vitro. Although the exact mechanism of prostaglandin protection was not revealed, these studies demonstrate that prostaglandins protect renal tubule epithelial cells from hypoxic injury at the cellular level independent of hemodynamic factors or inflammatory responses. Such a "cytoprotective" effect of prostaglandins may be a generalized phenomenon since it has also been demonstrated in gastrointestinal epithelium.

Topics: Acute Kidney Injury; Animals; Cell Hypoxia; In Vitro Techniques; Ischemia; Kidney; L-Lactate Dehydrogenase; Male; Mercuric Chloride; Microscopy, Electron; Misoprostol; Rats; Rats, Sprague-Dawley