Effects of Misoprostol, Cimetidine, and Ethanol on Rat Gastric Plasma Volume and Morphology

Abstract

Prostaglandins have effects on the gastric vasculature and blood flow that may be related to the phenomenon of "cytoprotection." We evaluated the effects of two potent antiulcer compounds--misoprostol, a prostaglandin E1 analog, and cimetidine, an H2-receptor antagonist--as well as a necrotizing agent, absolute ethanol (EtOH), on gastric plasma volume using the Evans blue-albumin binding technique. In addition, the effects of these two drugs on the morphology of the gastric mucosa were evaluated by light microscopy of epoxy resin sections. Fasted rats were given one of the following oral doses: (a) misoprostol, subantisecretory (100 micrograms/kg) or antisecretory (1 mg/kg); (b) cimetidine, subantisecretory (100 micrograms/kg, or 1 mg/kg) or antisecretory (50 mg/kg); or (c) EtOH only or EtOH following 30 min of pretreatment with one of the above doses of misoprostol or cimetidine. Animals were killed 30 or 90 min after a single dose or 30 min after two doses that were 60 min apart. The stomachs were then removed and processed for biochemical determination of Evans blue concentration. For morphology, rat stomachs were fixed and processed after exposure to each of the above concentrations of misoprostol and cimetidine. Results were as follows: (i) Misoprostol (but not cimetidine) caused a significant increase in stomach weight (subantisecretory dose = +15%, antisecretory dose = +21%) independent of changes in plasma volume. (ii) Misoprostol at both doses caused a transient (30-min) reduction in plasma volume (subantisecretory dose = -12%, antisecretory dose = -14%) that rebounded to slightly elevated levels within the following 60 min. (iii) Antisecretory doses of cimetidine caused an increase in plasma volume 30 min after a single dose (+37%) and at 90 min after two doses (+46%). (iv) EtOH only at 30 or 90 min produced elevated stomach weights (+25 and +28%, respectively) and plasma volumes (+300 and +250%, respectively), the latter of which was due in part to hemorrhagic lesions. (v) Cimetidine pretreatment (30 min) followed by EtOH did not significantly reduce plasma volume, stomach weight, or the gross hemorrhagic lesions compared to EtOH alone, but (vi) misoprostol pretreatment followed by EtOH significantly protected against hemorrhagic lesions and elevated tissue plasma volumes. Both drugs at all concentrations caused expansion of the mucosal interstitial space (lamina propria), but this edema was greater with misoprostol. Severe interfoveolar cell stretching and even epithelial breaks were found with misoprostol treatment. Cimetidine showed moderate mucosal edema and a "collapse" of interfoveolar epithelial cells so the intercellular spaces were reduced.(ABSTRACT TRUNCATED AT 400 WORDS)