Role of early vascular damage in the pathogenesis of gastric haemorrhagic mucosal lesions induced by indomethacin in rats.

Early vascular injury is a key element in the pathogenesis of gastric haemorrhagic mucosal lesions which develop rapidly after intragastric (i.g.) administration of ethanol, HCl or NaOH. The sequence of vascular events leading to gastric lesions has not, however, been investigated in detail with ulcerogenic non-steroidal anti-inflammatory drugs such as indomethacin (IND). Accordingly, experiments were performed in rats using the vascular tracer Monastral blue to assess whether vascular lesions precede and are subsequently associated with mucosal lesions induced by oral (p.o.) or subcutaneous (s.c.) administration of IND. Fasted female Sprague-Dawley rats (150-180 g) were given IND either at 100 mg/kg, p.o. or 200 mg/kg s.c. and killed 15, 30, 120 or 240 minutes later. Monastral blue, 3% saline 1 ml/kg, was injected intravenously under ether anaesthesia 3 minutes before autopsy and the formalin fixed, glycerol cleared stomachs were examined microscopically for deposition of the dye particles on damaged blood vessels. The percentage area of Monastral blue labelled vessels (measured by stereomicroscopic planimetry) at 15 minutes after oral IND was 10.1 +/- 1.5% (mean +/- s.e.m.) of glandular stomach and increased progressively to 64.5 +/- 3.0% at 240 minutes. Gastric haemorrhagic lesions (also measured by stereomicroscopic planimetry) were first evident at 30 minutes (0.2 +/- 0.03%; mean +/- s.e.m.), and developed progressively to 2.0 +/- 0.3% total area of glandular mucosa at 240 minutes. Subcutaneous injection of IND resulted in a delayed time of onset for the appearance and the extent of mucosal lesions (first appearing at 120 minutes, 0.1 +/- 0.03% area) compared with that from oral administration of the drug, but as with oral IND the vascular damage (first appearance at 15 minutes, 7.5 +/- 3.6%) clearly preceded the occurrence of gastric lesions. The observations of microvascular dye labelling were paralleled by observations of the electron-microscopic appearance of endothelial cell disruption in the region adjacent to superficial mucous cells and accumulation of red blood cells in the interstitium at 20-60 minutes. We conclude that vascular injury precedes haemorrhagic mucosal damage in the pathogenesis of IND-induced acute gastric mucosal lesions.