The potentiation of taurocholate‐induced rat gastric erosions following parenteral administration of cyclo‐oxygenase inhibitors

Abstract

Subcutaneous administration of anti‐inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally‐perfused gastric mucosa of anaesthetized rats. These doses of anti‐inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mm in 100 mm HCl). The increase in luminal acid‐loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti‐inflammatory agents. A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid‐taurocholate perfusion. BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid‐taurocholate induced gastric damage. The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo‐oxygenase in the genesis of the gastric lesions.

Capsaicin-Sensitive Sensory Nerves in Recovery of Gastric Mucosal Integrity after Damage by Sodium Taurocholate in Rats

“…Injury to the gastric mucosa is associated with an increase in GMBF (20). Whittle (21) reported that application of acidified TC to the stomach induced a hyperemic response, and this GMBF response was inhibited by concurrent admin istration of indomethacin, in agreement with the present findings. Ablation of capsaicin-sensitive sensory neurons also inhibited the hyperemic response induced by TC.…”

Cyclooxygenase Isozymes Involved in Adaptive Functional Responses in Rat Stomach after Barrier Disruption

“…COX-1 is constitutively expressed in normal gastric mucosa and considered to generate PGs involved in the maintenance of essential physiological functions (Whittle, 1983;Simmons et al, 1991;Futaki et al, 1993). Mucosal PGE 2 content in the normal stomach was significantly decreased by SC-560 but not rofecoxib.…”

“…These agents damage the surface epithelium of the gastric mucosa, resulting in acid back-diffusion, yet they rarely cause macroscopically visible damage and actually protect the stomach against necrotizing agents (Holzer et al, 1991;Takeuchi et al, 1993). Such hyperemic responses subside in the presence of NSAIDs, suggesting a role for endogenous PGs in this phenomenon (Whittle, 1983;Nobuhara and Takeuchi, 1984;Takeuchi et al, 1986Takeuchi et al, , 1987. We previously reported, using a selective COX-2 inhibitor, that endogenous PGs produced by COX-1 play an important role in maintaining the gastric hyperemic response and mucosal integrity after barrier disruption by taurocholate (TC) Na (Hirata et al, 1997), yet the relative contribution of the COX-1 and COX-2 isozymes to the maintenance of other functional responses such as acid secretion in the stomach after barrier disruption is not entirely clear.…”

“…It is known that the application of mild irritants to the stomach causes an increase in gastric mucosal blood flow (GMBF) as well as a decrease in acid secretion (Whittle, 1983;Takeuchi et al, 1986Takeuchi et al, , 1993. These agents damage the surface epithelium of the gastric mucosa, resulting in acid back-diffusion, yet they rarely cause macroscopically visible damage and actually protect the stomach against necrotizing agents (Holzer et al, 1991;Takeuchi et al, 1993).…”

“…COX-1, constitutively expressed in normal gastric mucosa, has been proposed to generate PGs involved in the maintenance of essential physiological functions (Simmons et al, 1991;O'Neill and Ford-Hutchinson, 1993), whereas COX-2, characterized by a rapid inducibility in response to various proinflammatory stimuli, has been thought to be responsible for pathological PG production at inflammatory sites (O'Banion et al, 1991;Xie et al, 1992). Studies using selective COX-2 inhibitors showed that the gastric ulcerogenic property of nonsteroidal antiinflammatory drugs (NSAIDs) is brought about by inhibition of COX-1 but not COX-2 (Whittle, 1983;Futaki et al, 1993). However, it has been recently shown that inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury, suggesting a role for COX-2 as well as COX-1 in maintaining the integrity of the stomach Tanaka et al, 2001).…”