Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal antiinflammatory drugs
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) produce gastric damage as adverse reaction in experimental animals and humans [12], [27]. Although multiple elements such as neutrophil activation, gastric hypermotility, microcirculatory disturbances, oxygen free radicals and luminal acid are involved in the pathogenesis of these lesions [1], [3], [13], [20], [21], [25], a deficiency of endogenous prostaglandins (PGs) is of prime importance in the background for the ulcerogenic response to NSAIDs [24], [27]. This contention is supported by the fact that NSAID-induced gastric lesions are effectively prevented by supplementation with exogenous PGs [16], [20], [21].
A PG deficiency caused by NSAIDs is due to cyclooxygenase (COX) inhibition. There are two isoforms of COX; COX-1 is found constitutively expressed in various tissues, including the stomach [4], [9], [11], [15], [17], while COX-2 does not appear to be expressed, or at least at very low levels, in most tissues and is rapidly up-regulated in response to growth factors and cytokines [10], [14], [18], [19]. This tissue specificity leads to the contention that COX-1 is critical for housekeeping action in the gastric mucosa [2], [7], whereas COX-2 is responsible for inflammation [11], [18], [28]. Indeed, studies using selective COX-2 inhibitors showed that the ulcerogenic property of NSAIDs is brought about by inhibition of COX-1 but not COX-2 [2], [6]. However, Wallace et al. [26] recently showed that inhibition of both COX-1 and COX-2 is required for NSAID-induced gastric injury, suggesting a “housekeeping” role of COX-2 as well as COX-1 in the stomach.
In the present study, we re-evaluated the gastric ulcerogenic effect of COX inhibitors, such as the nonselective COX inhibitors and the selective inhibitors of COX-1 (SC-560) [23], [26] or COX-2 (rofecoxib)[23] in rats, and investigated whether or not the inhibition of COX-1 is sufficient by itself for induction of gastric damage. In addition, since an importance of gastric hypermotility has been demonstrated in the pathogenic mechanism of NSAID-induced gastric damage [13], [16], [19], we also examined the effects of various COX inhibitors on gastric motility, in attempts to correlate their ulcerogenic property in the stomach.
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Animals
Male Sprague–Dawley rats (220–260 g, Nippon Charles River, Shizuoka, Japan) were used. The animals were kept in individual cages with raised mesh bottoms and deprived of food but allowed free access to tap water for 18 h prior to the experiments. Studies were carried out using 4–6 rats per group. The experimental procedures employed in the present study were approved by the Experimental Animal Research Committee of the Kyoto Pharmaceutical University.
Evaluation of gastric ulcerogenic property
The animals were given various NSAIDs (the
Effects of various COX inhibitors on the gastric mucosa and PGE2 contents
Oral administration of the nonselective COX inhibitors tested provoked lesions in the gastric mucosa within 8 h; the lesion score being 39.1±8.7 mm2, 47.8±4.3 mm2 or 36.6±3.1 mm2, respectively, for indomethacin (35 mg/kg), dicrofenac (40 mg/kg) or naproxen (40 mg/kg; Fig. 1). Characteristically, the damage was found in parallel to the long axis of the stomach and consisted mostly of hemorrhagic lesions, with some non-hemorrhagic injury. Neither SC-560 (30 mg/kg) nor rofecoxib (30 mg/kg) induced
Discussion
The present study confirmed that conventional NSAIDs, which nonselectively inhibit both COX-1 and COX-2 activities, produced damage in the stomach, with concomitant gastric hypermotility [1,3,13,20–22,25]. We also found that neither the selective COX-1 nor COX-2 inhibitor alone caused gross damage in the stomach, but the combined administration of these two inhibitors provoked gastric lesions. Of interest, the present study showed for the first time that inhibition of COX-1 up-regulated the
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