Indirect role of α2-adrenoreceptors in anti-ulcer effect mechanism of nimesulide in rats

Abstract

Nimesulide, a non-steroidal, anti-inflammatory drug, produces ulcerogenic effects in adrenalectomized rats but is gastro-protective in intact rats. The objective of this study was to determine whether adrenal gland hormones are involved in the anti-ulcer effects of nimesulide. The results revealed that 100 mg/kg nimesulide produces gastric ulceration in adrenalectomized rats, which is prevented by prednisolone and adrenaline. The anti-ulcer effects of adrenaline and prednisolone in adrenalectomized rats were in turn antagonized by yohimbine, a selective alpha(2)-receptor blocker, but not by doxazosine (alpha(1)-receptor blocker) or propranolol (beta-blocker). Adrenaline prevented the formation of indomethacin-induced ulcers in both adrenalectomized and intact rats, but prednisolone increased the indomethacin-induced ulcerous area in intact rats, whereas it decreased the size of the ulcers in adrenalectomized rats. In addition, prednisolone prevented ulcer formation in intact rats in which the adrenaline concentration had been decreased by metyrosine. These results suggest that glucocorticoids are anti-ulcerogenic in not only adrenalectomized rats but also in intact rats with diminished circulating levels of adrenaline. In the light of these data, the effect of nimesulide on plasma adrenaline concentrations was studied. In comparison to the adrenaline levels found in intact control rats, the administration of nimesulide at doses of 10, 20, 40 and 100 mg/kg decreased adrenaline concentrations by 12.8, 22.6, 30.4, and 58.2%, respectively, without affecting blood corticosterone concentrations. The anti-ulcer effect of nimesulide was observed to be dose-dependent, and the strength of this effect was directly correlated the decreasing concentration of adrenaline. The concentration of adrenaline was decreased by 60.9% in rats treated with 300 mg/kg metyrosine in which prednisolone produced anti-ulcer effects. In summary, we have shown that nimesulide produces its anti-ulcer effect by decreasing endogenous adrenaline concentrations and that glucocorticoids may induce anti-ulcer effects via alpha(2)-adrenoreceptors, but not via their own receptors.

Gastric anti-ulcerative and anti-inflammatory activity of metyrosine in rats

“…These findings indicate that the level of adrenalin must be low for an antiinflammatory effect to be observed. Furthermore, in our previous study nimesulide demonstrated antiinflammatory and anti-ulcerative activities resulting from decreased adrenalin levels [31]. In light of these observations we suggest that drugs that decrease adrenalin levels may also have anti-inflammatory and anti-ulcerative effects.…”

“…In previous studies metyrosine was shown to reduce circulating adrenalin levels significantly [22,31]. As mentioned previously, NSAIDs create an anti-inflammatory effect by reducing adrenalin levels [27].…”

“…As mentioned previously, NSAIDs create an anti-inflammatory effect by reducing adrenalin levels [27]. In addition, the role of a-2 adrenergic receptors in promoting anti-ulcerative effects has been previously demonstrated [31]. Thus, drugs that reduce adrenalin levels and block a-2 adrenergic receptors at the same time (such as indomethacin) may therefore have potent anti-inflammatory and ulcerative effects.…”

“…Interestingly, while nimesulide had antiulcerative effects in intact rats, it had ulcerative effects in adrenalectomized rats, pointing to the existence of anti-ulcerative factors originating from the adrenal glands [28]. Prednisolone, a glucocorticoid, is also ulcerative in intact rats and anti-ulcerative in adrenalectomized or metyrosine treated rats, indicating that a decrease in adrenalin levels is necessary for an anti-ulcerative effect [31]. In another study, the antiinflammatory effects of NSAIDs were found to disappear in adrenalectomized rats [30].…”

Occurrence of anticancer activity of prednisolone via adrenalectomy and inhibition of adrenaline in rats

“…25 Prednisolone, a glucocorticoid, produces ulcers in healthy intact rats and prevents ulcer formation in both adrenalectomized (endogenous adrenaline has been eliminated) rats and in intact rats that have received metyrosine (with reduced endogenous adrenaline). 26 Black (1988), Wallace (1987) and Weusten et al, 1993, demonstrated in their studies that glucocorticoids increase ulcer incidence in both human and animal subjects. [27][28][29] In our above-mentioned study, we showed that prednisolone produced antiulcer effects via the a2-adrenoreceptors in the absence of adrenaline in adrenalectomized rats, and in the presence of reduced adrenaline concentrations in rats given metyrosine.…”