The inhibition of
angiotensin-converting enzyme (ACE) or the blockade of
angiotensin (Ang) AT-1 receptors affords protection against acute gastric mucosal injury, but whether the major metabolite of renin-angiotensin system (RAS), Ang-(1-7), accelerates the healing process of preexisting
gastric ulcers remains unknown. Previous studies documented that Ang-(1-7) acting via its own Mas receptor exerts vascular responses opposing those of Ang II. We studied the effects of the Ang-(1-7)/Mas receptor axis on the healing rate of
acetic-acid-induced
gastric ulcers with or without the blockade of Mas receptors by
A 779 and compared it with the effects of activation and blockade of the AT-1 receptor by the treatment with Ang II and
losartan, respectively, the inhibition of ACE by
lisinopril, the NO/cNOS inhibition by
L-NAME and inhibition of
prostaglandin/COX system by
indomethacin in the presence of Ang-(1-7). Additionally, ex vivo metabolism of Ang I in gastric tissue was assessed by LC/MS method. At day 9 after
ulcer induction, the area of these
ulcers and the accompanying changes in total gastric blood flow (GBF) were determined as were gastric mucosal blood flow (GMBF) at
ulcer margin and gastric
oxygen uptake (GVO2). The gastric mucosal expression of mRNAs for constitutive
nitric oxide synthase (cNOS),
superoxide dismutase (SOD), and pro-inflammatory
cytokines interleukin 1β (IL-1β) and
tumor necrosis factor alpha (TNF-α) and plasma level of both
cytokines were determined by RT-PCR and ELISA. The 9 days treatment with Ang II dose-dependently increased the area of
gastric ulcers and this effect was accompanied by a significant fall in the GBF, GVO2 and GMBF at
ulcer margin. In contrast, treatment with Ang-(1-7) which produced a significant rise in the
luminal content of NO significantly reduced the area of
gastric ulcer and significantly increased the GBF, GVO2 and the GMBF at
ulcer margin. Similar GMBF changes and significant reduction the area of
gastric ulcer was observed in rats with
gastric ulcers treated with the agonist of Mas receptor,
AVE 0991. These effects of Ang-(1-7) and
AVE 0991 were eliminated by blockade of the Mas receptor with A779. Similarly to Ang-(1-7), treatment with
losartan or
lisinopril significantly reduced the area of
gastric ulcers and the accompanying increase in the GMBF at
ulcer margin and these effects were significantly attenuated by a concomitant administration of
L-NAME and
indomethacin. The rate of healing of
ulcers was associated with a decrease in ex vivo Ang-(1-7) formation and this effect was attenuated by
lisinopril. The treatment with Ang-(1- 7) or
AVE 0991 increased the expression of
mRNA for cNOS and SOD and downregulated that of IL-1β and TNF-α followed by the decrease in the plasma IL-1β and TNF-α levels. We conclude that the Ang-(1-7)/Mas receptor system accelerates the healing of preexisting
gastric ulcers via an increase in the gastric macro- and microcirculations, and an increase in gastric tissue oxygenation. These effects are mediated by PG and NO derived from overexpression of cNOS, an increase in the expression of antioxidizing
enzyme SOD 2 and an anti-inflammatory action involving the inhibition of expression and release of pro-inflammatory
cytokines IL-1β and TNF-α. Our results seem to underlie the importance of the Ang-(1-7), AT-1 and Mas receptors in the regulation of local vascular and metabolic effects associated with mechanism of
gastric ulcer healing.