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The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines.
J Physiol Pharmacol. 2016 Feb; 67(1):75-91.JP

Abstract

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.

Authors+Show Affiliations

Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Pharmacology Jagiellonian University Medical College, Cracow, Poland.Department of Pharmacology Jagiellonian University Medical College, Cracow, Poland.Department of Pharmacology Jagiellonian University Medical College, Cracow, Poland.Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Physiology Jagiellonian University Medical College, Cracow, Poland.Department of Pharmacology Jagiellonian University Medical College, Cracow, Poland.Department of Pharmacology Jagiellonian University Medical College, Cracow, Poland. mpbrzozo@cyf- kr.edu.pl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27010897

Citation

Pawlik, M W., et al. "The Renin-angiotensin System and Its Vasoactive Metabolite Angiotensin-(1-7) in the Mechanism of the Healing of Preexisting Gastric Ulcers. the Involvement of Mas Receptors, Nitric Oxide, Prostaglandins and Proinflammatory Cytokines." Journal of Physiology and Pharmacology : an Official Journal of the Polish Physiological Society, vol. 67, no. 1, 2016, pp. 75-91.
Pawlik MW, Kwiecien S, Ptak-Belowska A, et al. The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines. J Physiol Pharmacol. 2016;67(1):75-91.
Pawlik, M. W., Kwiecien, S., Ptak-Belowska, A., Pajdo, R., Olszanecki, R., Suski, M., Madej, J., Targosz, A., Konturek, S. J., Korbut, R., & Brzozowski, T. (2016). The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines. Journal of Physiology and Pharmacology : an Official Journal of the Polish Physiological Society, 67(1), 75-91.
Pawlik MW, et al. The Renin-angiotensin System and Its Vasoactive Metabolite Angiotensin-(1-7) in the Mechanism of the Healing of Preexisting Gastric Ulcers. the Involvement of Mas Receptors, Nitric Oxide, Prostaglandins and Proinflammatory Cytokines. J Physiol Pharmacol. 2016;67(1):75-91. PubMed PMID: 27010897.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The renin-angiotensin system and its vasoactive metabolite angiotensin-(1-7) in the mechanism of the healing of preexisting gastric ulcers. The involvement of Mas receptors, nitric oxide, prostaglandins and proinflammatory cytokines. AU - Pawlik,M W, AU - Kwiecien,S, AU - Ptak-Belowska,A, AU - Pajdo,R, AU - Olszanecki,R, AU - Suski,M, AU - Madej,J, AU - Targosz,A, AU - Konturek,S J, AU - Korbut,R, AU - Brzozowski,T, PY - 2015/10/19/received PY - 2016/02/12/accepted PY - 2016/3/25/entrez PY - 2016/3/25/pubmed PY - 2016/12/15/medline SP - 75 EP - 91 JF - Journal of physiology and pharmacology : an official journal of the Polish Physiological Society JO - J Physiol Pharmacol VL - 67 IS - 1 N2 - 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. SN - 1899-1505 UR - https://www.unboundmedicine.com/medline/citation/27010897/The_renin_angiotensin_system_and_its_vasoactive_metabolite_angiotensin__1_7__in_the_mechanism_of_the_healing_of_preexisting_gastric_ulcers__The_involvement_of_Mas_receptors_nitric_oxide_prostaglandins_and_proinflammatory_cytokines_ L2 - http://www.jpp.krakow.pl/journal/archive/02_16/pdf/75_02_16_article.pdf DB - PRIME DP - Unbound Medicine ER -