Endothelin-1-dependent up-regulation of leptin production in gastric mucosal injury by indomethacin.
Leptin, a multifunctional hormone that regulates food intake and metabolic and endocrine responses, has emerged recently as an important modulatory factor in gastric mucosal resistance to injury. In this study, we applied the animal model of gastric mucosal injury caused by indomethacin to investigate the role of endothelin-1 (ET-1) in the mucosal leptin production. Using groups of rats subjected to intragastric administration of indomethacin (at 0-60 mg/kg), we show that gastric mucosal damage reached a maximum 4 h following the drug, and was accompanied by a marked elevation (up to 3.5-fold) in the mucosal leptin level, up to 4-fold enhancement in the expression of endothelin-converting enzyme-1 (ECE-1) activity and up to 4.5-fold increase in ET-1 generation. Pretreatment with phosphoramidon, an inhibitor of ECE-1 activity, not only led to a decline in ECE-1 and ET-1 generation, but also produced a dose-dependent reduction in the mucosal level of leptin and the extent of mucosal damage caused by indomethacin. This effect of phosphoramidon, however, was subject to suppression by the exogenous ET-1 administration. Moreover, a marked drop in the mucosal level of leptin and the reduction in the severity of mucosal damage was attained following pretreatment with ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788. The results implicate ET-1 as a key factor in the regulation of leptin production associated with gastric mucosal response to injury, and show that the stimulatory effect of ET-1 on leptin production occurs via ET(A) receptor activation.
Slomiany
Bronislaw L
BL
Research Center, University of Medicine and Dentistry of New Jersey Dental School, Newark, NJ 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
Amalia
A
D000818:Animals; D019332:Endothelin-1 / Q000502:physiology*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D020738:Leptin / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D015854:Up-Regulation
D019332:Endothelin-1; D020738:Leptin; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D007213:Indomethacin