Role of beta-adrenoceptors in gastric mucosal integrity and gastroprotection induced by epidermal growth factor.
The central and peripheral adrenergic systems are involved in the regulation of gastric secretion but little is known about the role of alpha- and beta-adrenoceptors in gastroprotection. In this study, acute gastric lesions were produced by an intragastric (i.g.) application of 100% ethanol and gastric blood flow (GBF) was determined by H2-gas clearance technique in rats with or without i.g. or intraperitoneal (i.p.) administration of alpha- or beta-adrenoceptor agonists or antagonists. Phenylephrine, alpha1-adrenergic agonist, and clonidine, alpha2-agonist, significantly augmented the ethanol-induced lesions while decreasing the GBF and these effects were reversed by the blockade of alpha1-adrenoceptors with prazosin and alpha2-adrenoceptors with yohimbine. In contrast, isoproterenol (ISO) (0.01-10 mg/kg i.g.), beta-adrenoceptor agonist, reduced dose-dependently ethanol-induced mucosal injury and this effect was accompanied by an elevation of the GBF similarly as after epidermal growth factor (EGF) (100 microg/kg x h s.c.) or after classic protective agent, 16,16-dimethyl-PGE2 (PGE2) (10 microg/kg i.g.). The pretreatment with beta-antagonist, propranolol, diminished the protective and hyperemic effects of ISO and EGF but failed to affect those induced by PGE2. Suppression of nitric oxide (NO) synthase activity by L-NAME or sensory denervation with capsaicin attenuated significantly the ISO- and EGF-induced gastroprotection and elevation of GBF, whereas the inhibition of PG biosynthesis by indomethacin remained without any significant effect. Adrenal medullectomy or chemical sympathectomy by 6-hydroxydopamine by itself failed to influence significantly the ethanol-induced damage but completely abolished the protective and hyperemic effects of EGF being without any influence on those induced by PGE2. ISO combined with EGF, restored the protective and hyperemic effects of this peptide in medullectomized rats. We conclude that (1) local activation of beta-adrenoceptors by ISO affords protection and elevation of GBF, both these effects being mediated by arginine-NO pathway and sensory nerves and (2) sympathetic system and adrenal medulla contribute to the protective and hyperemic activity of EGF.
Brzozowski
T
T
Institute of Physiology, Jagiellonian University Medical School, Krakow, Poland.
Konturek
S J
SJ
Sliwowski
Z
Z
Pajdo
R
R
Drozdowicz
D
D
Stachura
J
J
D000315:Adrenalectomy; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D046508:Culture Techniques; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D004837:Epinephrine / Q000494:pharmacology; D000431:Ethanol; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply* / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D013272:Stomach Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D009569:Nitric Oxide; D000431:Ethanol; D004815:Epidermal Growth Factor; D015232:Dinoprostone; D007545:Isoproterenol; D003000:Clonidine; D004837:Epinephrine