Inhibition of epidermal growth factor receptor activation enhances in vivo histamine-stimulated gastric acid secretion in the rat.
Epidermal growth factor (EGF) and transforming growth factor alpha (TGFalpha) have been shown to inhibit gastric acid secretion through stimulation of the EGF receptor (EGFR). In this study we examined in vivo the effects of inhibition of the EGFR on histamine-stimulated acid secretion in the rat. Submaximal (1.5 mg/kg/hr) histamine-stimulated acid secretion was measured (microEq H(+)/2 hr) during infusion of EGFRtk inhibitors and ranitidine in anesthetized rats. EGFR phosphorylation in gastric mucosal tissue lysates was measured by Western blot analysis. Submaximal histamine-stimulated acid secretion was increased significantly by the EGFR inhibitors tyrphostin (Tyr) A46 and Tyr AG1478. Tyr A46 prevented TGFalpha (10 microg/kg/hr)-mediated inhibition of maximal (5.0 microg/kg/hr) histamine-stimulated acid output. Histamine caused a fourfold increase in EGFR phosphorylation which was inhibited by both Tyr and ranitidine. We conclude that the EGFRtk inhibitors, Tyr A46 and Tyr AG1478, significantly increased submaximal histamine-stimulated acid output and Tyr A46 prevented TGFalpha inhibition of histamine-stimulated acid secretion. These observations suggest that the EGFR is involved, in vivo, in the regulation of gastric acid secretion.
Section of Gastroenterology, Department of Internal Medicine, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma City, 73126, USA.
Hanumantha R
HR
Ancha
Hari B
HB
Ancha
Dustin S
DS
Tedesco
Angela R
AR
Ward
Richard F
RF
Harty
D000818:Animals; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D005744:Gastric Acid / Q000378:metabolism*; D006632:Histamine; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016211:Transforming Growth Factor alpha / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology*
D006635:Histamine H2 Antagonists; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C086599:tyrphostin A46; C101044:RTKI cpd; D006632:Histamine; D011899:Ranitidine; D066246:ErbB Receptors