Gastric mucosal protection against ethanol by EP₂and EP₄signaling through the inhibition of leukotriene C₄production

Abstract

Prostaglandin (PG)E derivatives are widely used for treating gastric mucosal injury. PGE receptors are classified into four subtypes, EP(1), EP(2), EP(3), and EP(4). We have tested which EP receptor subtypes participate in gastric mucosal protection against ethanol-induced gastric mucosal injury and clarified the mechanisms of such protection. The gastric mucosa of anesthetized rats was perfused at 2 ml/min with physiological saline, agonists for EP(1), EP(2), EP(3), and EP(4), or 50% ethanol, using a constant-rate pump connected to a cannula placed in the esophagus. The gastric microcirculation of the mucosal base of anesthetized rats was observed by transillumination through a window made by removal of the adventitia and muscularis externa. PGE(2) and subtype-specific EP agonists were applied to the muscularis mucosae at the window. Application of 50% ethanol dilated the mucosal arterioles and constricted the collecting venules. Collecting venule constriction by ethanol was completely inhibited by PGE(2) and by EP(2) and EP(4) agonists (100 nM) but not by an EP(1) or an EP(3) agonist. Ethanol-induced mucosal injury was also inhibited by EP(2) and EP(4) agonists. When leukotriene (LT)C(4) levels in the perfusate of the gastric mucosa were determined by ELISA, intragastric ethanol administration elevated the LTC(4) levels sixfold from the basal levels. These elevated levels were significantly (60%) reduced by both EP(2) and EP(4) agonists but not by other EP agonists. Since LTC(4) application at the window constricted collecting venules strongly, and an LTC antagonist reduced ethanol-induced mucosal injury, reductions in LTC(4) generation in response to EP(2) and EP(4) receptor signaling may be relevant to the protective action of PGE(2). The present results indicate that EP(2) and EP(4) receptor signaling inhibits ethanol-induced gastric mucosal injury through cancellation of collecting venule constriction by reducing LTC(4) production.

Adaptation of Mesenteric Collecting Lymphatic Pump Function Following Acute Alcohol Intoxication

“…The molecular mechanisms of tone generation in collecting lymphatics appear to resemble that of arterioles [15,39,49]. Alcohol causes dilation of gastric and mesenteric arterioles [25,46,52]. Studies of mesenteric arterioles showed that this response occurs irrespective of route of administration and appears to be due to direct interaction of the arterioles with alcohol as its metabolites acetaldehyde and acetate fail to produce the vasodilation response [1,2].…”

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…Mucosal cell injury. Several in vivo studies suggested that EP4 activation plays a protective role in rodent models of gastric ulcer via different mechanisms, such as VEGF induction, venous relaxation, and inhibition of apoptosis (Hatazawa et al, 2007;Hattori et al, 2008;Jiang et al, 2009), although there are reports that EP4 did not contribute to ulcer healing (Kunikata et al, 2001;Takeuchi et al, 2003). Takeuchi et al (2010b) found that an EP4 agonist reversed indomethacin-induced downregulation of VEGF expression and angiogenesis, and suggested that endogenous PGE 2 promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.…”

E-type prostanoid receptor 4 (EP4) in disease and therapy

“…Experimental gastric damage as induced by the COX inhibitor indomethacin or by a mixture of ethanol plus HCl in mice and rats are ameliorated by PGE 2 and an EP1 agonist (Suzuki et al, 2001; Takeuchi et al, 2001), while duodenal and intestinal lesions are prevented by EP3 and EP4 agonists (Kunikata et al, 2001; Kunikata et al, 2002). Part of the EP4 receptor-mediated intestinal mucosal protection might be due to stimulation of duodenal bicarbonate and mucus secretion (Takeuchi et al, 1997; Araki et al, 2000; Aihara et al, 2007), its anti-apoptotic effect on epithelial cells (Hoshino et al, 2003), vasodilation (Hattori et al, 2008) and vascular endothelial growth factor (VEGF) release to promote angiogenesis and mucosal healing (Hatazawa et al, 2007). …”