Peripheral urocortin inhibits gastric emptying and food intake in mice: differential role of CRF receptor 2

Intraperitoneal urocortin inhibits gastric emptying and food intake in mice. We investigated corticotropin-releasing factor receptor (CRF-R) subtypes involved in intraperitoneal urocortin actions using selective CRF-R antagonists. Gastric emptying was measured 2 h after a chow meal, and food intake was measured hourly after an 18-h fast in mice. Urocortin (3 microg/kg ip) inhibited gastric emptying by 88%. The CRF-R1/CRF-R2 antagonist astressin B (30 microg/kg ip) and the selective CRF-R2 antagonist antisauvagine-30 (100 microg/kg ip) completely antagonized urocortin action, whereas the selective CRF-R1 antagonist CP-154,526 (10 mg/kg ip) had no effect. Urocortin (1-10 microg/kg ip) dose dependently decreased the 2-h cumulative food intake by 30-62%. Urocortin (3 microg/kg)-induced hypophagia was completely antagonized by astressin B (30 microg/kg ip) and partially (35 and 31%) by antisauvagine-30 (100 or 200 microg/kg ip). The CRF-R1 antagonists CP-154,526 or DMP904 (10 mg/kg ip) had no effect. Capsaicin did not alter urocortin-inhibitory actions while blocking the satiety effect of intraperitoneal CCK. These data indicate that intraperitoneal urocortin-induced decrease in feeding is only partly mediated by CRF-R2, whereas urocortin action to delay gastric emptying of a meal involves primarily CRF-R2.     

Restraint stress delays solid gastric emptying via a central CRF and peripheral sympathetic neuron in rats

Central corticotropin-releasing factor (CRF) delays gastric emptying through the autonomic nervous system. CRF plays an important role in mediating delayed gastric emptying induced by stress. However, it is not clear whether a sympathetic or parasympathetic pathway is involved in the mechanism of central CRF-induced inhibition of solid gastric emptying. The purpose of this study was to investigate whether 1) CRF inhibits solid gastric emptying via a peripheral sympathetic pathway and 2) stress-induced inhibition of solid gastric emptying is mediated via a central CRF and peripheral sympathetic pathways. Using male Sprague-Dawley rats, CRF was injected intracisternally with or without various adrenergic-blocking agents. To investigate whether central CRF-induced inhibition of solid gastric emptying is mediated via a peripheral sympathetic pathway, rats underwent celiac ganglionectomy 1 wk before the gastric emptying study. After solid meal ingestion (90 min), gastric emptying was calculated. To investigate the role of endogenous CRF in stress-induced delayed gastric emptying, a CRF type2 receptor antagonist, astressin2-B, was intracisternally administered. Rats were subjected to a restraint stress immediately after the feeding. Intracisternal injection of CRF (0.1-1.0 microg) dose-dependently inhibited solid gastric emptying. The inhibitory effect of CRF on solid gastric emptying was significantly blocked by guanethidine, propranolol, and celiac ganglionectomy but not by phentolamine. Restraint stress significantly delayed solid gastric emptying, which was improved by astressin2-B, guanethidine, and celiac ganglionectomy. Our research suggests that restraint stress inhibits solid gastric emptying via a central CRF type2 receptor and peripheral sympathetic neural pathway in rats.     

Intravenous urocortin II decreases blood pressure through CRF(2) receptor in rats

Urocortin II (Ucn II) is a new member of the corticotropin-releasing factor (CRF) family that binds selectively to the CRF subtype 2 receptor (CRF(2)). CRF or urocortin injected intravenously (i.v.) induced hypotension. We investigated the influence of iv human Ucn II (hUcn II) on basal mean blood pressure (MAP) and on the sympathetic mediated hypertensive response to TRH analog, RX-77368 injected intracisternally (i.c.) 20 min after hUcn II in urethane-anesthetized rats. Ucn II (3, 10, and 30 microg/kg, i.v.) significantly decreased basal MAP from baseline by -20.9+/-6.5, -21.3+/-5.4 and -46.8+/-6.5 mm Hg, respectively, after 10 min. RX-77368 (30 ng, i.c.) elevated MAP for over 90 min with a maximal hypertensive response at 20 min. Ucn II (3, 10, and 30 microg/kg, i.v.) did not alter the 20 min net rise in MAP induced by RX-77368 (35.7+/-7.1, 32.6+/-3.3 and 24.6+/-6.9 mm Hg, respectively) compared with vehicle (33.6+/-4.3 mm Hg). The selective CRF(2) antagonist, astressin(2)-B (60 microg/kg, i.v.) abolished hUcn II hypotensive action while having no effect on basal MAP. These data show that iv hUcn II induces hypotension through peripheral CRF(2) receptor while not altering the responsiveness to sympathetic nervous system-mediated rise in MAP.     

Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats

Corticotropin releasing factor (CRF) is one of the most important factors in the mechanism of stress-induced stimulation of colonic motility. However, it is controversial whether stress-induced stimulation of colonic motility is mediated via central or peripheral CRF receptors. We investigated the hypothesis that peripherally injected CRF accelerates colonic motility through the central CRF receptor, but not the peripheral CRF receptor. A strain gauge transducer was sutured on the serosal surface of the proximal colon. Colonic motility was monitored before and after the peripheral injection of CRF. An in vitro muscle strip study was also performed to investigate the peripheral effects of CRF. Subcutaneous injection of CRF (30-100 microg/kg) stimulated colonic motility in a dose-dependent manner. The stimulatory effect of peripherally administered CRF on colonic motility was abolished by truncal vagotomy, hexamethonium, atropine, and intracisternal injection of astressin (a CRF receptor antagonist). No responses to CRF (10(-9) -10(-7) M) of the muscle strips of the proximal colon were observed. These results suggest that the stimulatory effect of colonic motility in response to peripheral administration of CRF is mediated by the vagus nerve, nicotinic receptors, muscarinic receptors, and CRF receptors of the brain stem. It is concluded that peripherally administered CRF reaches the area postrema and activates the dorsal nucleus of vagi via central CRF receptors, resulting in stimulation of the vagal efferent and cholinergic transmission of the proximal colon.     

Thyrotropin-releasing hormone (TRH) acts centrally to stimulate gastric contractility in rats

Changes in gastric contractility induced by intracisternal (ic) injection of thyrotropin-releasing hormone (TRH) or a stable TRH analog, RX77368 [p-Glu-His-(3,3'-dimethyl)-Pro NH2] were investigated in 24 h fasted-conscious rats. Gastric contractility was monitored using chronically implanted extraluminal force transducers sutured to the corpus. Response elicited by a standard meal was used as a physiologic standard. Intracisternal injection of TRH (1 microgram) or RX77368 (100 ng), unlike saline, stimulated high amplitude gastric contractions. The stimulation of gastric contractions induced by ic RX77368 was dose dependent (3-100 ng), rapid in onset, long lasting and not mimicked by the intravenous route of administration. Atropine (0.1 mg/kg) partially antagonized and vagotomy totally blocked the RX77368 (100 ng, ic)-induced stimulation of gastric contractility. These results demonstrated that TRH or RX77368 acts within the brain to elicit potent contractions of the stomach; TRH action appears vagally mediated probably through cholinergic mechanism.     

Intravenous injection of urocortin 1 induces a CRF2 mediated increase in circulating ghrelin and glucose levels through distinct mechanisms in rats

Urocortins (Ucns) injected peripherally decrease food intake and gastric emptying through peripheral CRF₂ receptors in rodents. However, whether Ucns influence circulating levels of the orexigenic and prokinetic hormone, ghrelin has been little investigated. We examined plasma levels of ghrelin and blood glucose after intravenous (iv) injection of Ucn 1, the CRF receptor subtype involved and underlying mechanisms in ad libitum fed rats equipped with a chronic iv cannula. Ucn 1 (10 μg/kg, iv) induced a rapid onset and long lasting increase in ghrelin levels reaching 68% and 219% at 0.5 and 3 h post injection respectively and a 5-h hyperglycemic response. The selective CRF₂ agonist, Ucn 2 (3 μg/kg, iv) increased fasting acyl (3 h: 49%) and des-acyl ghrelin levels (3 h: 30%) compared to vehicle while the preferential CRF₁ agonist, CRF (3 μg/kg, iv) had no effect. <!-- no-mfc -->Ucn 1's<!-- /no-mfc --> stimulatory actions were blocked by the selective CRF₂ antagonist, astressin₂-B (100 μg/kg, iv). Hexamethonium (10 mg/kg, sc) prevented Ucn 1-induced rise in total ghrelin levels while not altering the hyperglycemic response. These data indicate that systemic injection of Ucns induces a CRF₂-mediated increase in circulating ghrelin levels likely via indirect actions on gastric ghrelin cells that involves a nicotinic pathway independently from the hyperglycemic response.     

Peripheral adrenomedullin inhibits gastric emptying through CGRP8-37 -sensitive receptors and prostaglandins pathways in rats

The effects of intravenous (iv) adrenomedullin (AM) on gastric emptying were investigated in conscious rats. AM induced a maximal 50% inhibition of gastric emptying at a dose of 1.2 nmol/kg. AM was about two-fold less potent than alpha-calcitonin gene-related peptide (alpha-CGRP), which induced a similar 50% maximal inhibition of gastric emptying at 0.6 nmol/kg. Delayed gastric emptying induced by i.v. AM and alpha-CGRP was prevented by peripheral injection of the selective CGRP1 antagonist, CGRP8-37, and by pretreatment with indomethacin, while not altered by blockade of the sympathetic nervous system with propranolol. These data indicate that peripheral AM inhibits gastric emptying through the interaction with CGRP8-37 -sensitive receptors, likely CGRP1 receptors, and the recruitment of prostaglandin-dependent mechanisms.     

Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers

Leptin regulates energy homeostasis and body weight by balancing energy intake and expenditure. It was recently reported that leptin, released into the gut lumen during the cephalic phase of gastric secretion, is capable of initiating intestinal nutrient absorption. Vagal afferent neurons also express receptors for both CCK and leptin, which are believed to interact in controlling food intake. The present study was undertaken to investigate the central and peripheral effects of leptin on gastric emptying rate. Under anesthesia, male Sprague-Dawley rats (250-300 g) were fitted with gastric Gregory cannulas (n=12) and some had additional cerebroventricular cannulas inserted into their right lateral ventricles. Following recovery, the rate of gastric emptying of saline (300 mOsm/kg H(2)O) was determined after instillation into the gastric fistula (3 ml, 37 degrees C, containing phenol red, 60 mg/l as a non-absorbable dilution marker). Gastric emptying rate was determined from the volume and phenol red concentrations recovered after 5 min. Leptin, injected intraperitoneally (i.p.; 10, 30, 60, 100 microg/kg) or intracerebroventricularly (i.c.v.; 5, 15 microg/rat) 15 min before the emptying, delayed gastric emptying rate of saline at the dose of 30 microg/kg or 15 microg/rat (p<0.001). When CCK(1) receptor blocker L-364,718 (1 mg/kg, i.p.), CCK(2) receptor blocker L-365,260 (1 mg/kg, ip) or adrenergic ganglion blocker bretylium tosylate (15 mg/kg, i.p.) was administered 15 min before ip leptin (30 microg/kg) injections, leptin-induced delay in gastric emptying was abolished only by the CCK(1) receptor blocker (p<0.001). However, the inhibitory effect of central leptin on gastric emptying was reversed by adrenergic blockade, but not by either CCK antagonists. Our results demonstrated that leptin delays gastric emptying. The peripheral effect of leptin on gastric motility appears to be mediated by CCK(1) receptors, suggesting the release of CCK and the involvement of vagal afferent fibers. On the other hand, the central effect of leptin on gastric emptying is likely to be mediated by adrenergic neurons. These results indicate the existence of a functional interaction between leptin and CCK receptors leading to inhibition of gastric emptying and short-term suppression of food intake, providing an additional feedback control in producing satiety.     

Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats

Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU-28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (AT(1)R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of AT(1)R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in AT(1)R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on AT(1)R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (AT(1)R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.     

Discovery of Substituted Human Urocortin 1 Analogs with Improved CRF2 Receptor Selectivity and Increased Efficacy in Preventing Skeletal Muscle Atrophy

We have identified specific amino acid modifications of human Urocortin 1 (hUCN1) that lead to highly potent and selective Corticotropin Releasing Factor Receptor 2 (CRF2R) agonists that are efficacious in preventing skeletal muscle atrophy in animal models. We have demonstrated that the CRF2R versus CRF1R selectivity can be increased by modifying the 40 amino acid hUCN1 at amino acid positions 11, 12, 13, 35 and 39. Further improvement in drug properties, including reduced binding to the CRF binding protein, improved solubility, and improved in vivo potency, were achieved by modifying amino acids at positions 22, 23, 36, and 40. In vivo investigations of selected optimized hUCN1 analogs demonstrated significant anti-atrophy efficacy in a mouse casting model of hind leg muscle disuse atrophy.     

Mild irritant prevents ethanol-induced gastric mucosal microcirculatory disturbances through actions of calcitonin gene-related peptide and PGI2 in rats

Pretreatment with a mild irritant such as 1 M NaCl prevented ethanol-induced mucosal injury, which was abolished by indomethacin, suggesting involvement of endogenous PGs. With the use of intravital microscopy, we investigated the mechanism in microcirculation whereby a mild irritant prevents ethanol-induced mucosal injury. Microcirculation of the basal part of gastric mucosa in anesthetized rats was observed through a window with transillumination. Diameters of arterioles, collecting venules, and venules were measured with an electric microscaler. One molar NaCl alone caused dilation of arterioles and constrictions of collecting venules and venules, which were inhibited by indomethacin. Ethanol (50%) applied to mucosa constricted collecting venules and venules but dilated arterioles. Constriction of collecting venules resulted in mucosal congestion. Pretreatment with 1 M NaCl inhibited ethanol-induced constrictions of collecting venules and venules, and administration of indomethacin or a calcitonin gene-related peptide (CGRP) antagonist, CGRP-(8-37), abolished elimination of constrictions. Topical application (1 nM-10 microM) of PGE2 or beraprost sodium (a PGI2 analog) to microvasculature markedly and dose-dependently dilated arterioles, whereas that of PGE2, but not beraprost, slightly constricted collecting venules. Pretreatment of microvasculature with a nonvasoactive concentration of PGE2 (100 nM) or beraprost (1 nM) completely inhibited ethanol-induced constriction of collecting venules. The inhibitory effect of beraprost but not of PGE2 was abolished by CGRP-(8-37). Present results suggest that the mechanism whereby 1 M NaCl prevents ethanol-induced injury is elimination of constrictions of collecting venules and venules by CGRP whose release may be enhanced by PGI2 but not by PGE2.     

Comparison of the inhibitory effects of PYY(3-36) and PYY(1-36) on gastric emptying in rats

We compared the effects of the two molecular forms of the brain-gut peptide YY (PYY), PYY(1-36) and PYY(3-36), on gastric emptying. Unanesthetized rats received 20-min intravenous infusions of rat PYY(1-36) (0, 1.7, 5, 17, 50, 100, 170 pmol x kg(-1) x min(-1)) and rat PYY(3-36) (0, 0.5, 1.7, 5, 17, 50, 100, 170 pmol x kg(-1) x min(-1)), either alone or combined, and gastric emptying of saline was measured during the last 10 min of infusion. For comparison, human PYY(3-36) was administered at 0, 17, and 50 pmol x kg(-1) x min(-1). Gastric emptying was decreased by 11, 24, 26 and 38% in response to 17, 50, 100, and 170 pmol x kg(-1) x min(-1) of rat PYY(1-36); by 10, 26, 41, 53, and 57% in response to 5, 17, 50, 100, and 170 pmol x kg(-1) x min(-1) of rat PYY(3-36); and by 35 and 53% in response to 17 and 50 pmol x kg(-1) x min(-1) of human PYY(3-36), respectively. Estimated ED50s were 470 and 37 pmol x kg(-1) x min(-1) for rat PYY(1-36) and PYY(3-36), respectively. In general, within an experiment, coadministration of PYY(1-36) and PYY(3-36) inhibited gastric emptying by an amount that was comparable to that produced when either peptide was given alone. We conclude that 1) intravenous infusion of PYY(1-36) and PYY(3-36) each produces a dose-dependent inhibition of gastric emptying in rats, 2) PYY(3-36) is an order of magnitude more potent than PYY(1-36) in inhibiting gastric emptying, 3) human PYY(3-36) and rat PYY(3-36) inhibit gastric emptying similarly, and 4) PYY(1-36) and PYY(3-36) do not appear to interact in an additive or synergistic manner to inhibit gastric emptying.     

Human T cell responses to IL-1 and IL-6 are dependent on signals mediated through CD2.

We investigated the involvement of IL-1 and IL-6 in activation of resting human T lymphocytes via the Ti-Ag receptor/CD3-dependent and the CD2-dependent pathways, respectively. When lymphocytes were triggered through CD3-Ti, neither IL-1 nor IL-6 nor the combination of both cytokines was capable of inducing a proliferative response, whereas addition of monocytes or IL-2 to such a system mediated DNA synthesis and cellular mitosis. In contrast, in the presence of submitogenic concentrations of mAb directed at CD2, IL-1 and/or IL-6 produced marked comitogenic dose-dependent effects. Moreover, although the action of IL-1 was clearly dependent on expression of the IL-2/IL-2R system, proliferation to CD2 antibody plus IL-6 could not be blocked by mAb directed at the IL-2R and/or IL-4. T cell responsiveness to both IL-1 and IL-6 was facilitated in the presence of CD58-like signals as delivered by human rCD58, SRBC or a mAb (anti-T111A), which binds to an interaction site for CD58 on the human CD2 molecule. These findings indicate that CD2 and its ligand CD58 play an important role in T cell/monocyte interactions during primary immune responses by means of upregulating T cell susceptibility to monocyte-derived cytokines.     

NOVA1 acts on Impact to regulate hypothalamic function and translation in inhibitory neurons

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Capsaicin-sensitive vagal fibres and 5-HT3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat.

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28+/-0.09 ml/5 min; P < 0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82+/-0.09 vs. 2.38+/-0.04 ml/5 min; P < 0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 microg/kg) significantly reversed (2.56+/-0.14 ml/5 min; P < 0.05 and 2.61+/-0.07 ml/5 min; P < 0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56+/-0.07 ml/5 min; P < 0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95+/-0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT3 and CCK-A receptors, but not CCK-B receptors.     

Effect of insulin on alpha1-adrenergic actions in hepatocytes from euthyroid and hypothyroid rats. Possible involvement of two pathways in alpha1-adrenergic actions

The effect of insulin on the alpha1-adrenergic stimulation of glycogenolysis and ureogenesis, which is very small or undetectable in hepatocytes from control animals, is marked in hepatocytes from hypothyroid rats; the metabolic actions due to alpha1-adrenergic activation, but not those due to glucagon, were nearly blocked by insulin in cells from hypothyroid rats. The alpha1-adrenergic-mediated stimulation of phosphatidylinositol labelling was not affected by insulin in cells from either control or hypothyroid rats. The data suggest that the alpha1-adrenergic action proceeds through two pathways, one of which is very sensitive to insulin and predominates in cells from hypothyroid rats.     

The effects of gastric inhibitory polypeptide and insulin on fatty acid uptake in adipose tissue are not mediated through cyclic AMP in lean and obese Zucker rats

To determine the mechanism by which gastric inhibitory polypeptide (GIP) and insulin stimulate the in vitro fatty acid incorporation into adipose tissue (FIAT), we measured the cyclic AMP variations and FIAT in epididymal fat pads of lean Fa/-- and obese fa/fa Zucker rats. GIP was used at 1, 2 and 4 ng/ml and insulin at a concentration of 100 microU/ml. There was no significant variation of cAMP when FIAT was stimulated either by GIP, either by insulin or by both hormones. There was no correlation at all between FIAT increases and cAMP levels. We conclude that GIP and insulin act through cAMP independent mechanisms in adipose tissue. The modification by GIP of insulin binding to adipocytes or an easier passage of fatty acids through the membrane could constitute alternative solutions for such mechanisms.     

Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors

We demonstrated that prostaglandin (PG) E2 aggravates gastric mucosal injury caused by histamine in rats, and investigated using various EP agonists which EP receptor subtype is involved in this phenomenon. Rats were used after 18 hr fasting. Histamine (80 mg/kg) dissolved in 10% gelatin, was given s.c., either alone or in combination with i.v. administration of PGE2 or various EP agonists such as 17-phenyl PGE2 (EP1), butaprost (EP2), sulprostone (EP1/EP3), ONO-NT012 (EP3) and ONO-AE1-329 (EP4). The animals were killed 4 hr later, and the mucosa was examined for lesions. The mucosal permeability was determined using Evans blue (1%). Histamine alone induced few lesions in the gastric mucosa within 4 hr. PGE2 dose-dependently worsened the lesions induced by histamine, the response being inhibited by tripelennamine but not cimetidine. The effect of PGE2 was mimicked by 17-phenyl PGE2 and sulprostone, but not other EP agonists, including EP2, EP3, and EP3/EP4 agonists. The mucosal vascular permeability was slightly increased by histamine, and this response was markedly enhanced by co-administration of 17-phenyl PGE2 as well as PGE2. The mucosal ulcerogenic and vascular permeability responses induced by histamine plus PGE2 were both suppressed by pretreatment with ONO-AE829, the EP1 antagonist. These results suggest that PGE2 aggravates histamine-induced gastric mucosal injury in rats. This action of PGE2 is mediated by EP1 receptors and functionally associated with potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.