Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Cellular localization of ovarian histamine, its cyclic variations, and histaminergic effects on ovulation in the rat ovary perfused in vitro

Mast cells, visualized with toluidine blue staining and the Falck-Hillarp fluorescence technique, were mainly located around large blood vessels in the hilus region of the ovary in adult rats and in immature rats treated with PMSG. Histamine concentration in the rat ovary was significantly reduced after the LH surge in PMSG-treated animals, corresponding to a reduced number of ovarian mast cells. No marked change in the number of mast cells and histamine concentration was found in adult rats during the oestrous cycle. Histamine as well as the H1-agonist, 2-methylhistamine, and the H2-agonist, 4-methylhistamine, induced ovulations in the isolated perfused rat ovary. Ovulation rates were significantly lower than those evoked by LH. The histamine liberator, Compound 48/80, induced ovulations which were blocked by the combined effect of the H1- and H2-histamine receptor antagonists, cimetidine and pyrilamine. The anti-degranulating agent, disodium cromoglycate, did not block ovulations induced by Compound 48/80. The results show that the level of ovarian histamine, which is primarily stored in mast cells, can be influenced by PMSG treatment, and that the amine is able to induce ovulations in gonadotrophin-primed rats by an effect mediated by both H1 and H2 receptors.     

Histamine releases PGI2 from human pulmonary artery

Histamine caused a triphasic response of human pulmonary artery strips in vitro, consisting of a small initial contraction followed by pronounced relaxation preceding a second contractile response. These characteristics were not seen with other contractile stimuli including 5-hydroxytryptamine, leukotriene D4, and KCl. The relaxant component of this response was ablated by removal of endothelium from the vascular strips or by pretreatment of the tissue with 1 microM indomethacin. Measurement of the PGI2 degradation product 6-keto-PGF1 alpha in supernatants from histamine-challenged tissues confirmed the synthesis of PGI2. Supernatants from unstimulated or leukotriene-challenged tissues contained no detectable amounts of 6-keto-PGF1 alpha. The histamine H1 antagonist diphenydramine inhibited both the contractile and relaxant responses to histamine whereas the H2 antagonist cimetidine affected neither component. The released PGI2 significantly altered the dose-response curve to histamine without inhibiting the maximal contractile responses. We conclude that histamine induces PGI2 formation from pulmonary arterial endothelium via an H1 receptor.     

Histamine H2 receptor mediated relaxation of hamster (Mesocricetus auratus) uterus

Histamine and 4-methyl histamine produced relaxation of KCl depolarized hamster uterus in vitro. The relaxation was selectively antagonized by histamine H2 receptor antagonist cimetidine which failed to antagonize the isoprenaline induced relaxation. The histamine induced relaxation was, further, not mediated through catecholamine release. The study indicated that, as in the albino rat, histamine produces relaxation of the hamster uterus mediated via the H2 receptors.     

Histamine modulates the production of interferon-gamma and interleukin-2 by mitogen-activated human mononuclear blood cells

Histamine inhibited the production of interferon-gamma and interleukin 2 (IL-2) induced in human peripheral blood mononuclear cells by Staphylococcal Enterotoxin A (SEA) but had no effect on the expression of IL-2 receptors. The effects on lymphokine production were dose dependent with maximal inhibition occurring at histamine concentrations of 10(-4) to 10(-6) M. The H2-agonist 4-methylhistamine but not the H1-agonist 2-methylhistamine modulated lymphokine production in a similar manner as histamine. Histamine at concentrations of 10(-3) to 10(-8) M had no inhibitory effect directly on the activity of admixed IL-2 containing medium. The inhibitory effects of histamine could be reversed by the H2-antagonist cimetidine but not by the H1-antagonist diphenhydramine. This indicates that the inhibitory effects of histamine on lymphokine production are mediated through H2-receptors on mononuclear cells.     

Regulation of Norepinephrine Release from Isolated Bovine Irides by Histamine

In the present study, we investigated the effect of histamine on sympathetic neurotransmission from isolated, superfused bovine irides. We also studied the pharmacology of prejunctional histamine receptors that regulate the release of norepinephrine (NE) from this tissue. The effect of exogenous histamine and various histamine receptor agonists was examined on the release of [³H]-norepinephrine ([³H]NE) triggered by electrical field stimulation using the Superfusion Method. Histamine receptor agonists caused a concentration-dependent inhibition of field-stimulated [³H]NE overflow with the following rank order of potency: imetit > histamine > R-α-methylhistamine. In all cases, the inhibitory action of histamine receptor agonists was attenuated at high concentrations of these compounds. The histamine receptor antagonists, clobenpropit (H₃-antagonist/H₄-agonist) and thioperamide (H₃-antagonist) blocked the inhibitory response elicited by R-α-methylhistamine and imetit, respectively. Inhibitory effects of R-α-methylhistamine and clonidine were not additive suggesting that prejunctional H₃- and α₂-adrenoceptors coexist at neurotransmitter release sites. We conclude that histamine produces an inhibitory action on sympathetic neurotransmission in the bovine iris, an effect mimicked by selective H₃-receptor agonists and blocked by H₃-antagonists.     

Histamine agonist and antagonist drugs: interference with CNS control of GH release in rats

The effects of the administration into the brain ventricle of histamine, selective H1- and H2-receptor agonists and antagonists and chemically similar substances with nonspecific activity on basal and morphine-stimulated growth hormone (GH) secretion in normal male rats were studied. None of the drugs had any significant effect on baseline rat GH levels, but histamine and H1 agonists were able to decrease the rat GH release evoked by morphine. Mepyramine (H1 antagonist) had no consistent effect by itself but was effective in preventing the inhibitory action of 2-methylhistamine (H1 agonist). H2 agonists and antagonists and their chemical analogues were all inhibitory, but by a mechanism which is nonspecific and must be interpreted cautiously. These results confirm the inhibitory effect of histamine on rat GH release and indicate that H1 receptors in the CNS are responsible for this effect.     

Histamine is a potent inducer of IL-18 and IFN-gamma in human peripheral blood mononuclear cells

Histamine (10-7 to 10-4 M) concentration-dependently stimulated the production of IL-18 and IFN-gamma and inhibited the production of IL-2 and IL-10 in human PBMCs. Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of histamine on cytokine production were all antagonized by H2 receptor antagonists ranitidine and famotidine in a concentration-dependent manner, but not by H1 and H3 receptor antagonists. Selective H2 receptor agonists, 4-methylhistamine and dimaprit, mimicked the effects of histamine on five kinds of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 microM, respectively. These findings indicated that histamine caused cytokine responses through the stimulation of H2 receptors. All effects of histamine on cytokine responses were also abolished by the presence of either anti-IL-18 Ab or IL-1beta-converting enzyme/caspase-1 inhibitor, indicating that the histamine action is dependent on mature IL-18 secretion and that IL-18 production is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependently stimulated IL-12 and IFN-gamma production and inhibited the IL-2 and IL-10 production. IFN-gamma production induced by IL-18 was inhibited by anti-IL-12 Ab, showing the marked contrast of the effect of histamine. Thus histamine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18-initiating cytokine cascade without inducing IL-12 production.     

Formation of ovarian follicular cysts and corpora lutea after treatment with antihistamine or indomethacin in prepubertal gilts

Roles of histamine and prostaglandins in the induction of ovarian cysts after unilateral ovarian manipulation (MAN) and in the process of ovulation were evaluated in prepubertal gilts treated with pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG). Administration of pyrilamine maleate, an H1 receptor antagonist, before MAN or hCG injection reduced the number of cysts formed but did not alter ovulation rate. Administration of cimetidine, an H2 receptor antagonist, failed to alter the incidence, number, or diameters of cysts formed in response to MAN or the ovulation rate on non-MAN ovaries. Administration of indomethacin, an inhibitor of prostaglandin synthesis, before MAN or hCG injection did not alter the incidence, number, or diameters of cysts formed on MAN ovaries but reduced the number of corpora lutea on non-MAN ovaries. Excessive accumulation of fluid in ovarian cysts apparently was mediated by histamine interacting with the H1-type receptor. Enhanced secretion of prostaglandins produced by the cyclooxygenase pathway did not contribute to development of ovarian cysts but, unlike histamine, was required for formation of corpora lutea in prepubertal gilts treated with PMSG and hCG.     

Evidence of histamine receptor function in isolated horse penile dorsal arteries

The effect of histamine (10(-9)-10(-3) M) on horse penile dorsal artery was evaluated. Precontracted vessels showed a biphasic response (relaxation-contraction) to histamine, while at basal tone, histamine only induced a contractile effect. The H1 receptor agonist, 2-pyridylethylamine (PEA) (10(-9)-10(-3) M), induced concentration-dependent relaxation in precontracted rings and provoked vasoconstriction at basal tone. Mepyramine (10(-9)-10(8) M), an H1 receptor antagonist, competitively antagonized the relaxant response to histamine (pA2 = 9.7) and PEA (pA2 = 9.2). At basal tone, mepyramine (10(-10)-10(-8) M) also caused a rightward shift in the histamine contraction curve (pA2 = 10.1). Mepyramine (10(-9)-10(-8) M)/PEA Schild plots for resting vessels yielded a pA2 value of 9.4. A regulatory role for H2 and H3 receptors was precluded since there was no response to their agonists (dimaprit (10(-9)-10(-3) M), (R)-alpha-methylhistamine (10(-10)- 3 x 10(-4) M)), and antagonists (cimetidine (10(-5) M), thioperamide (10(-6) M)) did not affect control curves. Removal of the endothelium abolished the relaxant component causing a leftward shift in the contractile component in precontracted rings, with no effect on maximum contraction. Inhibitors of nitric oxide (NO) synthesis, L-NAME (3 x 10(-4) M) and L-NOARG (3 x 10(-4) M), modified the relaxant response while contraction was unaffected. L-Arginine (3 x 10(-4) M) potentiated maximum relaxation but did not affect contraction in precontracted rings. Effects of a prostanoid and K+ channels were ruled out. The biphasic response of precontracted vessels persisted in the presence of indomethacin (3 x 10(-6) M), tetraethylammonium (10(-3) M) and gliblenclamide (10(-5) M). L-NAME plus indomethacin, or this combination plus TEA or glibenclamide produced similar effects as isolated treatments. In resting vessels, histamine contraction was also unaffected by the lack of endothelium, or L-NAME, L-arginine or indomethacin pretreatment. The biphasic response to histamine is probably mediated by H1 receptors with a partial role for NO in the relaxant response in precontracted vessels. In the absence of tone, the contractile effect may be mediated by direct action on smooth muscle.     

Effect of histamine and histamine blockers on the ovulatory process in the vitro perfused rabbit ovary

An increase in the content of histamine in the ovary following luteinizing hormone (LH) release and the inhibition of ovulation in the rabbit by antihistamines suggest that histamine may be involved in the ovulatory process. The effects of various doses of histamine and antihistamines on ovulation were investigated using the in vitro perfused rabbit ovary system. Histamine (100 ng/ml) added to the perfusate at hourly intervals induced ovulation, although at a rate below that observed following human chorionic gonadotropin (hCG) administration. Cimetidine (10 micrograms/ml), an H2 blocker, inhibited histamine-induced ovulation, while the H1 blocker, chlorpheniramine (66.7 micrograms/ml), failed to do so. Neither cimetidine nor chlorpheniramine was able to block ovulation following hCG (50 IU). In all experimental groups in which histamine was used to induce ovulation, both extruded ova and follicular oocytes remained in an immature stage and displayed little evidence of degeneration. In contrast, a high percentage of ova exposed to hCG were mature. Ovarian edema was increased in ovaries in which ovulation occurred, regardless of treatment. A linear correlation was noted between ovulatory efficiency and degree of ovarian edema. Histamine may be an intermediary in the mechanism of follicular rupture, but does not support ovum maturation. However, the inability of H1 and H2 antagonists to block hCG-induced ovulation raises questions regarding the role of histamine in the physiologic process of ovulation.     

Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes

Aims

The diverse physiological functions of histamine are mediated through distinct histamine receptors. In this study we investigated the role of H₂R and H₄R in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood.

Main methods

Changes in reactive oxygen species (ROS) production by whole blood phagocytes after treatment with histamine, H₄R agonists (4-methylhistamine, VUF8430), H₂R agonist (dimaprit) and their combinations with H₄R antagonist (JNJ10191584) and H₂R antagonist (ranitidine) were determined using the chemiluminescence (CL) assay. To exclude the direct scavenging effects of the studied compounds on the CL response, the antioxidant properties of all compounds were measured using several methods (TRAP, ORAC, and luminol–HRP–H₂O₂ based CL).

Key findings

Histamine, 4-methylhistamine, VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner. On the other hand, only VUF8430 was able to inhibit PMA-activated whole blood CL. Ranitidine, but not JNJ10191584, completely reduced the effects of histamine, 4-methylhistamine and dimaprit. The direct scavenging ability of tested compounds was negligible.

Significance

Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by H₂R. Our results also suggest that H₄R agonists in concentrations higher than 10^− 6 M may also influence ROS production via binding to H₂R.     

Accelerated communication H1 contractile and H2 relaxant receptors in canine gastric muscularis mucosae

Histamine had two effects on the contractility of canine gastric muscularis mucosae in vitro: relaxation at or below 10 μM and contraction at higher concentrations. Selective agonists and antagonists were used to test the possibility that these effects were mediated by different receptor subtypes. The H₁-selective agonist 2-pyridylethylamine (2-PEA) and the H₂-selective agonist dimaprit contracted and relaxed this muscle, respectively, while the H₃-selective agonist R-α-methylhistamine had no effect. The H₁- and H₂-selective antagonists mepyramine and ranitidine selectively blocked 2-PEA-mediated contractions and dimaprit-mediated relaxations, respectively. Agonist responses, were unaltered by tetrodotoxin, suggesting a site of action other than nerves. Our results indicate that canine gastric corpus muscularis mucosae possesses both contractile H₁ and relaxant H₂ receptors.     

Effect of histamine and cimetidine on retinal and choroidal blood flow in humans

Intravenous administration of histamine causes an increase in choroidal blood flow and retinal vessel diameter in healthy subjects. The mechanism underlying this effect remains to be elucidated. In the present study, we hypothesized that H2 receptor blockade alters hemodynamic effects of histamine in the choroid and retina. Eighteen healthy male nonsmoking volunteers were included in this randomized, double-masked, placebo-controlled two-way crossover study. Histamine (0.32 microg.kg(-1).min(-1) over 30 min) was infused intravenously in the absence (NaCl as placebo) or presence of the H2 blocker cimetidine (2.3 mg/min over 50 min). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of cimetidine or placebo, and after coinfusion of histamine. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser-Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser-Doppler velocimetry. Histamine increased subfoveal choroidal blood flow (+14 +/- 15%, P < 0.001), fundus pulsation amplitude (+11 +/- 5%, P < 0.001), retinal venous diameter (+3.0 +/- 3.6%, P = 0.002), and retinal arterial diameter (+2.8 +/- 4.2%, P < 0.01) but did not change retinal blood velocity. The H2 antagonist cimetidine had no significant effect on ocular hemodynamic parameters. In addition, cimetidine did not modify effects of histamine on choroidal blood flow, fundus pulsation amplitude, retinal venous diameter, and retinal arterial diameter compared with placebo. The present data confirm that histamine increases choroidal blood flow and retinal vessel diameters in healthy subjects. This ocular vasodilator effect of histamine is, however, not altered by administration of an H2 blocker. Whether the increase in blood flow is mediated via H1 receptors or other hitherto unidentified mechanisms remains to be elucidated.     

Histamine releases PGI2 from human pulmonary artery

Histamine caused a triphasic response of human pulmonary artery strips in vitro, consisting of a small initial contraction followed by pronounced relaxation preceding a second contractile response. These characteristics were not seen with other contractile stimuli including 5-hdyroxytryptamine, leukotriene D₄, and KC1. The relaxant component of this response was ablated by removal of endothelium from the vascular strips or by pretreatment of the tissues with 1μM indomethacin. Measurement of the PGI₂ degradation product 6-keto-PGF_1α in supernatants from histamine-challenged tissues confirmed the synthesis of PGI₂. Supernatants from unstimulated or leukotriene-challenged tissues contained no detectable amounts of 6-keto-PGF_1α. The histamine H₁ antagonist diphenhydramine inhibited both the contractile and relaxant responses to histamine whereas the H₂ antagonist cimetidine affected neither component. The released PGI₂ significantly altered the dose-respons curve to histamine without inhibiting the maximal contractile responses. We conclude that histamine induces PGI₂ formation from pulmonary arterial endothelium via an H₁ receptor.     

Histamine regulates the generation of human cytolytic T lymphocytes

Human cytolytic T lymphocytes (CTL) were generated in the presence and absence of histamine in order to define the role of this autacoid in immune regulation. Histamine (10(-8)-10(-4) M) suppressed the generation of class I specific CTL but, at 10(-4) M, actually increased class II specific cytolysis. Histamine acted at the level of CTL generation; histamine was not present in the cytolytic assay. When histamine was added to the cytolytic assay with CTL grown without histamine, the lytic ability of the effector cells was similar to that of controls. Histamine-induced suppression of class I specific cytolysis was blocked by continuous culture with the H2 antagonist ranitidine but not with the H1 antagonist pyrilamine. These data suggest that suppression was mediated by the H2 receptor. Continuous culture with histamine had no effect on T cell proliferation or the expression of cell surface molecules. Histamine-induced suppression of class I specific cytolysis was reversed by the addition of PHA to the cytotoxicity assay, showing that the cytolytic machinery was intact. These data provide evidence that histamine is involved in regulation of cytolytic T cells.     

Further characterization of the receptors involved in the positive inotropic effect of histamine on rabbit papillary muscle

The effects of histamine on the force of contraction and calcium-dependent action potentials were studied in rabbit ventricular papillary muscles. The positive inotropic effect of histamine seems to be dependent on stimulation of H1 and H2 receptors. The H1 antagonist chlorpheniramine produced a competitive blockade of the positive inotropic effects of histamine. Cimetidine produced a competitive blockade, which was apparent only after blockade of H1 receptors. Histamine increased the maximum upstroke velocity of slow action potentials. This effect can be entirely accounted for by stimulation of H2 receptors. The phosphodiesterase inhibitor 3-isobutyl-methyl-xanthine potentiated the H2 receptor mediated effects of histamine on the force of contraction and slow action potentials. We conclude that rabbit ventricular muscle possesses both H1 and H2 receptors that mediate the positive inotropic effect of histamine. The H2-mediated effect seems to be causally related to an increase in the calcium slow inward current and is probably linked to an enhanced cellular cyclic adenosine monophosphate content. The mechanism of the H1-mediated positive inotropic effect remains unknown.     

Localization and hormonal regulation of ovarian production of histamine in the sheep

Concentrations of histamine were measured within the follicular wall, follicular fluid and ovarian interstitium throughout the periovulatory period in sheep. Histamine within follicular tissue declined after the onset of the preovulatory surge of luteinizing hormone (LH) and remained low until after ovulation, when levels then increased markedly. Alterations in histamine within the follicular wall were not reflected by corresponding changes within follicular fluid or ovarian interstitium. Release of histamine from tissue during short-term incubation was greatest for follicles obtained after ovulation, which was not influenced by presence of LH in the incubation medium. Luteinizing hormone caused depletion of stores of histamine from the wall of follicles collected before the preovulatory surge of LH. Histamine could act as a paracrine mediator in the follicular mechanisms of ovulation and(or) luteinization.     

Histamine Stimulation of Cyclic AMP Accumulation in Astrocyte-Enriched and Neuronal Primary Cultures from Rat Brain

Histamine stimulates cyclic AMP accumulation in astrocyte-enriched and neuronal primary cultures from rat brain in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine. The response in the astrocyte cultures (Emax = 304 +/- 44% over basal, EC50 = 43 +/- 5 microM) was much higher than in neuronal cultures (Emax = 24 +/- 2%, EC50 = 14 +/- 7 microM). The histamine effect in astrocytes was competitively inhibited by the H2 antagonists cimetidine (Ki = 1.1 +/- 0.2 microM) and ranitidine (Ki = 46 +/- 10 nM) but was insensitive to the H1 antagonist mepyramine (1 microM). The two selective H2 agonists impromidine and dimaprit behaved as partial agonists and showed relative potencies (139 and 0.5, respectively) consistent with an interaction with H2 receptors. The more selective H1 agonist 2-thiazolylethylamine (0.01-1 mM) did not potentiate the response to impromidine (10 microM). Thus, in contrast to what is generally observed in intact cell preparations from brain, the histamine-induced cyclic AMP accumulation in astroglial cells is mediated solely by H2 receptors. The small effect shown in neuronal cultures also appears to be mediated by H2 receptors.     

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.