In vitro and inhibition of anaphylactic reactions 1-methyl-3-isobutylxanthine]

1-methyl-3-isobutylxanthine (MIBX), a potent antiphosphodiesterase drug, inhibited the anaphylactic reactions both in vitro and in vivo: anaphylactic histamine release from the isolated mast cells of rats, anaphylactic contracture of the isolated trachea of guinea pigs, passive cutaneous anaphylaxis (PCA) in mice and anaphylactic bronchial constriction (ABC) in guinea pigs. MIBX inhibited the anaphylactic reaction of the trachea, PCA and ABC more than the corresponding reactions induced by histamine.     

Reduced anaphylactic responsiveness of strain 2 guinea pigs.

Strain 2 guinea pigs have been shown to have diminished anaphylactic responsiveness. In the present study, experiments were conducted comparing various characteristics of the anaphylaxis-resistant Strain 2 guinea pigs to those of an outbred anaphylaxis-prone Dunkin-Hartley strain. To bypass the possibility that differences in antibody titers accounted for the difference in anaphylactic reactivity, both strains of guinea pig were passively sensitized with the same amount of IgG antibody to ovalbumin. Measures of anaphylactic responsiveness to subsequent antigen challenge with ovalbumin included (i) systemically induced respiratory responses; (ii) isolated cardiac responses; and (iii) cutaneous responses. In all cases, using an amount of antibody sufficient to sensitize Dunkin-Hartley guinea pigs, the anaphylactic responses of the Strain 2 guinea pigs were either nonexistent or significantly less than those of the Dunkin-Hartley strain. To further determine which factors might be responsible for this difference, tissue histamine content, histamine releasability, and histamine responsiveness of the two strains were measured. The results of these studies indicated that the respiratory hyporesponsiveness of the Strain 2 guinea pigs may be due to a low pulmonary histamine content combined with reduced pulmonary responsiveness to histamine. However, since the cardiac histamine content and the responsiveness of the Strain 2 guinea pigs were not different from those of the Dunkin-Hartley strain, these factors cannot contribute to the reduced Strain 2 cardiac anaphylactic responsiveness. Compound 48/80 released equal quantities of histamine from the isolated hearts of the Strain 2 and the Dunkin-Hartley animals, but antigen challenge evoked histamine release only from the isolated Dunkin-Hartley hearts. We conclude that the cardiac anaphylactic hyporesponsiveness of the Strain 2 guinea pigs may be due to an inability of antigen to evoke release of anaphylactic mediators such as histamine.     

An extract of rat submandibular glands activates platelets and enhances cutaneous vascular permeability in rats and guinea pigs

Washed, [3H]serotonin-labeled platelets from rats and guinea pigs were stimulated in vitro with a novel protein extracted from rat submandibular salivary glands (RS-PAP) and with the phospholipid platelet- activating factor 1-0-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine (AGEPC). Rat platelets, which are refractory to AGEPC stimulation, underwent shape-change, aggregation and secretion of [3H]serotonin in response to graded doses of RS-PAP and AGEPC. Intradermal injections of histamine, RS-PAP and AGEPC caused a dose-related increase in local microvascular permeability in rats, as measured by the extravasation of plasma containing Evans blue dye. Similarly, histamine, RS-PAP and AGEPC increased cutaneous vascular permeability when injected intradermally in guinea pigs. The vascular permeability induced by histamine and RS-PAP, but not by AGEPC, was partially inhibited by pretreatment with an antihistamine (diphenhydramine HCl). Pretreatment of guinea pigs with captopril, an inhibitor of angiotensin-converting enzyme (ACE), partially inhibited cutaneous responses to subsequent intradermal injections of histamine, RS-PAP and AGEPC. Regardless of pretreatment with diphenhydramine or captopril, skin test sites injected with large amounts of RS-PAP became hemorrhagic within minutes and necrotic within 12 hours.     

Antiallergic/antiasthmatic effect of novel antiallergic hexapeptide-95/220 in various experimental models

The effects of newly synthesized antiallergic hexapeptide 95/220 was investigated on various allergic and asthmatic test models. This newly developed peptide was found to be more potent than clinically used drug disodium cromoglycate (DSCG). Hexapeptide 95/220 inhibited immediate hypersensitivity reactions such as passive cutaneous anaphylaxis (PCA) and mast cell degranulation in rats, antigen-induced bronchoconstriction in actively sensitized guinea pigs in dose dependent manner like DSCG. Antigen-induced contraction of guinea pig ileum was also markedly inhibited by this newly developed hexapeptide in the same fashion as ketotifen and DSCG did but at comparatively lower dose. Egg albumin-induced histamine release was also blocked by this hexapeptide from chopped lung tissues of sensitized guinea pigs. These results suggest that hexapeptide' 95/220 has potent inhibitory effect on immediate hypersensitivity reactions thereby inhibiting mediator release from mast cell. Moreover, this newly synthesized peptide is orally active and effective at lower doses as compared to standard drugs.     

A New Method for Extraction of Extravasated Dye in the Skin and the Influence of Fasting Stress on Passive Cutaneous Anaphylaxis in Guinea Pigs and Rats*

A method for quantitative extraction of extravasated dye from the skin was studied in guinea pigs and rats. A simple method with a low cost and good recovery was established as follows; A piece of the skin containing extravasated dye was soaked overnight in a stoppered glass tube containing 1 ml of 1 n KOH at 37 C. Then, 9 ml of a mixed solution of 0.6 n H₃PO₄ and acetone (5:13) was added to the tube. The tube was shaken vigorously for a few seconds and centrifuged at 3,000 rpm for 15 min. Absorbance of supernatant was measured at 620 nm. The recovery rate of the dye was about 95% both in guinea pigs and rats. Using this method we observed that fasting stress significantly reduced the intensity of skin reactions induced by chemical mediators, heterologous PCA and especially homologous PCA in guinea pigs.     

Prosopis juliflora pollen allergen induced hypersensitivity and anaphylaxis studies in guinea pigs

In vivo and in vitro allergenic activities of Prosopis juliflora pollen allergens were measured in guinea pigs. Intracutaneous skin test showed an early wheal flare response and a late erythema-redness, sensitized with various concentrations (100, 50, 25, 5 and 1.5 micrograms/ml) of Prosopis juliflora pollen extract after administration of a challenging dose. A 50 micrograms/ml sensitizing dose of Prosopis juliflora pollen allergen gave optimum skin response as both early and late effects. The nature of immunochemical reactivity between pollen allergens and reaginic antibodies were further characterized by histamine release test, gel diffusion test, radioallergosorbent test and passive cutaneous anaphylaxis test. These tests confirm allergenicity caused by Prosopis juliflora pollen allergens and showed the binding of allergens with reaginic antibody and its regulation in guinea pigs.     

Lack of adrenomedullin on antigen-induced bronchoconstriction in guinea pigs in vivo

Antigen challenge can provoke acute bronchoconstriction, recognized as immediate asthmatic response (IAR), but the evolving events in this reaction are not well defined. Recently, a novel peptide, designated adrenomedullin, was isolated from human pheochromocytoma, and has been shown to have potent systemic and pulmonary vasodilator activity.The purpose of this study was to elucidate the influence of adrenomedullin in the development of IAR. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride, and then artificially ventilated. Ovalbumin was inhaled after an intravenous administration of adrenomedullin. Other studies were performed in naive guinea pigs to investigate the airway responses to inhaled methacholine or histamine after an intravenous administration of adrenomedullin. Antigen challenge caused bronchoconstriction in sensitized guinea pigs. Adrenomedullin did not inhibit the antigen-induced bronchoconstriction in sensitized guinea pigs or the dose-dependent responses to inhaled methacholine or histamine in naive animals in spite of its vasodilating effect. We conclude that an intravenous administration of adrenomedullin does not influence antigen-induced bronchoconstriction or bronchial responsiveness to inhaled methacholine or histamine in vivo.     

The immunopathological effects of intracolonic injection of Mycobacterium bovis BCG cell wall emulsions in guinea pigs

Summary The immunological and pathological responses of guinea pigs to an intramural colonic injection of emulsions containing cell wall (CW) extracts of Mycobacterium bovis BCG and mineral oil were studied from week 1 to week 36 post-inoculation. The emulsions contained variable concentrations of BCG CW attached to (lipid-phase), or separate from (aqueous-phase), the mineral oil. Delayed cutaneous hypersensitivity to PPD was present throughout the course of the study in a variable percentage of guinea pigs inoculated with either type of emulsion. PPD-induced blast transformation of peripheral blood lymphocytes, studied in guinea pigs which received lipid-phase emulsion, was also detectable throughout the course of the study, with maximal response seen 2 weeks post-inoculation. The intracolonic inoculations were well tolerated, with the exception of the most concentrated lipid-phase emulsion (3 mg/ml BCG CW and 5% oil), after which one of eight guinea pigs died due to a colonic impaction and rupture at the site of inoculation. The pathological response to either type of emulsion was a focal granulomatous colitis, which tended to be more severe as the concentration of BCG CW and oil increased. Extracolonic lesions were usually limited to a granulomatous lymphadenitis of lymph nodes draining the injection site; however, the most concentrated lipid-phase emulsion occasionally produced granulomatous inflammatory foci in the liver and lungs. In general, the lesions induced by the lipid-phase emulsions were more severe than those induced by aqueous-phase emulsions, but the intensity of both types of lesions peaked at 2 or 4 weeks post-inoculation. It was concluded that the guinea pig may serve as a useful model to study BCG immunotherapy of colonic neoplasms, since intracolonic injection of BCG CW resulted in systemic immunity toward mycobacterial antigens and a localized accumulation of macrophages without untoward complications. The abbreviations used in this paper are: BCG CW, bacillus Calmette-Guérin cell walls; PPD, purified protein derivative; PBL, peripheral blood lymphocytes; cpm, counts per minute; SI, stimulation index; DCH, delayed cutaneous hypersensitivity     

IgG1 antibody-dependent mediator release after passive systemic sensitization of basophils arriving at cutaneous basophil hypersensitivity reactions

When antigen is injected into a 24-hr cutaneous basophil hypersensitivity (CBH) reaction of an actively sensitized guinea pig, local basophils degranulate and release histamine. This reaction is called cutaneous basophil anaphylaxis and may be antibody mediated. We now report passive sensitization of basophils at CBH sites by systemic transfer of anti-picryl immune serum. Keyhole limpet hemocyanin- (KLH) immunized animals were skin tested with KLH to elicit 24-hr CBH reactions at day 7. Anti-picryl serum was injected i.v. at various times. On day 7, blue dye was injected i.v., and then 24-hr CBH sites vs nearby normal skin were challenged with 0.1 microgram picryl-human serum albumin (Pic-HSA). An immediate increase in vascular permeability (blueing) was noted at normal skin sites due to systemic passive cutaneous anaphylaxis (PCA), and augmented blueing occurred at CBH sites compared with normal skin. Systemic passive sensitization of CBH sites occurred when antiserum was administered as little as 1 hr before challenge of CBH site. However, local administration of anti-picryl serum (as in a local PCA reaction) was not able to sensitize tissue basophils, whether antigen was administered locally or systemically. The serum factor that mediated cutaneous basophil anaphylaxis was heat-stable (56 degrees C X 4 hr) 7S IgG1 antibody. Electron microscopy of Pic-HSA-challenged CBH sites in animals that received IgG1 antibody showed that local basophils undergo anaphylactic degranulation by exocytosis. These studies suggest that basophils arriving at CBH reactions are sensitized for anaphylactic function by antibody that can be acquired in the circulation, but possibly not at the local site.     

哮喘豚鼠肺内ADM表达变化及对离体气管条张力的作用

目的：通过观察肾上腺髓质素（ADM）mRNA在豚鼠哮喘模型肺内的表达及对哮喘豚鼠离体气管条张力的影响,研究ADM在支气管哮喘（简称哮喘）发病机制中的作用。方法：用原位杂交方法检测ADM mRNA在豚鼠哮喘模型肺内的表达,用组胺诱导豚鼠离体气管条收缩后,观察不同浓度的ADM对其收缩作用影响。结果：原位杂交结果显示正常及哮喘豚鼠肺内均有ADM mRNA的表达,但哮喘组较正常组明显增多（P＜0．05）,ADM可抑制组胺诱导的哮喘豚鼠离体气管条的收缩,并呈量效关系,当浓度达10^-8mol/L时抑经达到最大,而且即使加大ADM的浓度,抑制率未继续明显增加,并对致敏气管螺旋条的舒张作用明显大于正常气管螺旋条。结论：哮喘时,肺内ADM mRNA的表达明显增多,ADM可抑制组胺诱导的豚鼠离体气管条的收缩,浓度为10^-8mol/L时抑制率达到最大。提示ADM在哮喘发病过程中起重要作用。     

Differential responsiveness of various substrains of inbred strain 2 guinea pigs to immunotherapy with the methanol extraction residue (MER) of BCG

Summary The immunotherapeutic effects of the methanol extraction residue (MER) of BCG were investigated in strain 2 guinea pigs bearing the transplantable line 10 hepatocarcinoma, a tumor originally induced in guinea pigs at the National Institutes of Health (NIH) by ingestion of the carcinogen diethylnitrosamine. MER was more effective in mediating tumor regression in guinea pigs obtained from the Weizmann Institute of Science (WI), Rehovot, Israel, than in animals obtained from the National Institutes of Health (NIH). These differences indicate the dramatic effects which minor histoincompatibilities between cancer cells and animal substrains may have on experimental results, and highlight the need for immunotherapy experiments to be conducted on laboratory tumors grown in their autochthonous hosts. MER was effective only when injected directly into growing tumor nodules and had no effect on tumor development when administered distally. In contrast, all animals which received both MER and tumor cells developed specific cell-mediated anti-tumor immune responsiveness at higher levels than did non-MER-treated tumor-bearing controls as measured by delayed cutaneous hypersensitivity and in vitro lymphocyte reactivity experiments. Furthermore, the results of the latter but not the former studies suggested that guinea pigs which received MER were able to mount such an immune response more rapidly than their non-treated counterparts. This apparent stimulation of anti-tumor immunity was observed in treated animals regardless of substrain or site of MER injection, and could not be correlated with the outcome of immunotherapy.     

IgE antibody-mediated cutaneous basophil hypersensitivity reactions in guinea pigs

Cutaneous basophil hypersensitivity (CBH) reactions are a heterogeneous group of delayed time course basophil-rich immune responses that can be mediated in the guinea pig by T cells, B cells, or IgG1 antibody. This study examined whether guinea pig IgE antibody could also mediate CBH reactions. IgE antibody to picryl or oxazolone determinants was induced by immunizing Hartley strain guinea pigs pretreated with cyclophosphamide. Hyperimmune serum from these animals was passed through a heavy chain-specific anti-IgG1 affinity column. The presence of IgE anti-hapten antibody in the filtrate fraction was verified by passive cutaneous anaphylaxis (PCA) testing with a 7-day period of local passive sensitization and by the heat lability (56 degrees C, 4 hr) of PCA activity. This IgE-rich fraction and the IgG1 fraction eluted from the column with base (0.2 M Na2CO3, pH 11.3) were transferred i.v. to separate groups of normal guinea pigs. Both fractions mediated delayed time course reactions that contained basophils. Macroscopic and microscopic reactions mediated by the IgE-rich fraction were abolished with heat (56 degrees C, 4 hr). Thus, two antigen-specific factors in guinea pig serum can mediate delayed time course basophil-containing reactions: IgG1 and IgE antibodies. IgE-mediated CBH reactions are similar to the late-phase reaction that follows IgE-dependent wheal-and-flare reactions in humans. The finding that guinea pig IgE can mediate a late reaction that contains basophils makes this a possible model for the human late-phase response, and suggests that some forms of CBH may play a role in human allergic disease.     

Antiallergic mechanisms of beta-adrenergic stimulants in rats.

Antiallergic mechanisms of beta-adrenergic stimulants were investigated in rats. Isoproterenol administered intravenously inhibited IgE antibody-mediated homologous passive cutaneous anaphylaxis (PCA) and histamine-induced cutaneous reaction (HCR) elicited at the same time in the same rats significantly. The inhibition of PCA was more potent than that of HCR, suggesting that PCA is inhibited by at least 2 mechanisms. One is the inhibition of vascular permeability increase. In vivo histamine release in the rat peritoneal cavity caused by intravenous antigen was inhibited by the intravenous administration of isoproterenol or salbutamol dose-dependently. On the contrary, when the histamine release in the peritoneal cavity was caused by intraperitoneal antigen, isoproterenol or salbutamol administered simultaneously with antigen failed to inhibit the reaction. Furthermore, antigen-induced histamine release from sensitized peritoneal exudate cells in vitro was not inhibited by isoproterenol or salbutamol. These results indicate that the primary target of beta-adrenergic stimulants is the vascular endothelium, and that the direct inhibition of chemical mediator release from mast cells does not play an important role for the inhibition of PCA and in vivo histamine release in the peritoneal cavity in rats. Beta-adrenergic stimulants therefore may prevent intravenously administered antigen from activating sensitized mast cells through affecting endothelial cells.     

Muscarinic-receptor functioning in tracheas from normal and ovalbumin-sensitive guinea pigs

Responses to bilateral vagal nerve stimulation, to field stimulation, and to exogenous methacholine and histamine were compared in tracheas isolated from (a) saline injected (i.p.) and saline-aerosol exposed guinea pigs (control), (b) ovalbumin-sensitized and saline-aerosol exposed (sensitized) guinea pigs, and (c) ovalbumin-sensitized and 2% ovalbumin-aerosol exposed (challenged) guinea pigs. Tracheal pressor responses (cmH2O; 1 cmH2O = 98.1 Pa) to nerve and field stimulation, and maximal responses to methacholine and histamine were significantly increased in animals from group c compared with groups a and b. Dose-response lines in response to the two agonists, expressed as percent maximal contraction, did not differ among the groups. The M1 antagonist pirenzepine (0.1-10 nM) selectively reduced responses to nerve stimulation in all three groups. The M2 antagonist gallamine potentiated responses to nerve or field stimulation in all three groups. We conclude that M1, M2, and M3 muscarinic receptor functioning is similar in control and ovalbumin-sensitized guinea pigs. Changes in post-receptor transduction mechanisms may mediate the increased responsiveness noted in animals from group c.     

Repeated antigen challenge induced airway hyperresponsiveness to neurokinin A and vagal non-adrenergic, non-cholinergic (NANC) stimulation in guinea pigs.

The effect of repeated weekly antigen challenges by aerosol on bronchopulmonary responses to ACh, histamine, neurokinin A or atropine-resistant (NANC) component of vagal stimulation, has been studied in guinea pigs. Bronchospastic responses were measured in anaesthetized animals, 7 days after the last challenge with antigen (or vehicle). No difference was observed between control and antigen challenged guinea pigs in their responsiveness to acetylcholine (1-300 mumol kg-1 i.v.) or histamine (1-300 mumol kg-1 i.v.). On the other hand, amplitude of bronchospasm induced by neurokinin A (1-3 mumol kg-1 i.v.) or NANC vagal stimulation (20 Hz, 1 msec, 10 V, trains of 5-20 sec) was significantly increased in guinea pigs previously challenged with antigen, as compared to controls. These results suggest that repetitive antigen exposure in sensitized guinea pigs generates an increase in the responsiveness to exogenously administered or endogenously released tachykinins, at a time when no generalized hyperresponsiveness to other spasmogens could be observed.     

A plant histaminase modulates cardiac anaphylactic response in guinea pig

The effect of a copper amine oxidase (histaminase) purified from the pea seedling as free or immobilized enzyme on the response to specific antigen was studied in isolated hearts from actively sensitized guinea pigs. In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction, followed by dilation and an increase in the amount of histamine and nitrites, the oxidation product of nitric oxide, in the perfusates. In the presence of both forms of histaminases, the positive inotropic and chronotropic responses as well as the coronary constriction and the release of histamine were fully blocked. The amount of nitrites, appearing in the perfusates when anaphylaxis is elicited in the presence of both forms of histaminases, is significantly increased, as well as nitric oxide synthase activity and cyclic GMP content in cardiac tissue, while cardiac calcium overload was significantly prevented. These observations demonstrate that the decrease in the anaphylactic release of histamine and the subsequent abatement of the cardiac response to antigen can be accounted for by the inactivation by histaminase of the released histamine and by a stimulation of endogenous nitric oxide production.     

Chronic tobacco smoke exposure increases airway sensitivity to capsaicin in awake guinea pigs.

Tobacco smoke (TS) exposure induces airway hyperreactivity, particularly in sensitive individuals with asthma. However, the mechanism of this airway hyperreactivity is not well understood. To investigate the relative susceptibility of atopic and nonatopic individuals to TS-induced airway hyperreactivity, we exposed ovalbumin (OA)-sensitized and nonsensitized guinea pigs to TS exposure (5 mg/l air, 30-min exposure, 7 days/wk for 120-156 days). Two similar groups exposed to compressed air served as controls. Airway reactivity was assessed as an increase in enhanced pause (Penh) units using a plethysmograph that allowed free movement of the animals. After 90 days of exposure, airway reactivity increased in OA-TS guinea pigs challenged with capsaicin, bradykinin, and neurokinin A fragment 4--10 aerosols. In addition, substance P content increased in lung perfusate of OA-TS guinea pigs in response to acute TS challenge compared with that of the other groups. Airway hyperirritability was not enhanced by phosphoramidon but was attenuated by a cocktail of neurokinin antagonists, nor was airway hyperreactivity observed after either methacholine or histamine challenge in OA-TS guinea pigs. Chronic TS exposure enhanced neither airway reactivity to histamine or methacholine nor contractility of isolated tracheal rings. In conclusion, chronic TS exposure increased airway reactivity to capsaicin and bradykinin aerosol challenge, and OA-TS guinea pigs were most susceptible to airway dysfunction as the result of exposure to TS compared with the other groups. Increased airway reactivity to capsaicin suggests a mechanism involving neurogenic inflammation, such as increased activation of lung C fibers.     

Influence of body temperature on histamine-induced bronchoconstriction in guinea pigs

The effects of body temperature on histamine-induced bronchoconstriction were investigated in anesthetized, paralyzed, and mechanically ventilated guinea pigs. Four groups of guinea pigs were studied with constant body temperatures of 40, 38, 35, and 32 degrees C, respectively. Histamine was infused for 5 min at a rate of 50 ng.kg-1.s-1. Body cooling from 40 to 32 degrees C augmented the bronchomotor responses to histamine, which eventually rose almost fourfold. The enhancement of histamine-induced bronchoconstriction induced by body cooling was not suppressed by pretreating guinea pigs with 5 mg/kg hexamethonium or 5 mg/kg hexamethonium plus 3 mg/kg atropine; neither was the enhancement of histamine-induced bronchoconstriction suppressed in pithed guinea pigs, demonstrating that the autonomic nervous system is not involved in potentiating bronchoconstriction at low body temperatures. These results suggest that, at low body temperatures, increased airway responsiveness to histamine may be because of some direct effect of temperature on bronchial airway smooth muscle.     

Antiallergic effect of ardisiaquinone A, a potent 5-lipoxygenase inhibitor

The antiallergic effects of ardisiaquinone A, a potent 5-lipoxygenase inhibitor, were examined. Pretreatment with ardisiaquinone A (0.1–10 μM) significantly inhibited compound 48/80-induced production of cysteinyl-leukotrienes (cys-LTs; LTC₄, LTD₄ and LTE₄) in rat peritoneal mast cells, but not histamine release. The IC₅₀ value was 5.56 μM. Pre-administration with ardisiaquinone A (0.1–1 mg/kg, s.c.) dose-dependently inhibited rat homologous passive cutaneous anaphylaxis (PCA) and the maximal inhibitory ratio was 22.3 ± 3.9% at the dose of 1 mg/kg. Ardisiaquinone A (1–5 mg/kg, s.c.) dose-dependently prevented the allergen-induced increase of tracheal pressure in ovalbumin-sensitized guinea pigs, especially during the late phase.

In conclusion, the findings of this study show that 5-lipoxygenase inhibitor ardisiaquinone A partially attenuates the allergen-induced increases of vascular permeability and tracheal pressure via the inhibition of cys-LTs production in mast cells.     

Comparison of the effects of estradiol-17beta and the synthetic estrogen, RU-2858, on lordosis behavior in adult female rats and guinea pigs

Female sexual behavior (as assessed by lordosis responses) in adult ovariectomized guinea pigs and rats was measured after a single subcutaneous injection of either the synthetic estrogen RU-2858 or estradiol-17β (E) and a subsequent injection of progesterone (P). Thresholds for responsiveness to each estrogen were determined over a range of doses from 1 to 640 μg/kg of body weight. RU-2858 was able to stimulate lordosis at doses several times lower than E in both guinea pigs and rats. In general, guinea pigs were less sensitive to both estrogenic compounds than rats and were particularly insensitive to E. Approximately 40% of guinea pigs given RU-2858 displayed lordosis prior to P injection. Subsequent P injection did not greatly enhance the intensity of lordosis responses in these animals. These guinea pigs were also more sensitive than the remaining 60% of RU-2858-injected guinea pigs on several indexes of lordosis intensity (e.g., lordosis threshold, duration of heat, duration of individual lordosis responses). Rats did not respond behaviorally to RU-2858 without a subsequent P injection nearly as frequently as did guinea pigs. At the doses used in this study, E did not facilitate lordosis behavior in rats or guinea pigs in the absence of a subsequent P injection.