Main occluding area in partially edentulous patients: changes before and after implant treatment.

The 'main occluding area', the location where food crushing occurs during the first stroke of mastication, is reported to be an important concept; however, it is currently limited to findings in individuals with normal dentition. The purpose of this study was to assess the changes in the location, area and bite force of the main occluding area before and after implant treatments. We enrolled 50 partially edentulous and 22 normally dentate subjects. To identify the location of the main occluding area, each subject was instructed to freely bite once on a dental stopping using the partially edentulous side or the normally dentate area. The location, occluding contact area and bite force of the main occluding area before and after the implant treatments were analysed. The main occluding area was located at a reproducible location in the partially edentulous and normally dentate subjects. This location was principally the first molar region, and for the partially edentulous patients with missing teeth in the molar regions, it moved from the premolar region to the first molar region after treatment. The occluding contact area and bite force for the main occluding area increased (P < 0·05) after the implant treatment in the partially edentulous patients with missing teeth in the molar regions. These results suggest that the main occluding area can be restored to the first molar region after implant treatment and may be an important factor in the assessment of prosthodontic treatment.

Modern precipitation of hydrogenetic ferromanganese minerals during on-site 15-year exposure tests.

Redox-sensitive metallic elements, Mn and Fe, are oxidized in deep sea waters and form abundant ferromanganese crusts and nodules on the world's ocean floors at ultraslow rates of growth. This process of oxidation and the mechanism of precipitation are yet unknown. In this paper, the results of the first successful, long-term, on-site experiment of mineral precipitation that ascertains modern, ongoing hydrogenetic deposition of oxide materials from normal seawaters at water depths of 900-4500 m of geologically active and inactive environments are presented. We succeeded in the in-situ precipitation experiment on the sea floor and characterized the precipitates using high-resolution and submicron-scale chemical, mineralogical, and structural analyses. The installed artificial plates of glass, ceramics, and plastic yielded spread-out particles of sizes varying from one to a few micrometers in diameter, of coccoid-like irregular shapes, with a maximum of 1,000-10,000 individual particles/mm2/year after 12-15 years of exposure. The results indicated a continuous substantial growth of the hydrogenetic minerals if both Mn and Fe are supplied to the bottom waters. The mineralogical, chemical, and structural properties of the precipitates are similar to those of the natural precipitates on the seabed that are made up of hydrogenetic ferromanganese crusts and nodules, together with settling sediments, suspended hydrothermal particles, or microbial precipitates from cultivated Mn-oxidizing bacteria. Our work presents new realistic insight into proposed genetic models of marine hydrogenetic ferromanganese deposits in modern diverse ocean environments.

The enhancement effect of three sugar alcohols on the fungicidal effect of benzethonium chloride toward Candida albicans.

OBJECTIVE: The purpose of this study was to evaluate if the sugar alcohols erythritol, xylitol and sorbitol enhance the fungicidal effect of benzethonium chloride (BTC) toward in vitro candidal biofilms. METHODS: An in vitroCandida albicans biofilm was formed on a plastic coverslip coated with type I collagen. The enhancement of the fungicidal effect was evaluated using microbial assay after treating the biofilm with the test solutions (sugar alcohols: erythritol, xylitol, and sorbitol, each containing BTC solution). RESULTS: No fungicidal effect was observed with sugar alcohols without BTC. The fungicidal effect of erythritol-containing BTC increased with the erythritol concentration. Further, the level of enhancement of erythritol was the highest in three sugar alcohols. CONCLUSION: Sugar alcohols, especially erythritol, enhanced the fungicidal effect of BTC toward in vitro candidal biofilms.

Putative precursors of endothelin have less vasoconstrictor activity in vitro but a potent pressor effect in vivo.

Endothelin (ET-21) induced a sustained contraction of rat thoracic aortae (EC50 = 2.65 x 10(-10) M) in vitro, and caused a potent pressor effect in vivo after intravenous administration to rats. In contrast, the precursor deduced from porcine cDNA coding ET-21 (pET-39) had 100-fold less contractile activity in vitro (EC50 = 3.26 x 10(-8) M), and so did the precursor from human cDNA (hET-38) (EC50 = 1.48 x 10(-8) M). However, both pET-39 and hET-38 caused almost the same dose-dependent pressor effects as ET-21 in vivo. After intravenous bolus injection at 1 nmol/kg, ET-21 caused an initial transient drop of the arterial pressure, and then induced a gradual pressor effect. On the other hand, hET-38 caused only a gradual rise of the arterial pressure. There may be different mechanism(s) for ET-21 and hET-38 which induce changes in the arterial pressure in vivo.

Differential vasodilator properties of KRN2391, cromakalim, nitroglycerin and nifedipine in rabbit isolated femoral artery and vein.

1. The selectivity for artery and vein of KRN2391, cromakalim, nitroglycerin and nifedipine was examined in isolated femoral artery and vein preparations of the rabbit. 2. All drugs produced a concentration-dependent relaxation in both femoral artery and vein. 3. Nitroglycerin was more potent in femoral vein than in femoral artery at all concentrations. The EC50 value obtained in the vein was about 14 times smaller than that obtained in artery. 4. Cromakalim and nifedipine were almost equipotent on both vascular preparations. Cromakalim at the highest concentration (10(-5) M) produced 88 and 78% relaxation in femoral artery and vein, respectively. The maximum relaxation induced by nifedipine (10(-6) M) was less than 50% in both preparations. 5. KRN2391 was active at a lower concentration in the vein than in the artery and its maximum relaxation at 10(-5) M was about 90% in both preparations. 6. Glibenclamide (10(-6) M) inhibited the vasorelaxation caused by KRN2391 in both artery and vein. Methylene blue (10(-5) M) also inhibited the relaxant action of KRN2391 but this action was slight in the artery. 7. These results suggest that KRN2391 and nitroglycerin are more potent in the vein than in the artery and cromakalim and nifedipine are equipotent in both. It is considered that the relaxation induced by low concentrations of KRN2391 reflects predominantly its action as a nitrate and that at high concentrations it acts as a K+ channel opener in addition to its nitrate action. The different vascular selectivities of these drugs are thought to relate to the differences in their mechanisms of action in vascular smooth muscle.

Receptor binding affinity and biological activity of C-terminal elongated forms of endothelin-1.

Endothelin-1 (21 amino acids; ET-21) is considered to be derived from a precursor, proendothelin (38 amino acids; ET-38). In order to make the physiological significance of this conversion clear, we synthesized various C-terminal elongated derivatives of ET-21, such as ET-22, ET-23, ET-25, ET-31, ET-36 and ET-38 (each number implies the number of amino acid residues), and measured their receptor binding affinities and biological activities. When inhibition of [(125)I]ET-21 binding to cultured rat smooth muscle cells (A10 cells) was measured, ET-21 inhibited with the highest affinity (IC(50) = 1.6 x 10(?10) M) and the affinity of ET-38 was 30-fold less than that of ET-21. The binding affinities of the C-terminal elongated peptides were reduced with increasing number of amino acid residues, except for ET-22 whose affinity was lower than those of other peptides (IC(50) = 1.6 x 10(?8) M). When contractions of rat aortic segments induced by these peptides were measured, ET-21 was the most potent (EC(50) = 2.8 x 10(?10) M). All C-terminal elongated peptides, including ET-38, were more than 100-fold less active. It is noteworthy that ET-22 was the least potent peptide (EC(50) = 1.2 x 10(?7) M). When bolus doses of C-terminal elongated peptides were administered to chemically denervated rats, the time-dependent change in blood pressure induced by each peptide was different from that induced by ET-21. Although ET-21 elicited a three phase depressor/pressor blood pressure response (an initial rapid hypotension, then a rapid transient hypertension followed by a slowly developing long-lasting hypertensive effect), the C-terminal elongated peptides, including ET-38, did not cause the initial transient hypotensive response. Very interestingly, the ability of the peptides to induce the rapid phase of hypertension in vivo does not seem to be correlated with the affinity of each peptide for the smooth muscle cell receptor, since the peptides with lower affinities for the smooth muscle receptor, such as ET-22, ET-23 and ET-25, showed more potent hypertensive effects. On the other hand, the slow and long-lasting hypertensive effect is likely to be related to the affinity of the compounds. The maximal hypertensive effects of cumulatively administered ET-21 derivatives were similar to those of ET-21. These results suggest that ET-21 is the most potent vasoconstrictor among the peptides and that the conversion from ET-38 to ET-21 may be important as an activation process.

Characteristics of KRN2391, a novel vasodilator, compared with those of cromakalim, pinacidil and nifedipine in rat aorta.

The characteristics of KRN2391, a novel vasodilator, were studied in rat isolated aorta. The effects of KRN2391, cromakalim, pinacidil and nifedipine on the contractions induced by 20, 40 and 80 mM K+ and by 10(-7) M norepinephrine (NE) were measured first. KRN2391, cromakalim and pinacidil selectively inhibited the contractions induced by 20 mM K+ and NE rather than those induced by high concentrations of K+. Nifedipine could not completely inhibit the NE-induced contractions. The vasorelaxant effect of KRN2391 was inhibited by K+ channel blockers and guanylate cyclase inhibitors. KRN2391, cromakalim and pinacidil increased the 86Rb efflux rate coefficient. Thus, KRN2391 exhibits a vasodilator profile similar to that of the K+ channel openers and induces an increase in 86Rb efflux. It is suggested that opening of the membrane K+ channels may be partly involved in the vasorelaxant mechanism of KRN2391.

Vasorelaxant action of Ki1769, a new pyridinecarboximidamide, in isolated porcine coronary artery.

The characteristics of KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethansulfonate) and its phenethyl and 2-hydroxyethyl derivatives (Ki1769 and Ki3315) were studied in isolated porcine coronary arteries. KRN2391, Ki1769 and Ki3315 produced concentration-dependent relaxation of coronary arteries contracted by 25 mM KCl and the order of relaxant potency was KRN2391 > Ki1769 > Ki3315. At the maximum effect, KRN2391 produced nearly complete relaxation but Ki1769 produced about 66% relaxation. The maximum effect of Ki3315 could not be obtained because of its solubility. The relaxation induced by KRN2391 was antagonized by glibenclamide and methylene blue but relaxations caused by Ki1769 and Ki3315 were antagonized by glibenclamide alone. The antagonistic effect of glibenclamide on Ki1769- and Ki3315-induced relaxations was more potent than that on KRN2391-induced relaxation. KRN2391 induced relaxation of coronary arteries contracted by 40 mM KCl in a concentration-dependent manner but the effect of KRN2391 was smaller against 40 mM KCl-induced contractions than against 25 mM KCl-induced contractions. Ki1769 had almost no effect on coronary arteries contracted by 40 mM KCl. These results suggest that pyridinecarboximidamide derivatives which do not possess a nitroxyl group have vasodilating ability based on a K+ channel opening action.

Demonstration of beta 1-adrenoceptor mediating relaxation of porcine coronary artery by radioligand binding and pharmacological methods.

beta-adrenoceptors in the porcine coronary artery were characterized by a radioligand binding assay using (-)-[3H]dihydroalprenolol (DHA) and also by measuring the relaxant response of isolated coronary artery to norepinephrine. Specific (-)-[3H]DHA binding in the porcine coronary artery was saturable, reversible and of high affinity (Kd = 1.6 nM) with a maximal number of binding sites of 63 fmol/mg protein, and it showed a pharmacological specificity as well as stereoselectivity which characterized beta-adrenoceptors. The Hofstee analysis of inhibition of (-)-[3H]DHA binding by atenolol, practolol and ICI 118551 has shown that the averaged concentration of beta 1 and beta 2-adrenoceptors in this tissue was 68% and 32% respectively. The relaxant response of isolated coronary artery to norepinephrine was competitively antagonized by (-)propranolol, (+)propranolol, atenolol, practolol and ICI 118551. The pA2 values of these adrenoceptor antagonists were significantly correlated with the Ki values for beta 1 but not beta 2-adrenoceptors determined by the (-)-[3H]DHA binding assay. Thus, the present study demonstrates that the relaxant response of porcine coronary artery to norepinephrine is predominantly mediated through the stimulation of beta 1-adrenoceptors on vascular smooth muscles.

Assessment in pig coronary artery of long-lasting and potent calcium antagonistic actions of the novel dihydropyridine derivative mepirodipine hydrochloride.

Ca antagonistic properties of mepirodipine hydrochloride [+)-(3'S,4S)-3-(1'-benzyl-3'-pyrrolidinyl methyl 2,6-dimethyl-4- (m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride, YM-09730-5) were assessed by studying the pharmacological actions and binding characteristics of the drug in the stem coronary artery. IC50 values of YM-09730-5 (3.5 x 10(-10) mol/l) and nifedipine (6.6 x 10(-9) mol/l) for 40 mmol/l K-induced tonic contraction of pig coronary artery indicated that YM-09730-5 was about 20 times more potent than nifedipine in Ca antagonistic action. However, YM-09730-5 showed an onset of inhibitory action 3 to 5 times slower than nifedipine. A 40-min preincubation of the target tissue with YM-09730-5 also inhibited the contractions produced by acetylcholine, histamine, 5-hydroxytryptamine, and high Ca, and pD2' values were between 8.0 and 7.0; while nifedipine was less potent. The specific binding of [3H]nitrendipine to the membrane of pig coronary artery was inhibited by YM-09730-5, thereby indicating that [3H]nitrendipine and YM-09730-5 compete for the similar receptor sites of dihydropyridine-sensitive Ca channels. Suppression of high K-, Ca- and agonist-induced contractions by YM-09730-5 (3 x 10(-9) mol/l-10(-7) mol/l) remained even after washings at 20-min intervals for more than 3 h; and, in particular at a high concentration of YM-09730-5, the suppression was slightly antagonized by excess Ca or a Ca-agonist. The contraction inhibited by nifedipine, on the other hand, was readily restored by several washings.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats.

1. In conscious spontaneously hypertensive rats (SHR), the oral administration of KRN2391 (0.1-3.0 mg/kg) produced a dose-dependent decrease in blood pressure. The antihypertensive effect of KRN2391 was about 2 and 20 times more potent than those of pinacidil and nifedipine, respectively, but about 2 times less potent than that of cromakalim. 2. During oral administration of KRN2391 (0.5 and 1.0 mg/kg) once daily for 5 weeks, its antihypertensive effect did not diminish in conscious SHR. 3. In anaesthetized SHR, KRN2391 (3-100 micrograms/kg, i.v.) produced a decrease in blood pressure in a dose-dependent manner. Its antihypertensive effect was antagonized by glibenclamide (20 mg/kg, i.v.). 4. In isolated aorta obtained from SHR, KRN2391 (0.01-100 microM) produced a concentration-dependent relaxation. Its concentration-relaxation curve was shifted to the right by glibenclamide (1 microM) and methylene blue (3 microM). 5. These results indicate that the antihypertensive effect of KRN2391 in SHR is due to its direct action on vascular smooth muscle based on a K+ channel opening action and a nitrate action. In addition, KRN2391 is absorbed from the gastrointestinal tract into blood and does not induce tolerance despite possessing some nitrate action.

Usefulness of antithrombin III and alpha 2-plasmin inhibitor in early differentiation of fulminant hepatitis and severe form of acute hepatitis.

To evaluate the usefulness of antithrombin III (AT III) and alpha 2-plasmin inhibitor (alpha 2PI) in early differential diagnosis of fulminant hepatitis from the severe form of acute hepatitis, the activities of AT III and alpha 2PI were measured in plasma of 15 patients with fulminant hepatitis and 6 patients with severe form of acute hepatitis. The activities of prothrombin time (PT), hepaplastintest (HPT) and thrombotest (TT) were also evaluated. The mean values and the standard errors (SE) for PT, HPT and TT were 21.1 +/- 2.6%, 14.0 +/- 1.6% and 10.3 +/- 1.7%, respectively, in the early stage of fulminant hepatitis and 25.3 +/- 2.4%, 21.6 +/- 4.6% and 15.8 +/- 3.6%, respectively, in the severe form of acute hepatitis. No significant difference in the tests between these two diseases was noted. On the other hand, the mean values +/- SE for AT III and alpha 2PI were 13.7 +/- 4.6% and 25.6 +/- 8.6% in fulminant hepatitis and 70.2 +/- 28.5% and 98.7 +/- 9.7% in the severe form of acute hepatitis. A significant difference between the two diseases was observed. From the above, it is concluded that measuring AT III and alpha 2PI along with PT, HPT and TT is useful for early diagnosis of fulminant hepatitis.

Characteristics of Ki1769, a novel vasodilator, in isolated rat aorta.

The vasorelaxant mechanism of a newly synthesized vasodilator, Ki1769 [N-cyano-N'-(2-phenethyl)-3-pyridinecarboximidamide], was studied in isolated rat aorta in comparison with cromakalim. Ki1769 (10(-8)-10(-5) M) and cromakalim (10(-8)-10(-5) M) produced a concentration-dependent relaxation and the EC50 values for Ki1769 and cromakalim were (8.60 +/- 1.90) x 10(-7) M and (1.36 +/- 0.18) x 10(-7) M, respectively. Ki1769- and cromakalim-induced relaxations were competitively antagonized by glibenclamide with pA2 values of 6.83 and 6.93, respectively. Charybdotoxin, apamine, atropine, propranolol and indomethacin did not affect the Ki1769-induced relaxation. An increase in 86Rb efflux was induced by Ki1769. Glibenclamide attenuated the increase in 86Rb efflux produced by Ki1769. These results suggest that the vasorelaxant effect of Ki1769 is based on the glibenclamide-sensitive K channel-opening action.

Cardiovascular effects of KRN2391, nitroglycerin and cromakalim in dihydroergotamine-treated pithed rats.

1. The effects of KRN2391 on the cardiovascular system were compared with those of nitroglycerin and cromakalim in pithed rats treated with dihydroergotamine (DHE) in order to examine the effects of these drugs on venous blood vessels. 2. DHE (100 micrograms/kg, i.v.) produced increases in mean blood pressure (MBP), cardiac output (CO) and central venous pressure (CVP) without changes in total peripheral vascular resistance (TPR) and heart rate (HR) based on venoconstriction. The DHE-treated pithed rats, nitroglycerin (30 micrograms/kg, i.v.) decreased CO and CVP whereas cromakalim (30 micrograms/kg, i.v.) produced a slight increase in CO followed by a decrease and did not affect CVP. KRN2391 (30 micrograms/kg, i.v.) produced a decrease in CVP without affecting CO. Decreases in MBP and TPR were induced by all drugs. 3. These results suggest that nitroglycerin acts predominantly as a venodilator and KRN2391 and cromakalim showed a venodilating action in addition to an arterial dilating action in DHE treated pithed rats. However, the venodilating action of KRN2391 in this condition is more potent than that of cromakalim.

Pharmacological analysis of the vasodepressor effect of KRN2391 in pithed rats.

1. The antagonism by glibenclamide of the vasodepressor effects of KRN2391, cromakalim and nitroglycerin was compared in pithed rats with blood pressure supported by an infusion of phenylephrine. 2. Cumulative administration of KRN2391 (3-300 micrograms/kg, i.v.), cromakalim (3-300 micrograms/kg, i.v.) and nitroglycerin (1-300 micrograms/kg, i.v.) produced dose-dependent decreases in diastolic blood pressure. 3. In rats given glibenclamide (20 mg/kg, i.v.) the dose-vasodepressor curves for KRN2391 and cromakalim were shifted to the right. However, glibenclamide had no effect on the vasodepressor effect of nitroglycerin. 4. The ED50mmHg values increased about 5.9 fold for KRN2391 and 9.5 fold for cromakalim in glibenclamide-treated rats. 5. These results suggest that the vasodepressor effect of KRN2391 is due to both glibenclamide-sensitive and insensitive mechanisms. This glibenclamide-insensitive effect of KRN2391 is thought to reflect its nitrate action.

Cyanoamidines. II. Synthesis and pharmacological activity of N-arylalkyl-N'-cyano-3-pyridinecarboxamidines.

A new series of cyanoamidines, N-arylalkyl-N'-cyano-3-pyridinecarboxamidines was synthesized and evaluated for inhibitory effects on 40 mM KCl-induced contraction and norepinephrine (NE)-induced contraction of rat aorta strips. The N-phenethyl cyanoamidine 4c showed potent vasodilatory action. Further in vitro screening program using 4c as a lead compound resulted in the discovery of highly potent N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine (5j). Compound 5j induced the greatest increase in 86Rb+ efflux among cyanoamidine series. Subsequent modification of the pyridine ring of 5j was performed with evaluation for intravenous and oral antihypertensive activities. Introduction of an amino group at the 5-position of the pyridine ring furnished the new potassium channel opener, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine+ ++ (9e; KRN4884), which showed highly potent antihypertensive activity and a long duration of antihypertensive action after oral administration. KRN4884 is under further development as an antihypertensive agent.

Comparative vasodepressor effects of 3-pyridine derivatives possessing the cyanoamidine or amide structure in pithed rats.

The potency and mechanism of the vasodepressor action of N-cyano-3-pyridinecarboximidamide and nicotinamide, which are 3-pyridine derivatives possessing cyanoamidine and amide structures, respectively, were studied in pithed rats infused with phenylephrine. The N-substituents of cyanoamidine and amide in the derivatives studied comprised 2-nitroxyethyl (KRN2391 and nicorandil), phenethyl (Ki769 and Ki765) and 2-(2-chlorophenyl)ethyl (Ki3005 and Ki4261) moieties. These derivatives produced vasodepressor actions in a dose-dependent manner, except for Ki4261 which did not show any action below the solubility limit. When the vasodepressor effects of compounds possessing the same N-substituents in cyanoamidine and amide derivatives were compared, the potency of cyanoamidine derivatives was greater than that of amide derivatives, Ki3005 being the most potent. The vasodepressor effects of cyanoamidine and amide derivatives were antagonized by glibenclamide, although the antagonism of the depressor effects of KRN2391 and nicorandil was less pronounced than that of the other derivatives. These results suggest that N-substituents, in addition to the cyanoamidine structure, play an important role in determining the vasodepressor potencies of 3-pyridine derivatives. Furthermore, the vasodepressor effects of these derivatives appear to be based on their K+ channel-opening actions, although those of KRN2391 and nicorandil seem to be partly mediated by a nitrate-like action in addition to their K+ channel-opening action.

Antihypertensive properties of KRN4884, a novel long-lasting potassium channel opener.

The antihypertensive action of KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ), a newly synthesized 3-pyridine derivative was examined in conscious spontaneously hypertensive rats (SHRs). A single administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) produced a dose-dependent and long-lasting antihypertensive effect. The 7-day repeated administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) did not diminish antihypertensive activity during the treatment period or induce rebound hypertension after the discontinuation of treatment. To examine the mechanism of the antihypertensive effect of KRN4884, we studied its vasorelaxing effects in rat isolated aortae precontracted with 25 mM KCl. Single application of KRN4884 showed a slower onset of inhibitory action than that of levcromakalim. KRN4884 was approximately 26-fold more potent than levcromakalim and 10-fold less potent than nilvadipine. KRN4884- and levcromakalim-induced vasorelaxation were antagonized by glibenclamide. Furthermore, we observed the recovery of the contraction inhibited by these drugs after repeated washing. The inhibitory effect of KRN4884 was restored only after four washes, whereas that of levcromakalim was completely restored after one wash. The nilvadipine-induced inhibitory effect was the most resistant to washing among these drugs. These results suggest that KRN4884 shows a long-lasting antihypertensive effect based on its potent potassium channel-opening action. The long-lasting action may be due to a slow association/dissociation with/from the binding sites on vascular smooth muscle.

Reciprocal regulation of cultured human mast cell cytokine production by IL-4 and IFN-gamma.

BACKGROUND: T(H)1 and T(H)2 cytokines are thought to regulate allergic inflammation. OBJECTIVE: Two key regulatory cytokines, IL-4 and IFN-gamma, were examined for their effects on cytokine production by cultured human mast cells (CHMCs). METHODS: CHMCs were obtained by culturing cord blood-derived CD34(+) cells in the presence of stem cell factor and IL-6 for 14 to 16 weeks. CHMCs were passively sensitized with human myeloma IgE and supplemented with or without IL-4 or IFN-gamma. After the sensitization, CHMCs were stimulated with anti-FcepsilonRIalpha mAb. Concentrations of secreted cytokines were measured by using ELISA, and cytokine messenger RNA was analyzed by using quantitative competitive RT-PCR. RESULTS: IL-4 profoundly enhanced FcepsilonRI-mediated production of macrophage inflammatory protein (MIP) 1alpha, IL-8, and GM-CSF. For example, the enhancement by IL-4 (10 ng/mL) of the production of MIP-1alpha, IL-8, and GM-CSF was 25-, 7-, and 90-fold, respectively, after 6 hours. IL-4 also enhanced levels of FcepsilonRI-induced cytokine messenger RNA but to a lesser degree. In contrast, IFN-gamma inhibited FcepsilonRI-induced production of MIP-1alpha, IL-8, and GM-CSF. For example, the inhibition by IFN-gamma (10 ng/mL) of FcepsilonRI-mediated production of MIP-1alpha, IL-8, and GM-CSF was 80%, 75%, and 95%, respectively. IFN-gamma also suppressed FcepsilonRI-induced messenger RNA expression of these cytokines. Neither IL-4 nor IFN-gamma affected the kinetics of cytokine production by CHMCs. CONCLUSION: These data suggest that IL-4 and IFN-gamma may influence allergic reactions by modulating human mast cell cytokine production.