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PubMed1997

Effect of the inducible nitric oxide synthase inhibitors aminoguanidine and L-N6-(1-iminoethyl)lysine on zymosan-induced plasma extravasation in rat skin.

The effect of nitric oxide synthase (NOS) inhibitors on plasma extravasation in a rat model of zymosan-induced inflammation has been investigated. Plasma extravasation was determined in response to intradermal test agents over 0 to 45 min or 0 to 4 h by the accumulation of i.v. injected 125I-labeled human serum albumin. Zymosan (1-100 microg/site) produced a dose- and time-dependent plasma extravasation. N(G)-nitro-L-arginine methyl ester (30-300 nmol/site), but not aminoguanidine (AG; 10-300 nmol/site) or L-N6-(1-iminoethyl)lysine (L-NIL; 10-300 nmol/site), significantly (p < 0.01) inhibited zymosan-induced (10 microg/site) plasma extravasation over 0 to 45 min. However, both AG and L-NIL produced significant (p < 0.05) inhibition over 0 to 4 h. The inhibition produced by AG was reversed by i.v. L-arginine or by coinjection of the vasodilator, calcitonin gene-related peptide. Zymosan (10-100 microg/site) induced an increase in dermal blood flow (laser-Doppler flowmetry) and this was inhibited by AG. Neutrophils were depleted selectively with antiserum, but this did not affect plasma extravasation except at the highest dose of zymosan (100 microg/site). Furthermore, zymosan-induced edema was not modified at either time point by pretreatment with the cyclooxygenase inhibitor indomethacin (30 micromol/kg, s.c., -30 min). In conclusion, in this model of dermal inflammation, it is suggested that inducible NOS inhibitors selectively remove an inducible NOS component that, at least in part, acts to increase microvascular blood flow and thus the edema formation observed during 0 to 4 h. There is no evidence of a contributory role for neutrophils or cyclooxygenase products in this model.

Animals↗
PubMed1998

Protective effects of melatonin in zymosan-activated plasma-induced paw inflammation.

The aim of the present study was to investigate the protective effect of the pineal hormone melatonin in a model of acute local inflammation (zymosan-activated plasma-induced paw oedema), in which oxyradicals, nitric oxide (NO) and peroxynitrite are known to play a crucial role in the inflammatory process. The intraplantar injection of zymosan-activated plasma elicited an inflammatory response that was characterized by a time-dependent increase in paw oedema, neutrophil infiltration and increased levels of nitrite/nitrate in the paw exudate. The maximal increase in paw volume was observed at 3 h after administration (maximal in paw volume: 1.34 +/- 0.09 ml). At this time point, myeloperoxidase activity and lipid peroxidation were markedly increased in the zymosan-activated plasma-treated paw (226 +/- 10.2 mU/100 mg wet tissue, 31 +/- 2.1 mM/mg wet tissue, respectively). However, zymosan-activated plasma-induced paw oedema was significantly reduced in a dose-dependent manner by treatment with melatonin (given at 62.5 and 125 microg/paw) at 1, 2, 3, 4 h after injection of zymosan-activated plasma. Melatonin treatment also caused a significant reduction of the myeloperoxidase activity and lipid peroxidation and inhibited nitrite/nitrate levels in the paw exudate. The paw tissues were also examined immunohistochemically for the presence of nitrotyrosine (a marker of peroxynitrite formation). At 3 h following injection of zymosan-activated plasma, staining for nitrotyrosine was also found to be localised in the inflamed paw tissue. Treatment with melatonin (125 microg/paw) reduced the appearance of nitrotyrosine in the tissues. Our findings support the view that melatonin exerts anti-inflammatory effects.

Animals↗
PubMed1991

Phagocytic cell chemiluminescence using different zymosan preparations.

This study compared the effectiveness of opsonized and unopsonized zymosan prepared in our laboratories with a commercially available opsonized preparation used for induction of luminol-dependent oxidative burst in phagocytic cells. The production of chemiluminescence (CL) by human whole blood, isolated human neutrophils, normal BALB c mouse splenocytes, and an immortal BALB c mouse macrophage cell line (J774A.1) was tested in an automated luminometer. Recombinant murine or human interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) were used as priming agents in some of the experiments. With human leukocytes and normal mouse spleen cells the laboratory-prepared zymosans (regardless of opsonization) induced equal or significantly greater CL than did the commercially prepared zymosan. In addition, greatly increased CL was evident with IFN-gamma- and LPS-primed neutrophils tested with our zymosans compared with the commercial preparation. These results suggest that effective zymosans capable of inducing strong, reproducible CL responses from several different phagocytic cell populations can be readily made in the laboratory.

Animals↗
PubMed1987

Phospholipid and arachidonic acid metabolism in zymosan-stimulated human monocytes: modulation by cAMP.

Receptor-ligand interaction in mononuclear phagocytes is intimately linked to alterations in membrane phospholipids and release of arachidonic acid (AA). In addition, synthesis of bioactive lipids from released AA can result in further modification of cell responses. Upon challenge with opsonized zymosan, [3H]-arachidonic acid ([3H]-AA)-labeled human monocytes released 25 +/- 2% of their incorporated radiolabel within 30 min. Pretreatment of the monocytes with 5 X 10(-4) M isobutylmethylxanthine (IBMX) or 1 X 10(-3) M dibutyryl cyclic AMP (d-cAMP) inhibited total [3H]-AA release in the presence of zymosan by 47% and 42%, respectively. Analysis of incorporated [3H]-AA in cellular phospholipid pools indicated that significant amounts of label were lost from both phosphatidylcholine (PC) and phosphatidylinositol (PI) during zymosan stimulation. Treatment with d-cAMP substantially inhibited the loss of label from PC, but had no affect on PI. HPLC analysis of cell supernatants from zymosan-treated cells indicated that 5-HETE was the predominant metabolite generated from [3H]-AA, and its production was depressed during treatment with d-cAMP. Phospholipase activity in human monocyte homogenates was not effected by d-cAMP or IBMX at the highest concentrations used, whether these were added directly to the homogenate or by pretreatment of whole cells, demonstrating that inhibition required an intact cell. These results suggest that human monocytes exposed to opsonized zymosan release AA via two mechanisms and that modulation by cAMP is indirectly effecting a phospholipase directed towards PC.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Increased negatively of interstitial fluid pressure in rat skin contributes to the edema formation induced by Zymosan.

Increased negatively of interstitial fluid pressure (Pif) contributes to rapid edema formation in several acute inflammatory reactions attesting to an "active" role for the loose connective tissues in the transcapillary fluid exchange and edema formation under these circumstances. The present study reports the effect of the complement activator Zymosan on Pif, transcapillary fluid, and albumin flux. Micropipettes (tip diameter 5 to 7 microns) connected to a servo-controlled counterpressure system were used to measure Pif in rat dermis. When compared to saline injection, subdermal injection of 1 mg Zymosan in 10 microliters 0.15 M NaCl increased total tissue water by 1.6 ml/g dry weight in 5 min, corresponding to about 150% increase in interstitial fluid volume. Pif increased from +0.4 to +3.7 mm Hg. Increased negativity of Pif can be masked by the edema formation which will increase Pif. Measurements were therefore also performed after circulatory arrest, when transcapillary fluid flux and edema formation are abolished. Using this experimental protocol Pif fell from +0.3 mm Hg to -2.5 mm Hg 5 min after subdermal injection of Zymosan and remained at this level throughout the observation period of 90 min. Injection of saline alone after circulatory arrest increased Pif transiently by about 1 mm Hg. Thus, subdermal injection of Zymosan causes increased negativity of Pif by about 4 mm Hg. Although the lowering of Pif itself will explain a minor part of the increased fluid filtration, the results attest to the role of loose connective tissues being active in the edema-generating process also in the inflammatory reaction induced by Zymosan.

Animals↗
PubMed1995

Vitamin A or zymosan pretreatment attenuates alpha-naphthylisothiocyanate-induced liver injury.

alpha-Naphthylisothiocyanate (ANIT) is a cholangiolitic hepatotoxicant that causes periportal hepatic injury in the rat that is neutrophil- and platelet-dependent. Since macrophages have recently been implicated as participants in some chemically induced hepatotoxicities, we evaluated the role of these cells in ANIT-induced hepatic injury. Rats were treated with gadolinium chloride (GdCl3), an agent which decreases hepatic macrophage numbers and activity, zymosan, an agent which increases hepatic macrophage numbers, or vitamin A, which increases hepatic macrophage activity. GdCl3 did not ameliorate ANIT-induced hepatotoxicity, as demonstrated by a lack of attenuation of any of the markers of hepatic insult evaluated. In contrast, pretreatment with either zymosan or vitamin A decreased ANIT hepatotoxicity. Zymosan administration reduced blood neutrophil numbers and influx of neutrophils into the peritoneum after intraperitoneal glycogen administration but did not affect hepatic neutrophil accumulation in ANIT-treated rats. To determine if macrophages were important in the protection by vitamin A, rats were cotreated with GdCl3 and vitamin A. GdCl3 did not alter the protection from ANIT hepatotoxicity afforded by vitamin A. Vitamin A treatment decreased ANIT and glutathione concentrations in bile at 1 and 4 hr after ANIT administration but had a minimal effect on plasma ANIT concentration. In summary, pretreatment of rats with zymosan or vitamin A but not GdCl3 attenuated ANIT-induced liver injury. The protection afforded by zymosan may derive from its effects on neutrophils or platelets. The protection by vitamin A appears to result from its effect on the transport of ANIT into bile. The results suggest that hepatic macrophages are not required for the manifestation of ANIT hepatotoxicity.

1-Naphthylisothiocyanate↗
PubMed2000

Lipoproteins modify the macrophage uptake of triacylglycerol emulsion and of zymosan particles by similar mechanisms.

The uptake of lipids and formation of foam cells are key events in atherosclerosis and in eruptive xanthomata formation in primary hyperchylomicronemia. Here we have compared the influence of low density lipoprotein (LDL), oxidized LDL (oxLDL), high density lipoprotein (HDL), and delipidated HDL (apoHDL) on the uptake by macrophages of zymosan (an insoluble fraction of yeast cell walls) and of triglyceride-rich emulsion (EM) particles that resemble chylomicrons, but, like zymosan, are equally devoid of protein components. Zymosan internalization is known to occur through unspecific phagocytosis, whereas natural chylomicrons are taken up by several specific lipoprotein receptors. We found that phagocytosis is not promoted as much by oxLDL as by normal LDL. HDL-coated zymosan was found to be inert and apoHDL slightly enhanced phagocytosis. LDL and apoHDL promoted the uptake of EM while oxLDL and HDL significantly inhibited the uptake. Therefore, the data support that HDL, and not apoHDL, particles inhibit EM uptake. We concluded that by using lipoprotein-coated zymosan particles, we could demonstrate different biological effects of LDL, oxLDL, HDL, and apoHDL on macrophage phagocytosis and that this method could be useful to delineate components of the various lipoproteins important for the propagation or inhibition of the formation of foam cells.

Animals↗
PubMed1989

Possible involvement of a 95-kDa protein phosphorylation in phorbol 12-myristate 13-acetate-induced suppression of zymosan phagocytosis in guinea pig macrophages.

Recently, we characterized a surface antigen (Z-1) of guinea pig macrophages by monoclonal anti-Z-1 antibody. The Z-1 antigen consists of two different polypeptide chains; alpha (140 kDa) and beta (95 kDa). This antigen is closely correlated with the phagocytic activity of the cells for zymosan and presumably functions as a receptor for zymosan. In the present study, the effect of phorbol 12-myristate 13-acetate (PMA) on the function of Z-1 was examined. Incubation of ortho-[32P]phosphate-labeled macrophages with PMA greatly increased the phosphorylation of the beta subunit of Z-1 but not that of the alpha subunit. Optimal phosphorylation was observed when cells were incubated with 300 ng/ml of PMA for 60-120 min. The PMA-induced phosphorylation was markedly suppressed by treatment of the macrophages with H-7, an inhibitor of protein kinase C. A chemotactic peptide, N-formyl-Met-Leu-Phe (fMLP) also caused phosphorylation of the beta subunit. Unlike PMA, fMLP maximized the phosphorylation within 30 s. Purified Z-1 was an excellent substrate for the exogenously added protein kinase C only in the presence of both Ca2+ and phosphatidylserine. H-7 completely inhibited the in vitro phosphorylation. These data suggest that the beta subunit of Z-1 is phosphorylated by protein kinase C. The phosphorylation of Z-1 by PMA and fMLP coincided with inhibition of zymosan phagocytosis. A linear relationship was obtained between the level of phosphorylation of Z-1 and the degree of inhibition of zymosan phagocytosis induced by PMA. Thus, the results suggest that zymosan uptake is negatively regulated by protein kinase C-mediated phosphorylation of the beta subunit of Z-1.

Animals↗
PubMed1987

Activation of anion channels by zymosan particles in membranes of peritoneal macrophages.

Patch-clamp recordings were used to study the effect of zymosan adsorption on membranes of freshly isolated peritoneal macrophages of mouse. Superfusion of adherent macrophages by zymosan in the on-cell pipette configuration stimulated the appearance of anion channels after a varying time delay in the minute range. The channel is activated by passing through a stage of fluctuations of increasing amplitude. Once the full channel current has been reached, the fluctuations become transformed into the typical current pattern of three well-defined conducting channel states. The adoption of the two substates appeared to be dependent on zymosan. Up to nine simultaneously open anion channels could be observed with a single channel conductance of 220-400 pS. Absence of external Ca2+ had no inhibiting influence on the effect of zymosan. Anion channels could in some cases be observed under control conditions, after attachment of the pipette to the membrane. The channel activation could be mimicked by addition of A23187 to calcium-containing bath solutions. There is evidence that a zymosan-mediated rise of intracellular Ca2+ might be involved in the stimulus response coupling. The activation of calcium-dependent potassium channels was not observed.

Animals↗
PubMed1994

Ethanol inhibits zymosan-stimulated eicosanoid production in mouse peritoneal macrophages.

Resident peritoneal macrophages synthesized and released eicosanoids when challenged by zymosan, a phagocytosable particle. Incubation of these cells with ethanol resulted in dose-dependent inhibition of arachidonic acid release and eicosanoid generation in response to zymosan. Ethanol affected the extent but not the ratio of eicosanoids released. When assayed in a cell-free system, endogenous phospholipase A2 activity was neither affected by the presence of ethanol in the incubation medium nor by preincubation of the cells with ethanol. Ethanol also inhibited arachidonic acid release in response to phorbol myristate acetate, a compound that, like zymosan, triggered a pertussis-toxin-sensitive response. When cells that had been previously treated with pertussis toxin were used, no further inhibitory effect of ethanol was seen in response to both zymosan and phorbol myristate acetate. On the other hand, ethanol had no effect on arachidonic acid release stimulated by ionophore A23187 or lipopolysaccharide, two compounds that triggered a pertussis-toxin-insensitive response. Moreover, ethanol was able to nearly abolish arachidonic acid release in response to fluoroaluminate, a direct activator of G-proteins. Altogether, the results of this study suggest that ethanol inhibits zymosan-stimulated eicosanoid production by interacting with a G-protein--or a G-protein-mediated process--that is critically involved in arachidonic acid mobilization.

Acyltransferases↗
PubMed1992

Zymosan induces selective release of arachidonic acid from rabbit alveolar macrophages via stimulation of a beta-glucan receptor.

Zymosan, which is composed primarily of alpha-mannan and beta-glucan polymers, is a well recognized activator of macrophages. The type receptor by which unopsonized zymosan induces arachidonic acid release was investigated. It was found that particulate beta-glucan and zymosan stimulated an identical dose-dependent release of arachidonic acid. This release of arachidonic acid by zymosan was blocked by soluble beta-glucans whereas soluble mannan had no effect. This inhibition was not due to a general toxic effect of the soluble beta-glucans as they had no effect on calcium ionophore-induced release of arachidonic acid. Beta-glucan-induced fatty acid release from these cells was shown to be fairly specific for arachidonic acid. These data reveal that zymosan stimulates the specific release of arachidonic acid from rabbit alveolar macrophages, at least in part, via a beta-glucan receptor.

Animals↗
PubMed1987

Effects of immune complexes, zymosan preparations and ionophore A 23187 on leukotriene formation in human leukocytes.

Incubation of human leukocytes with opsonized zymosan or IgG immune complexes led to a time dependent release of leukotrienes (LT) B4 and C4. After 3-4 min, the levels of LTB4 were 93 and 35 pmol/3*10(7) cells, respectively [corrected]. These amounts were 2-4 times lower than those released by leukocytes stimulated with the calcium ionophore A 23187. The levels of LTC4 were 8 and 20 times lower than those of LTB4 after incubation with opsonized zymosan or immune complexes, respectively. Heat-inactivation of the serum prior to zymosan coating decreased the effect of opsonized zymosan. Uncoated zymosan was an even weaker stimulus of leukotriene formation. These results suggest that both complement factors and immunoglobulins play a pivotal role in activating leukotriene synthesis in a mixed suspension of human leukocytes.

Antigen-Antibody Complex↗
PubMed1993

Enhancement of Fc epsilon RII/CD23 expression on U937 cells with opsonized zymosan: the requirement of a Fc gamma RI/CD64 mediated signal associated phagocytosis.

The kinetics of surface Fc epsilon RII/CD23 was tested on monocytic cell line U937 stimulated with opsonized zymosan. Zymosan opsonized with human serum enhanced not only the expression of surface Fc epsilon RII/CD23 but also Fc epsilon RII/CD23 mRNA detected by Northern blot and in situ hybridization techniques. This stimulation showed a marked synergism with IL-4 in the induction of Fc epsilon RII/CD23. Heat-inactivation of serum did not affect the inducibility of Fc epsilon RII/CD23 by opsonized zymosan, suggesting the involvement of serum substances other than complement. Zymosan treated with human gamma-globulin also induced Fc epsilon RII/CD23, indicating the possible involvement of Fc gamma receptors. The Fc epsilon RII/CD23 inducing effect of opsonized zymosan was partially blocked by pretreatment with heat-aggregated human gamma-globulin or an anti-Fc gamma RI monoclonal antibody but not by the anti-Fc gamma RII or Fc gamma RIII antibody. Our results showed the involvement of signals from Fc gamma receptor associated phagocytosis in the induction of Fc epsilon RII/CD23.

Blotting, Northern↗
PubMed1992

Pathways for arachidonic acid mobilization in zymosan-stimulated mouse peritoneal macrophages.

Resident peritoneal macrophages release arachidonic acid when challenged by zymosan, a phagocytosable particle. The present study was designed to investigate the pathways for arachidonic acid mobilization in zymosan-stimulated macrophages. Experiments were conducted with [3H]arachidonic acid-labeled macrophages to establish the relative contribution of acyltransferases, phospholipase A2, and diacylglycerol lipase to overall arachidonic acid release. Upon zymosan stimulation, [3H]arachidonic acid incorporation into phospholipids was significantly enhanced. Stimulus-induced activation of arachidonic acid incorporated was not observed immediately, but was found 5 min after cell challenge. On the other hand, the results indicated a rapid accumulation of intracellular free [3H]arachidonic acid that paralleled the appearance of both [3H]glycerol-labeled lysophosphatidylcholine and [3H]glycerol-labeled lysophosphatidylinositol, the by-products of phospholipase A2 action on phosphatidylcholine and phosphatidylinositol, respectively. A transient accumulation of [3H]arachidonate-carrying diacylglycerol was also observed. However, no appreciable alterations in the levels of [3H]monoacylglycerol were found. The phospholipase A2 inhibitor nordihydroguaiaretic acid substantially prevented the zymosan-induced arachidonic acid release. In contrast, RHC 80267, a diacylglycerol lipase inhibitor, though preventing diacylglycerol breakdown, did not have any effect on [3H]arachidonic acid release From these results, it is concluded that: (1) the phospholipase A2 pathway controls arachidonic acid release upon zymosan stimulation; (2) the diacylglycerol lipase pathway appears not to be involved in arachidonic acid release by stimulated cells; (3) the acyltransferases play a remarkable role in controlling free arachidonic acid levels, but they do not participate in the increase of free fatty acid levels observed upon cell stimulation.

Acyltransferases↗
PubMed2005

Molecular characterization of the lipopolysaccharide/platelet activating factor- and zymosan-induced pathways leading to prostaglandin production in P388D1 macrophages.

P388D1 cells release free arachidonic acid (AA) and prostaglandin E2 (PGE2) upon stimulation with platelet-activating factor (PAF) and zymosan. The response to PAF is dependent on priming of the cells with bacterial lipopolysaccharide (LPS). In the LPS/PAF pathway, both AA and PGE2 release are dependent on transcription and translation, whereas in the zymosan pathway the release of these compounds appears to be largely independent of these processes. Using quantitative real-time PCR, we analyzed the expression of mRNAs that encode proteins potentially responsible for the dependency of the LPS/PAF pathway on gene expression. These include all the phospholipases A2 (PLA2) that we detected in P388D1 cells, cyclooxygenases (COX), COX-1 and COX-2, the membrane-associated prostaglandin E synthase-1 (mPGES-1), the lipocalin-type prostaglandin D2 synthase (PGDS), hematopoietic PGDS and the subunit G(alpha i2) of heterotrimeric G-proteins. None of the mRNAs encoding PLA2s, PGDSs, or G(alpha i2) are substantially altered during LPS priming. However, cyclooxygenase-2 is up-regulated during LPS priming and after stimulation of the cells with zymosan. A modest but significant increase of mPGES-1 mRNA was also detected upon stimulation with zymosan. Thus, the dependency of the LPS/PAF-induced PGE2 production on gene expression can be attributed to the production of cyclooxygenase-2. The dependency of AA release on gene expression is not due to altered expression of any of the PLA2s. We suggest that an accessory regulatory protein affecting the release of AA must be responsible. Using HPLC we separated lipids that are secreted upon stimulation with LPS/PAF and zymosan and found that in both pathways PGD2 is the dominant prostaglandin produced and also detected PGE2, PGF(2alpha) and AA besides several unidentified compounds.

Animals↗
PubMed2006

Anti-nociceptive effect of thalidomide on zymosan-induced experimental articular incapacitation.

The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.

Analgesics↗
PubMed2005

The hemodynamic effects of zymosan in the perfused rat liver.

The actions of zymosan on hepatic microcirculation and on the cell membrane permeability were investigated using the multiple-indicator dilution technique. The experimental system was the perfused rat liver. [(3)H]Water, [(3)H]sucrose and [(14)C]urea or [(14)C]bicarbonate were simultaneously injected into the portal vein. Mean transit times, distribution spaces, variances, linear superpositions and transfer coefficients across the plasma membrane were calculated. Zymosan had no net effect on the great vessels space but increased the extracellular sucrose space and decreased the aqueous cell space. Zymosan impaired the flow-limited distribution and increased the normalized variances of all tracers. The increase in the portal pressure caused by zymosan results most probably from a constriction just after or at the exit of the sinusoids. Impairment of the flow-limited distribution of tracers in the sinusoidal bed indicates that zymosan induces the formation of permeability barriers, which could make the access of the solutes to transporters or enzymes located on the outer surface of the plasma membrane difficult.

Algorithms↗
PubMed2000

Inflammatory hyperalgesia induced by zymosan in the plantar tissue of the rat: effect of kinin receptor antagonists.

The Randall-Selitto paradigm (maximal tolerated pressure externally applied by a mechanical device) was used to develop a rat model of localized inflammatory hyperalgesia in order to compare the analgesic effects of bradykinin (BK) B1 and B2 receptor antagonists and of a non-steroidal anti-inflammatory drug (NSAID). Intra-plantar injection of zymosan (12.5 mg per paw) induced a considerable inflammation as evidenced from gross and histological evaluation and a mechanical hyperalgesia at 6 h. The contra-lateral paw of zymosan-treated animals or saline vehicle-injected paws did not exhibit a decreased pressure tolerance, relative to pre-injection measurements. Since the B1 receptor may be induced under inflammatory situations, we examined the amount of corresponding mRNA using quantitative RT-PCR. We found a significant increase of B1 receptor mRNA in the zymosan--but not the saline-injected paw at 6 h. Drugs were given subcutaneously 2 h before the 6 h readings to test their analgesic potential. The kinin B1 receptor antagonists [Leu8]des-Arg9-BK (3-30 nmol/kg) and R-715 (100 nmol/kg), the B2 receptor antagonists Hoe 140 (15 nmol/kg) and LF 16.0687 (3 and 10 mg/kg), as well as the NSAID diclofenac sodium (1 and 3 mg/kg) significantly reversed zymosan-induced hyperalgesia. We conclude that zymosan-induced hyperalgesia is a model suitable for the rapid evaluation of analgesic drugs with a peripheral site of action interfering either with kinin receptors or with prostanoid formation. In this regard, results of the present study confirm that blocking kinin B1 receptors is a novel approach for treatment of inflammatory pain.

Analgesics, Non-Narcotic↗