Tumor necrosis factor receptor 2 as a possible marker of COPD in smokers and ex-smokers.

INTRODUCTION: Oxidative stress and systemic inflammation are higher in smokers and patients with COPD; however, markers that may help differentiate between smokers and patients with COPD have not yet been identified. We hypothesized that tumor necrosis factor-alpha receptor (TNFR) and soluble form of the receptor for advanced glycation end products (sRAGE) can be indicators of COPD in asymptomatic patients. PATIENTS AND METHODS: We evaluated 32 smokers (smoking history >10 pack-years), 32 patients with mild/moderate COPD (smokers and ex-smokers), and 32 never smokers. Concentrations of C-reactive protein (CRP), interleukin (IL)-6, TNFR1 and TNFR2, advanced glycation end products (AGEs), and the sRAGE were measured in serum. RESULTS: There were higher CRP and AGEs concentrations in smokers and in patients with COPD (P<0.001 and P=0.01, respectively) compared to controls, without statistical difference between smokers and patients with COPD. Concentrations of sRAGE, IL-6, and TNFR1 did not differ between study groups. TNFR2 was significantly higher in patients with COPD than in smokers (P=0.004) and controls (P=0.004), and the presence of COPD (P=0.02) and CRP (P=0.001) showed a positive association with TNFR2. Positive associations for smoking (P=0.04), CRP (P=0.03), and IL-6 (P=0.03) with AGEs were also found. The interaction variable (smoking × COPD) showed a positive association with IL-6. CONCLUSION: Our data suggest that TNFR2 may be a possible marker of COPD in asymptomatic smokers and ex-smokers. Although smokers and patients with early COPD presented other increased systemic inflammation markers (eg, CRP) and oxidative stress (measured by AGEs), they did not differentiate smokers from COPD.

Apocynin influence on oxidative stress and cardiac remodeling of spontaneously hypertensive rats with diabetes mellitus.

PURPOSE: Although increased oxidative stress is a major component of diabetic hypertensive cardiomyopathy, research into the effects of antioxidants on cardiac remodeling remains scarce. The actions of antioxidant apocynin include inhibiting reactive oxygen species (ROS) generation by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and ROS scavenging. We evaluated the effects of apocynin on cardiac remodeling in spontaneously hypertensive rats (SHR) with diabetes mellitus (DM). METHODS: Male SHR were divided into four groups: control (SHR, n = 16); SHR treated with apocynin (SHR-APO; 16 mg/kg/day, added to drinking water; n = 16); diabetic SHR (SHR-DM, n = 13); and SHR-DM treated with apocynin (SHR-DM-APO, n = 14), for eight weeks. DM was induced by streptozotocin (40 mg/kg, single dose). Statistical analyzes: ANOVA and Tukey or Mann-Whitney. RESULTS: Echocardiogram in diabetic groups showed higher left ventricular and left atrium diameters indexed for body weight, and higher isovolumetric relaxation time than normoglycemic rats; systolic function did not differ between groups. Isolated papillary muscle showed impaired contractile and relaxation function in diabetic groups. Developed tension was lower in SHR-APO than SHR. Myocardial hydroxyproline concentration was higher in SHR-DM than SHR, interstitial collagen fraction was higher in SHR-DM-APO than SHR-APO, and type III collagen protein expression was lower in SHR-DM and SHR-DM-APO than their controls. Type I collagen and lysyl oxidase expression did not differ between groups. Apocynin did not change collagen tissue. Myocardial lipid hydroperoxide concentration was higher in SHR-DM than SHR and SHR-DM-APO. Glutathione peroxidase activity was lower and catalase higher in SHR-DM than SHR. Apocynin attenuated antioxidant enzyme activity changes in SHR-DM-APO. Advanced glycation end-products and NADPH oxidase activity did not differ between groups. CONCLUSION: Apocynin reduces oxidative stress independently of NADPH oxidase activity and does not change ventricular or myocardial function in spontaneously hypertensive rats with diabetes mellitus. The apocynin-induced myocardial functional impairment in SHR shows that apocynin actions need to be clarified during sustained chronic pressure overload.

Serum Vitamin A and Inflammatory Markers in Individuals with and without Chronic Obstructive Pulmonary Disease.

BACKGROUND: Vitamin A is essential for the preservation and integrity of the lung epithelium and exerts anti-inflammatory effects. OBJECTIVE: Evaluating vitamin A in the serum and sputum and testing its correlation with inflammatory markers in individuals with or without COPD. Methods. We evaluated dietary intake, serum and sputum vitamin A, tumor necrosis factor alpha, interleukin- (IL-) 6, IL-8, and C-reactive protein in 50 COPD patients (age = 64.0 ± 8.8 y; FEV1 (forced expiratory volume in the first second) (%) = 49.8 ± 16.8) and 50 controls (age = 48.5 ± 7.4 y; FEV1 (%) = 110.0 ± 15.7). RESULTS: COPD exhibited lower serum vitamin A (1.8 (1.2-2.1) versus 2.1 (1.8-2.4) µmol/L, P < 0.001) and lower vitamin A intake (636.9 (339.6-1349.6) versus 918.0 (592.1-1654.6) RAE, P = 0.05) when compared with controls. Sputum concentration of vitamin A was not different between groups. Sputum vitamin A and neutrophils were negatively correlated (R (2) = -0.26; P = 0.03). Smoking (0.197, P = 0.042) exhibited positive association with serum vitamin A. COPD was associated with lower serum concentrations of vitamin A without relationship with the systemic inflammation. CONCLUSIONS: Serum concentration of vitamin A is negatively associated with the presence of COPD and positively associated with smoking status. Sputum retinol is quantifiable and is negatively influenced by neutrophils. Although COPD patients exhibited increased inflammation it was not associated with serum retinol.

Lycopene supplementation reduces TNF-α via RAGE in the kidney of obese rats.

BACKGROUND: The kidney is a target organ for injuries caused by advanced glycation end products (AGEs) in obesity. The receptor of AGEs (RAGE) is proinflammatory and appears to have a role in the pathogenesis of renal disease due to obesity. OBJECTIVE: The aim was to verify the effect of obesity on renal damage and the effect of lycopene on these complicationsDesign and Methods:Male Wistar rats were randomly assigned to receive a control diet (C, n=7) or a high-fat diet plus sucrose (HD+S, n=14) for 6 weeks. After this period, the HD+S animals were randomized into two groups: HD+S (n=7) and HD+S supplemented with lycopene (HD+S+L, n=7). The animals received maize oil (C and HD+S) or lycopene (HD+S+L) for a 6-week period. RESULTS: The HD+S and HD+S+L animals demonstrated insulin resistance (OGTT glucose after 150 min; C: 117.6±3.9

Oxidative stress on cardiotoxicity after treatment with single and multiple doses of doxorubicin.

The mechanism of doxorubicin (DOX)-induced cardiotoxicity remains controversial. Wistar rats (n = 66) received DOX injections intraperitoneally and were randomly assigned to 2 experimental protocols: (1) rats were killed before (-24 h, n = 8) and 24 h after (+24 h, n = 8) a single dose of DOX (4 mg/kg body weight) to determine the DOX acute effect and (2) rats (n = 58) received 4 injections of DOX (4 mg/kg body weight/week) and were killed before the first injection (M0) and 1 week after each injection (M1, M2, M3, and M4) to determine the chronological effects. Animals used at M0 (n = 8) were also used at moment -24 h of acute study. Cardiac total antioxidant performance (TAP), DNA damage, and morphology analyses were carried out at each time point. Single dose of DOX was associated with increased cardiac disarrangement, necrosis, and DNA damage (strand breaks (SBs) and oxidized pyrimidines) and decreased TAP. The chronological study showed an effect of a cumulative dose on body weight (R = -0.99, p = 0.011), necrosis (R = 1.00, p = 0.004), TAP (R = 0.95, p = 0.049), and DNA SBs (R = -0.95, p = 0.049). DNA SBs damage was negatively associated with TAP (R = -0.98, p = 0.018), and necrosis (R = -0.97, p = 0.027). Our results suggest that oxidative damage is associated with acute cardiotoxicity induced by a single dose of DOX only. Increased resistance to the oxidative stress is plausible for the multiple dose of DOX. Thus, different mechanisms may be involved in acute toxicity versus chronic toxicity.

Comparison of oxidative stress in ASA physical status I patients scheduled for minimally invasive surgery under balanced or intravenous anesthesia.

BACKGROUND: The effects of anesthetics on inflammation and oxidative parameters, evaluated in patients without comorbidities undergoing minor surgery, remain unknown. The present study aimed to investigate the inflammatory and oxidative stress status in adult patients undergoing elective minimally invasive surgery, using different anesthetic techniques. METHODS: Thirty patients classified as ASA physical status I, who were scheduled for minor surgeries (tympanoplasty or septoplasty), were randomly allocated into two groups: balanced (BAL) anesthesia maintained with isoflurane or total intravenous anesthesia (TIVA) with propofol. Blood samples were drawn prior to the induction of anesthesia (baseline), 120 min after the beginning of anesthesia and one day after surgery. The proinflammatory cytokine IL-6 was determined by flow cytometry; DNA oxidation was evaluated by the single cell gel electrophoresis assay, and plasma malondialdehyde (lipid peroxidation biomarker) and antioxidant status were determined through fluorometry. RESULTS: Increased IL-6 was observed one day after surgery in both groups (P=0.0001). Malondialdehyde levels did not change among the time points assessed or between the groups (P>0.05). Whereas BAL anesthesia had no effect on acid nucleic and antioxidant status, TIVA decreased oxidized/alkylated purines (P=0.03) and increased antioxidant status (P=0.002) during anesthesia. The two groups did not differ significantly in DNA oxidation or antioxidant status (P>0.05). CONCLUSION: BAL anesthesia maintained with isoflurane and TIVA maintained with propofol are safe by virtue of not causing oxidative stress status in ASA physical status I patients undergoing minimally invasive surgeries. Moreover, even in minor surgeries, TIVA with propofol produces an antioxidant effect in patients.

Oxidative stress status of highly prolific sows during gestation and lactation.

Elevated oxidative stress is reported to be associated with pregnancy complications in highly prolific sows. Oxidative DNA damage and the antioxidant status were determined in blood samples collected during the course of gestation and lactation in multiparous sows. Blood samples were drawn from sows (n = 5) on days 30, 60, 90 and 110 of gestation (G30, G60, G90 and G110, respectively), on day 3, 10 and 18 of lactation (L3, L10 and L18, respectively) and on day 5 of postweaning (W5). Lymphocytes were isolated from the fresh blood and cryopreserved in each time point. Lymphocyte DNA damage was analyzed by alkaline single-cell gel electrophoresis (comet assay) to determine the single- and double-strand brakes and endogenous antioxidant concentrations using an HPLC system with UV detection. The comet assay showed elevated (P < 0.05) DNA damage (between 38% and 47%) throughout the gestational and lactational periods than during early gestation (G30; 21%). Plasma retinol concentration was reduced (P < 0.05) at the end of gestation (G110) compared with G30. Plasma α-tocopherol concentrations also showed a similar trend as to retinol. This study indicates that there is an increased systemic oxidative stress during late gestation and lactation, which are not fully recovered until the weaning compared with the G30, and that antioxidant nutrients in circulation substantially reduced in the mother pig at G110.

Glyceraldehyde-3-phosphate dehydrogenase as a surface associated antigen on human breast cancer cell lines MACL-1 and MGSO-3.

Breast cancer is a major health burden, responsible for >10% of all cases of cancer worldwide. Advances in breast cancer diagnosis and treatment have contributed to an improved rate of survival, although mortality rates remains significantly high. The establishment of breast cancer cell lines is an important model for understanding biological processes involved in this disease and for identifying potential therapeutic targets. The novel human breast cancer cell lines, MACL-1 and MGSO-3, were used in this study to identify possible surface antigens by antibodies directed against two commercial breast cancer cell lines MCF-7 and MDA-MB-231. We purified a 37 kDa antigen by affinity chromatography from MDA-MB-231, and its N-terminal amino acid sequence was homologous to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Therefore, immunohistochemical experiments, using specific monoclonal antibodies, evidenced a co-localization of GAPDH and Na+/K+-ATPase on the surface of commercially available and recently established breast cancer cell lines. It is of note that Na+/K+-ATPase was used as a plasma membrane marker. This finding opens new perspectives for breast cancer diagnosis and treatment since GAPDH could be used as a biomarker or as a potential therapeutic target in breast cancer.

Establishment and characterization of MACL-1 and MGSO-3 cell lines derived from human primary breast cancer.

Breast cancer is a major health burden worldwide. It is responsible for over 1 million of 10 million cases of cancer in the world. Advances in breast cancer detection and treatment have contributed to improve the rate of survival, although mortality rates remains significantly high. Despite all these advances, more efficient diagnostic methods and effective treatments are necessary. The establishment of breast cancer cell lines is an important tool to understand biological processes involved in this disease, as well as the identification of potential therapeutic targets. In the present work, two cell lines, MACL-1 and MGSO-3, were established from human primary breast cancer based on differential centrifugation, followed by growth in culture for over 70 passages. Characterization of the cell lines included morphology analysis, determination of doubling time, telomerase expression, tumor antigen expression, colony formation in soft agar, and xenograft implantation into nude mice. Morphological examination demonstrated a typical epithelial morphology and PCR analyses showed that both cell lines were telomerase positives. Moreover, MACL-1 and MGSO-3 were capable of growing in soft agar culture, which suggests its metastatic potential, and both demonstrated a positive tumorigenic potential in nude mice. These experimental models open new perspectives on the investigation of breast cancer pathobiology.

Parametric sensibility study of the sinoatrial node math model.

The results of the parametric sensibility study to the sinoatrial node math model was presented. The model was proposed by H. Zhang, A. V. Holden and M.R. Boyett. The sensitivity analysis indicates that the sodium and potassium ionic concentrations need to be controlled in order to maintain the normal behavior of the node. The calcium concentrations changes simulated don't produce significant effects over the operation of the node. One response surface model was developed as a simplification of original model. The diastolic depolarization rate was redefined in order to allow its measure in potential waves for peripheral node cells.

Whole-body protein turnover in malnourished patients with child class B and C cirrhosis on diets low to high in protein energy.

The purpose of this study was to determine the rate of whole-body protein turnover in moderately and severely alcoholic, malnourished, cirrhotic patients fed with different amounts of protein or energy. Six male patients (Child classes B and C) and four age- and sex-matched healthy control subjects were studied for 18 d in fasting and feeding states; a single oral dose of [(15)N]glycine was used as a tracer and urinary ammonia was the end product. The kinetic study showed that patients had higher protein catabolism while fasting (patients: 3.14 +/- 1.2 g of lean body mass/9 h; controls: 1.8 +/- 0.3 g of lean body mass/9 h; P < 0.02). Although not statistically significant, protein catabolism (grams of lean body mass/9 h) was lower with the hyperproteic/hyperenergetic diet when compared with fasting. Nitrogen retention was consistent with the lower protein-catabolism rate; a statistically significant increase in nitrogen balance was observed when patients were fed with the hyperproteic/hyperenergetic diet compared with fasting (4.3 +/- 3.2 g of nitrogen/d and -2.2 +/- 1.9 g of nitrogen/d, respectively; P < 0.01). These data indicate that Child class B and C cirrhotic patients are hypercatabolic and that long-term nutritional intervention with a hyperproteic/hyperenergetic diet is likely needed to improve their clinical and nutritional status.

Comparison of omega-3 fatty acids and sulfasalazine in ulcerative colitis.

Fish oil omega-3 fatty acids exert antiinflammatory effects on patients with ulcerative colitis. However, a comparative study in patients with mild to moderate ulcerative colitis receiving only sulfasalazine or omega-3 fatty acids has not been performed. We sought to detect changes in the inflammatory disease activity with the use of either fish oil omega-3 fatty acids or sulfasalazine in patients with ulcerative colitis. Ten patients (five male, five female; mean age = 48 +/- 12 y) with mild to moderate active ulcerative colitis were investigated in a randomized cross-over design. They received either sulfasalazine (2 g/d) or omega-3 fatty acids (5.4 g/d) for 2 m.o. Disease activity was assessed by clinical and laboratory indicators, sigmoidoscopy, histology, and whole-body protein turnover (with 15N-glycine). Treatment with omega-3 fatty acids resulted in greater disease activity as detected by a significant increase in platelet count, erythrocyte sedimentation rate, C-reactive protein, and total fecal nitrogen excretion. No major changes in protein synthesis and breakdown were observed during either treatment. In conclusion, treatment with sulfasalazine is superior to treatment with omega-3 fatty acids in patients with mild to moderate active ulcerative colitis.

[Use of proteic metabolism (15N-glycine) in the early detection of disease exacerbation in patients with non-specific ulcerative colitis]. / Utilização do metabolismo protéico (15N-glicina) na detecção precoce de agravamento da atividade da doença em pacientes portadores de retocolite ulcerativa inespecífica.

Disease activity was assessed in 10 (five males and five females) ulcerative colitis patients through the following parameters: clinical, laboratory, sigmoidoscopic and histological. Protein metabolism was also assessed with 15N-glycine and urinary ammonia as end product. Only one patient had exacerbation of the disease two months after the study started. This patient presented in the beginning of the study protein synthesis and breakdown of 4.51 and 3.47 g protein/kg/day, respectively, values higher than all other patients, showing an hypermetabolic state, suggesting an increase of the disease activity. However, this increase was not detected by others indicators and indexes utilized. These data allow to suggest the hypothesis that protein metabolism predicts precociously the exacerbation of disease activity in ulcerative colitis patients.

Antinociceptive profile of the pseudopeptide B2 bradykinin receptor antagonist NPC 18688 in mice.

1. The purpose of this study was to investigate the topical and systemic anti-hyperalgesic effect of the newly-developed pseudopeptide B2 receptor antagonist, NPC 18688, in different models of nociception in mice. 2. Given systemically 30 min beforehand, NPC 18688 (10-300 nmol kg-1, i.p.) caused no agonist effect, but produced a dose-related and significant inhibition of abdominal constrictions caused by intraperitoneal injection of acetic acid (0.6%), acetylcholine (ACh, 4.5 mg kg-1) or kaolin (50 mg kg-1). The calculated mean ID50s and the percentages of maximal inhibitions (MI) for these effects were: 77, 34 and > 300 nmol kg-1 and 65 +/- 6, 70 +/- 5 and 40 +/- 3%, respectively. The anti-hyperalgesic effect of NPC 18688 (100 nmol kg-1, i.p.) occurred rapidly (30 min) and lasted for at least 150 min. Hoe 140 (3-30 nmol kg-1, i.p.) given 30 min beforehand also inhibited, in a graded manner, acetic acid and ACh-induced writhing, with mean ID50s and MI of 6 and 9 nmol kg-1 and 56 +/- 7 and 62 +/- 6%, respectively. 3. NPC 18688 (10-300 nmol kg-1, i.p.) caused a graded inhibition of both phases of formalin (2.5%)-induced pain, its effects being more potent in relation to the second phase of the formalin test. The calculated mean ID50s and the MI were > 300 and 60 nmol kg-1 and 20 +/- 3 and 60 +/- 5% against the first and second phases of formalin-induced nociception, respectively. NPC 18688 at the same doses also inhibited, in a dose-related manner, formalin-induced paw oedema (MI of 35 +/- 3%). 4. When injected locally in the mouse paw, NPC 18688 (2, 10 and 20 nmol/paw) had no agonist activity. However, when co-injected with formalin NPC 18688 (2-20 nmol/paw), it produced significant inhibition of both phases of formalin response, with MI of 40 +/- 3 and 33 +/- 2%, respectively. NPC 18688 at 10 nmol/paw also significantly inhibited formalin-induced paw oedema (25 +/- 2%). 5. Given intraperitoneally, NPC 18688 (30-300 nmol kg-1) determined a graded inhibition of the nociceptive response caused by intraplantar injection of capsaicin (1.6 micrograms/paw) (40 +/- 2%). However, NPC 18688 (up to 300 nmol kg-1, i.p.), given 30 min beforehand, had no significant analgesic effect when analyzed in the tail flick and in the hot plate pain models, nor did it change the performance of animals in the rota rod test. 6. The action of NPC 18688 was quite selective for the B2 receptor, and like Hoe 140, (1 to 100 nmol kg-1, i.p.) it caused graded inhibition of bradykinin (BK, 3 mol/paw)-induced increase in mouse paw volume, with mean ID50s of 61 and 6 nmol kg-1, respectively. In addition, at 100 nmol kg-1, the dose at which NPC 18688 significantly antagonized BK (3 nmol)-mediated rat paw oedema in naive animals, it had no significant effect on des-Arg9-BK (100 nmol/paw)-induced oedema in paws that had been desensitized to BK. NPC 18688 (210 nmol kg-1), like Hoe 140 (230 nmol kg-1) given s.c. 30 min beforehand, completely abolished BK (28 nmol)-induced hypotension, without affecting the fall of mean arterial blood pressure induced by i.v. injection of ACh (2 nmol kg-1). Finally, NPC 18688 (1 microM) did not affect ACh-mediated contraction in the guinea-pig ileum or toad rectus abdominii in vitro. 7. These results demonstrate that the newly-developed and selective pseudopeptide B2 receptor antagonist, NPC 18688, although less potent than the available second generation of B2 peptide BK receptor antagonists, exhibits topical and long-lasting systemic anti-hyperalgesic properties when analysed in several models of nociception in mice, making it a useful tool for investigating the participation of BK and related kinins in physiological and pathological processes. Finally, this new class of selective pseudopeptide B2 receptor antagonist may constitute a new strategy for developing the third generation of potent and long-lasting orally-active non-peptide BK antagonists, which may be useful for the management of clinical disorders involving BK and relate

Potent antinociceptive activity of a hydroalcoholic extract of Phyllanthus corcovadensis.

This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3-60 mg kg-1, i.p.) or (100-500 mg kg-1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg-1, respectively. In the tail-flick model HE (up to 500 mg kg-1, p.o.) was without effect, while morphine (1-10 mg kg-1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg-1). HE (1-300 mg kg-1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg-1, respectively. In contrast, morphine (1-5 mg kg-1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2.5 mg kg-1. Indomethacin (1-10 mg kg-1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg-1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg-1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for participation of B1 and B2 kinin receptors in formalin-induced nociceptive response in the mouse.

1. This study was designed to investigate the role of bradykinin (BK), as well as the subtype of BK receptors involved, in formalin-induced hindpaw pain in the mouse by use of selective B1 and B2 receptor antagonists. In addition, we have analysed whether or not BK may be involved in formalin-induced hindpaw oedema in the mouse. 2. The pretreatment of animals with captopril (2 and 5 mg kg-1, s.c.) significantly increase the first and the second phases of formalin-induced pain. 3. Co-injection of the selective B1 receptor antagonist des-Arg9[Leu8]-BK (0.2-0.4 nmol/paw), together with formalin, caused graded and similar inhibitions of both phases of formalin-induced pain. Similar results were obtained with the B2 antagonists NPC 349 (D-Arg[Hyp3,Thi5,8-D-Phe7]-BK) and NPC 567 (D-Arg[Hyp3, D-Phe7]-BK) (0.2 and 0.6 nmol/paw). Higher concentrations of these antagonists (1 nmol/paw) failed to antagonize formalin-induced pain. 4. The new potent and selective B2 receptor antagonists, Hoe 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-BK), NPC 17731 (D-Arg[Hyp3, trans-4-propoxy-D-proline (transpropyl)7, Oic8]-BK), and NPC 17761 (D-Arg[Hyp3, trans-4-propoxy-D-proline (trans thiophenyl)7, Oic8]-BK) (0.02 to 1.0 nmol/paw), also caused significant inhibitions of both phases of formalin-induced pain. When Hoe 140 was injected subcutaneously 30 min before formalin injection (9.9 and 99 nmol kg-1), it significantly attenuated both phases of formalin-induced pain. The putative non-peptide BK antagonist, MV 8612 (1.6 to 9.6 nmol/paw), but not MV 8608 (5.5 to 33 nmol/paw), caused a graded inhibition of both phases of formalin induced pain, being, however, more active against the first phase.5. The pretreatment of animals with morphine (2.6 to 13 micromol kg-1, s.c.) caused dose-dependent and equipotent inhibitions of both phases of formalin-induced pain. In contrast, in domethacin (2.7 to 27 micromol kg-1) antagonized only the second phase of formalin-induced pain.6. The B2 receptor antagonists, Hoe 140, NPC 17731, NPC 17761, NPC 349 and NPC 567, all caused a significant inhibition of formalin-induced hindpaw oedema. A similar inhibition was also observed within domethacin but not with captopril or morphine.7. Our results provide strong evidence for the important role of endogenous BK, acting through both B1 and B2 receptors, in the genesis of both phases of formalin-induced persistent pain in the mouse. In addition, the current results also demonstrate that the inflammatory oedema associated with the later phase of formalin-induced pain seems to be mediated by endogenous BK, via activation of B2 receptors.

In vivo cercaria-schistosomulum transformation: inhibitory effect of oxamniquine.

High doses of oxamniquine (given intramuscularly) produced inhibition of cercaria-schistosomulum transformation following intraperitoneal injections of cercariae into mice. Cercariae, tail-less cercarial bodies, and schistosomula were recovered from the peritoneal cavity of drug-treated mice in numbers significantly different from those recovered from untreated mice. Since untreated animals induced transformation of almost all the injected cercariae, the data suggest the compound is active during the process of host-larvae adaptation.