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Coronary risk factors such as diabetes mellitus, hypertension and hyperlipidemia are thought to be linked to insulin resistance (IR). It has been shown that IR may aggravate ischemic heart disease (IHD). We consider that to evaluate IR of patients with IHD is significant when attempting to suppress the aggravation of IHD. This study aimed to evaluate IR of patients after coronary artery bypass grafting (CABG) and to examine for availability of homeostasis model assessment (HOMA-R), which is usually employed in daily practice as a simple index of IR. The IR of twelve patients after CABG and ten healthy subjects was evaluated with the use of the glucose clamp technique, which is the most reliable method for evaluating IR. In this method, IR was quantitated by the rate of whole-body glucose disposal. Furthermore, we looked at the association between HOMA-R and the glucose clamp technique in the patients after CABG. The results were as follows : M-value was lower in the patients after CABG than in the healthy subjects (5.20 ± 2.37mg/kg/min vs. 8.89 ± 3.26mg/kg/min, p = 0.007). A significant correlation between the index of HOMA-R and the rate of whole-body glucose disposal measured by the glucose clamp technique was found in the patients after CABG (r= -0.85, p = 0.004). In conclusion, the patients after CABG possessed IR, and HOMA-R was a useful index of IR in the patients after CABG. [ABSTRACT FROM AUTHOR]

The article investigates the relation of inhaled monoethanolamine (MEA) to the occurrence of bronchoconstriction. Changes in airway opening pressure were measured in guinea pigs as an index of bronchoconstriction. It was found that stronger bronchoconstriction is caused by an aerosol of 3.3% MEA solution inhaled through a tracheal cannula, compared to an aerosol of potassium hydroxide solution. Also, premedication with intravenously injected atropine sulfate, a muscarinic receptor agonist or diphenhydramine hydrochloride was observed to suppress MEA-induced bronchoconstriction.

BACKGROUND: Upregulation of oligopeptide transport activity by dietary protein, certain dipeptides and amino acids has been reported in the rat intestine and a human intestinal cell line. OBJECTIVE: In this study, the pharmacokinetics of cefdinir were investigated after L-phenylalanine supplementation and a high-protein diet (HPD) in humans to explore changes in the activities of intestinal and renal oligopeptide transporters. METHODS: A normal-protein diet (NPD, 73.2 +/- 2.6 g/day), NPD + l-phenylalanine (7.5 g/day), or HPD (141.3 +/- 3.7 g/day) was given to six male healthy volunteers for 12 days followed by a single dose of cefdinir after an overnight fast in a randomized three-way crossover study with a 22-day washout. Blood and urine were collected over a 12-h period after administration of cefdinir. Concentrations of cefdinir in plasma and/or urine were measured by high-performance liquid chromatography. RESULTS: Plasma concentrations and urinary excretion of the drug did not change throughout the study. Physiological variables and laboratory values did not reveal any differences between the three periods except for serum and urinary nitrogen levels and serum triglyceride. DISCUSSION: A reason for the unchanged pharmacokinetics of cefdinir may be due to lower doses of L-phenylalanine and protein in humans than in animals when converting animal effective doses to humans. CONCLUSION: In humans, L-phenylalanine supplementation and HPD do not seem to upregulate intestinal and renal oligopeptide transport in the ranges of duration and dose examined. [ABSTRACT FROM AUTHOR]

Background: Upregulation of oligopeptide transport activity by dietary protein, certain dipeptides and amino acids has been reported in the rat intestine and a human intestinal cell line. Objective: In this study, the pharmacokinetics of cefdinir were investigated afterl-phenylalanine supplementation and a high-protein diet (HPD) in humans to explore changes in the activities of intestinal and renal oligopeptide transporters. Methods: A normal-protein diet (NPD, 73·2 ± 2·6 g/day), NPD + l-phenylalanine (7·5 g/day), or HPD (141·3 ± 3·7 g/day) was given to six male healthy volunteers for 12 days followed by a single dose of cefdinir after an overnight fast in a randomized three-way crossover study with a 22-day washout. Blood and urine were collected over a 12-h period after administration of cefdinir. Concentrations of cefdinir in plasma and/or urine were measured by high-performance liquid chromatography. Results: Plasma concentrations and urinary excretion of the drug did not change throughout the study. Physiological variables and laboratory values did not reveal any differences between the three periods except for serum and urinary nitrogen levels and serum triglyceride. Discussion: A reason for the unchanged pharmacokinetics of cefdinir may be due to lower doses ofl-phenylalanine and protein in humans than in animals when converting animal effective doses to humans. Conclusion: In humans,l-phenylalanine supplementation and HPD do not seem to upregulate intestinal and renal oligopeptide transport in the ranges of duration and dose examined. [ABSTRACT FROM AUTHOR]

Objective: Quazepam, nitrazepam and diazepam are administered under fed or fasted conditions for insomnia or anxiety disorder. Light bedtime food may have clinically relevant effects on the plasma levels of those drugs and hence on psychomotor performance. This study assessed the effect of light food on the pharmacokinetics and pharmacodynamics of these drugs. Method: Twenty-one eligible subjects were randomized to one of three groups of seven subjects: quazepam 20 mg, diazepam 5 mg or nitrazepam 5 mg. Each healthy subject took a single oral dose of the assigned drug after overnight fasting and after light food, on a separate occasion. Blood samples were collected until 72 h after dosing. The plasma samples were assayed using high-pressure liquid chromatography with spectrophotometric detection. Reaction time, critical flicker fusion test and visual analogue scales were conducted. Results: The peak plasma concentration ( Cmax) and area under the concentration–time curve (AUC) of quazepam with light food were 1·2-fold [90% confidence interval (CI): 1·1–1·5; P < 0·05] and 1·5-fold (90% CI: 1·3–1·9; P < 0·05) higher than that without light food, respectively. For nitrazepam and diazepam, the time to peak was delayed about 1 h in fed condition ( P > 0·05). However it had no effect on their Cmax and AUC. Reaction time of quazepam with light food was prolonged at 4 and 6 h after dosing and its area under the effect–time curve from 0 to 10 h was increased ( P < 0·05). Conclusion: Light food increased the bioavailability of quazepam and affected psychomotor performance. Light food delayed Tmax of nitrazepam and diazepam but had no effect on Cmax and AUC. [ABSTRACT FROM AUTHOR]

The study compared maximum drug concentration (C(max)) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for C(max) and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of C(max) were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized C(max) and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human C(max) and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability. [ABSTRACT FROM AUTHOR]

Background: MKC-733, a 5-HT3 receptor partial agonist, is a novel enteroprokinetic compound. Objective: The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined. Methods: The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22-67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0·2 and 0·5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low ( n = 6) and high ( n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms. Results: Percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo treatment in the whole group (70·4 ± 33·5% vs. 47·1 ± 36·6%, mean ± SD, P < 0·05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo (7·1 ± 0·9 vs. 5·9 ± 0·5, P < 0·05; 60·0 ± 35·8% vs. 13·3 ± 19·4%, P < 0·05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo ( P < 0·05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted. Conclusion: Multiple doses of 0·5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population. [ABSTRACT FROM AUTHOR]

Background: MKC-733, a 5-HT3 receptor partial agonist, is a novel enteroprokinetic compound. Objective: The aim of this study was to explore the effects of MKC-733 on bowel motility and symptoms in a small group of subjects with constipation. Tolerability was also examined. Methods: The study was conducted in a single-blind and dose-escalation manner on 14 male and female subjects with constipation aged 22–67 years. After a 1 week run-in period, subjects were treated with placebo (b.i.d.) for 1 week, and 0·2 and 0·5 mg of MKC-733 (b.i.d.) for 2 weeks sequentially. Geometric mean and per cent elimination of surrogate markers of bowel motility were measured by a radio-opaque marker technique at the end of each treatment period. They were analysed on the whole group and subgroups with low ( n = 6) and high ( n = 8) bowel motility based upon the geometric mean value after placebo treatment. Subjects kept diaries of their bowel habits and gastrointestinal symptoms. Results: Percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo treatment in the whole group (70·4 ± 33·5% vs. 47·1 ± 36·6%, mean ± SD, P < 0·05). In the low bowel motility group, both geometric mean and percent elimination increased after treatment with 0·5 mg MKC-733 compared with placebo (7·1 ± 0·9 vs. 5·9 ± 0·5, P < 0·05; 60·0 ± 35·8% vs. 13·3 ± 19·4%, P < 0·05). Stool frequency increased after the first-week treatment with MKC-733 compared with placebo ( P < 0·05). Numbers of sensation of incomplete evacuation and gastrointestinal symptoms decreased to half and less after the treatment with MKC-733. No serious adverse effect was noted. Conclusion: Multiple doses of 0·5 mg MKC-733 improve bowel motility, which was clearly demonstrated in the subjects with decreased bowel motility. MKC-733 at the doses studied might be effective in increasing stool frequency and reduce gastrointestinal symptoms related to constipation. MKC-733 was well tolerated. Further studies will be needed to clarify efficacy and safety of MKC-733 on a larger population. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine the effects of exercise on waist circumference and plasma lipids in obese men with heart disease. METHODS: Ten obese men with heart disease were randomly assigned to participate either in a control group (n=5)or in a three month exercise group(n=5). Measurements were taken of the waist circumference, total cholesterol (TC), high-density lipoprotein(HDL-C), and triglyceride(TG). Participants in the exercise group were asked to perform exercise that expended 200 kcal day beyond their usual level of physical activity. All patients were asked to maintain all isocaloric diet for the duration of the treatment period. RESULTS: The patients in the exercise group increased their physical activity by a mean of 237.4 kcal/day (p < 0.01)from pre- to post-intervention. Waist circumference decreased in the exercise group significantly (94.4 ± 3.7 ± 92.9 ± 4.6cm ; p <0.05)and did not change in the control group. The level of TC, HDL-C and TG did not change in either of the groups. CONCLUSIONS: The results indicated that a 3 month exercise training program induces favorable alterations of waist circumference in obese men with heart disease. However, there were no effects on the plasma lipid levels. [ABSTRACT FROM AUTHOR]

We examined the effects of selective cyclooxygenase COX) inhibition on hepatic warm ischemia/reperfusion I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-α also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-α. Moreover, the effects of the thromboxane (TX) A[sub2] (TXA[sub2]) synthase inhibitor OKY-046 and the TXA[sub2] receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-α production, and that TXs derived from COX are partly responsible for I/R-induced liver injury. [ABSTRACT FROM AUTHOR]

After coronary artery bypass grafting (CABG), 6l consecutive patients (60.9 ± 10.5 years old, male: female 54:7) participated in supervised cardiac rehabilitation (average 15.2 days). The rehabilitation program included 30 minutes endurance training by upright cycle ergometer at anaerobic threshold (AT) level twice a day, 6 times a week. Training intensity was 68.6% of peak V̇O2 and 51.8% of work rate at AT. An educational program of diet and daily exercise counseling was also included. We evaluated exercise tolerance before and after rehabilitation by cardiopulmonary exercise testing. Peak V̇O2 was improved from 14.3 ± 3.0 to 16.6 ± 3.2 ml/min/kg (p<0.0001) and AT also increased from 10.2 ± 1.7 to 10.7 ± 1.6 ml/min/kg (p=0.008) before and after rehabilitation. These changes were more evident in patients who had less exercise capacity but were not significant between groups for age, rehabilitation period and preoperative clinical diagnosis. We performed effectively comprehensive cardiac rehabilitation including AT level endurance training for patients after CABG. [ABSTRACT FROM AUTHOR]

Over the last 7 years, snowboarding has become established as a popular sport in Japan. The present-day skier uses a high, rigid boot and multiple angle release bindings, but most snowboarders use a low, soft boot and rigid bindings. This study evaluates ankle ligament injuries in snowboarding and skiing. We report on 37 snowboarders and 48 skiers who sustained ankle ligament injury during 3 ski seasons. With the aid of stress roentgenograms, the extent of injury was established and conservative treatment was performed on all patients. Comparing skiers' versus snowboarder' injuries, 24(65%) versus 25(52%) were male, the mean age was 24.8 versus 22.1 years, constituting 6.8% versus 4.3% of all injuries, 35(94%) versus 46(96%) were involved the lateral ligamentous structures, and sprains of the ankle were classified as grade I:10(27%), grade II: 21(57%), and grade III: 6(16%) versos 12(25%), 33(69%), and 3(6%), respectively. A high percentage of injury in their first to third year of snowboarding and skiing was demonstrated in this study. It is important to understand the ankle ligament injuries that can occur during snowboarding and skiing. With proper diagnosis, appropriate treatment for these injuries can he provided. Additional research is needed to better understand the characteristics of these injuries. [ABSTRACT FROM AUTHOR]

Objective: The present experiments were performed to ascertain whether or not all plasma components are extravasated when vascular permeability is increased.¶ Animals: Male Sprague-Dawley strain rats (specific pathogen-free) 8 weeks old (for histamine exudation) or 9–10 weeks old (for carrageenin pleurisy) were used.¶ Methods: Histamine or λ-carrageenin was injected into the rat right pleural cavity to induce rat pleurisy. Protein components in the inflammatory exudate and plasma were separated by high performance liquid chromatography. Coagulation time was assessed, and the fibrinogen levels in the pleural exudate were determined by thrombin time. The fibrinogen levels were also visualized by immunoblot analysis. Tumor necrosis factor-α (TNF-α, 0.4 μg/rat, intrapleurally), anti-rat CD18 monoclonal antibody (anti-CD18 antibody, 1 mg/kg, i.v.) and granulocyte-colony stimulating factor (G-CSF, 100 μ/kg, s.c. twice daily for 4 days) were used.¶ Results: In the histamine-induced extravasation, the level of plasma protein components with large molecules over 900 kD in the exudate was 62 % of that in the rat's own plasma. The amount of fibrinogen in the pleural exudate was 1/8 of that in the plasma and was faintly detected in immunoblot analysis, but it was clearly detected after the treatment of rats with TNF-α. In rat carrageenin pleurisy, fibrinogen was hardly detected in immunoblot analysis in the exudate collected 0.5 h after carrageenin, when neutrophils did not migrate into the exudate. However, it was clearly present after neutrophil migration started 2 h later. The increase in the neutrophil counts in the exudate caused by G-CSF enhanced the fibrinogen level in the exudate, whereas intravenous injection of anti-CD18 antibody suppressed the fibrinogen level in immunoblot analysis.¶ Conclusions: Venular permeability increase in the rat histamine exudation induced minimal extravasation of plasma proteins with large molecules, such as fibrinogen, while fibrinogen molecule was detected in rat carrageenin-injected pleurisy, when neutrophil diapedesis occurred. Thus, only when neutrophils started to migrate into the perivascular space was fibrinogen clearly detected in the exudate. [ABSTRACT FROM AUTHOR]

Objective and Design: Effects of cyclooxygenase inhibitors on noxious thermal stimuli were investigated in non-inflamed and inflamed rats.¶ Materials: Male Sprague-Dawley rats were used in this study.¶ Treatment: Cyclooxygenase inhibitors, indomethacin, mofezolac, NS-398, and JTE-522 were administered orally at a dose of 10 mg/kg 1 h prior to and 4 h after the intravenous injection of lipopolysaccharide (1 mg/kg).¶ Methods: The nociceptive response was evaluated from the escape latency of foot withdrawal to the thermal stimuli with a beam of light. Expression of cyclooxygenase was examined by reverse transcription-polymerase chain reaction.¶ Results: In normal rat, administration of indomethacin, relatively cyclooxygenase-1-selective inhibitor, mofezolac, or cyclooxygenase-2-selective inhibitors, NS-398 and JTE-522 had no effects on the escape latency against thermal stimuli. Injection of lipopolysaccharide into rat induced the expression of mRNA for cyclooxygenase-2 in the subcutaneous tissue of foot pad. The escape latency at 8 h was significantly shortened by the injection. This hyperalgesia could be reversed by pretreatment of rat with NS-398 or JTE-522, but not with mofezolac.¶ Conclusions: Cyclooxygenases may have little participation in peripheral skin thermal nociception in non-inflamed condition, although cyclooxygenase-2 could be responsible for the hyperalgesia during inflammation induced by lipopolysaccharide.¶ [ABSTRACT FROM AUTHOR]

In addition to housekeeping cyclooxygenase (COX)-1, which is constitutively expressed in many body cells, an inducible COX-2 has been described and cloned. Induction or presence of COX-2 has been reported not only in isolated cells, but also in cells in various tissues, as well as in both physiological and pathophysiological states, including acute exudative inflammation, proliferative inflammation, animal arthritis, rheumatoid arthritis, angiogenesis, bone absorption, gastric ulcer, colon cancer, hyperalgesia, Alzheimer's disease and certain states of the kidney, brain and female reproductive organs. This review article introduces results from recent works in these fields. COX-1- or COX-2-knockout mice may provide many clues on the roles of COX-2, but may simultaneously cause unnecessary confusion in the recognition of the roles of COX-2, and this is discussed. Recently the roles of COX-2 in exudative inflammation and the anti-inflammatory effects of selective COX-2 inhibitors have been questioned. This is discussed in the text. Prostanoids mediate signals to adjacent cells to provide fine regulation of cellular function. Because of the short duration of the expression of COX-2 gene and protein, COX-2 must play some roles different from those of COX-1 gene and protein in vivo. It is not yet possible to identify all the roles of COX-2, but in some tissues, such as the kidney, the brain and others, COX-2 may be expressed constitutively, whereas the prostaglandin generation by COX-2 may replace that by COX-1 in some states (or vice-versa). Precise analyses of the expression of COX-2 may disclose fine modulation of cellular and organ functions by PGs. Several selective or preferential COX-2 inhibitors have been developed and were shown to be effective in clinical trials. Most were reported to be free of adverse gastrointestinal effects, but it should be noted that in the healing process of gastric ulcers and in sodium-restricted states, adverse effects of selective COX-2 inhibitors could be expected. Soon, with more detailed knowledge of the delicate roles of COX-2 in vivo, effective and safe application of COX-2 inhibitors should be realized. [ABSTRACT FROM AUTHOR]

Capsaicin acts specifically on primary afferent neurons to release neuropeptides, including calcitonin gene-related peptide (CGRP), and prevents ethanol-induced mucosal injury. To investigate the microvascular changes in the gastric mucosa in response to ethanol using intravital microscopy to elucidate the mechanism of capsaicin-induced gastroprotection. Ethanol (50%) applied to the mucosa constricted the collecting venules and venuls but dilated arterioles. The constriction of the collecting venules resulted in mucosal congestion, which caused mucosal injury. Application of capsaicin to the mucosa dilated the arterioles but not the collecting venules or venules. Arteriolar dilation was inhibited by a CGRP antagonist, CGRP-(8–37). Prior application of capsaicin prevented ethanol-induced constriction of the collecting venules, and the action of capsaicin was inhibited by prior application of CGRP-(8–37). The results suggest that the inhibition of ethanol-induced gastric injury by capsaicin is attributable to the suppression of collecting venule constriction, via CGRP release. [ABSTRACT FROM AUTHOR]

To determine the role of endogenous substance P in ethanol-induced mucosal damage, two experiments were performed. In the first experiment, the stomachs of anesthetized rats were doubly cannulated and gastric damage was induced with 5ml of 30% ethanol in the gastric lumen. The damage was ameliorated by pretreatment with capsaicin (0.16 and 1.6 mM) and spantide (100 mg/kg, i.v.). In the second experiment, the gastric mucosa of these rats was perfused with physiological saline containing pepstatin (10 microliters/ml). Endogenous substance P (SP) in the perfusate was measured by enzyme immunoassay (EIA). The peak SP levels were increased by capsaicin (0.16-1.6 mM) in a concentration-dependent manner. Perfusion with 50% ethanol for 5 min increased the SP levels approximately threefold. Perfusion with 1.6 mM capsaicin, followed by 50% ethanol, reduced the injured area to about one-quarter of the original injured area. The peak SP levels during perfusion with 50% ethanol after pretreatment with 1.6 mM capsaicin did not differ from those observed after vehicle pretreatment (control). The area under the curve for SP release during 50% ethanol perfusion after vehicle perfusion was not reduced by previous perfusion with 1.6 mM capsaicin followed by 50% ethanol, indicating that the prevention of ethanol-induced injury by capsaicin may be due to excess amounts of different neuropeptides released simultaneously. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX)-2 was induced in an acute exudative inflammatory model (rat carrageenin-induced pleurisy) in which prostaglandin E2, 6-keto-prostaglandin F1α, and thromboxane B2 were generated in the pleural fluid. Selective COX-2 inhibitors, such as NS-398, inhibited the plasma exudation and generation of prostaglandin E2, but not that of thromboxane B2 and 6-keto-prostaglandin F1α, in the pleural fluid. In proliferative inflammatory models, COX-2 was induced, and selective COX-2 inhibitors suppressed granuloma formation, particularly, microvessel formation. COX-2 was induced during angiogenesis in a sponge model implanted into skin of rat, and the COX-2 inhibitor suppressed the angiogenesis. As induction of COX-2 was reported in osteoblasts, COX-2 was involved in most characteristic responses of acute exudative inflammation, granuloma formation, bone resorption, and pain in rheumatoid arthritis. The prevention of these COX-2 responses provides a rationale for the effectiveness of COX-2 inhibitors in the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

We have developed an ELISA for BK-(1-5) (Arg-Pro-Pro-Gly-Phe). In rat carrageenin-induced pleurisy, in which a plasma exudation peak was observed 5 h after carrageenin, BK levels in the exudates were negligible (<60 pg/rat). BK-(1-7) (des-Phe-Arg-BK) was detectable (900-400 pg/rat) over the entire course of the inflammation. However, a larger amount of BK-(1-5) was detectable in association with the increase in plasma exudation, showing a peak (8800±1200 pg/rat) 3 h after carrageenin. Bromelain (10 mg/kg, i.v.) and soy bean trypsin inhibitor (0.3 mg/rat, intra-pleural) significantly reduced BK-(1-5) levels (by 60-93%, 3, 7 and 19 h after carrageenin) and plasma exudation rates (by 61-74%, 3 and 7 h after carrageenin). Dexamethasone (0.3 mg/kg, i.p.) reduced BK-(1-5) levels (by 78%) and decreased plasma exudation (by 70%) 3 h after carrageenin. In nasal allergy patients, antigen challenge of nasal mucosa elevated BK-(1-5) levels and active kallikrein levels in nasal washes. These results verify that BK-(1-5) determined by ELISA is a good indicator for release of kinins in vivo. [ABSTRACT FROM AUTHOR]

Administration of human recombinant granulocyte colony-stimulating factor (G-CSF, 100 μg/kg/day, s.c) to rats for 4 days significantly increased circulating neutrophil counts (by 1130%), together with an increase in mononuclear leukocyte counts (by 119%). Infiltrated pleural neutrophil counts in G-CSF-treated rats (G-CSF-r) 5h after the intrapleural injection of zymosanactivated serum were significantly higher (by 155%) than those in control rats (Vehicle-r). In carrageenin-induced pleurisy, counts of infiltrated pleural neutrophils in G-CSF-r 5 and 7h after carrageenin were significantly higher (by 119% and 116%) than those in Vehicle-r. G-CSF treatment increased the volume of pleural exudate and the plasma exudation rate by 122% and 226%, compared to values in Vehicle-r 5h after carrageenin. Cobra venom factor (75 μg/kg, i.v.) significantly reduced pleural neutrophil migration in G-CSF-r (by 53%) and Vehicle-r (by 49%). Bromelain (10 mg/kg, i.v.) and aspirin (100 mg/kg, p.o.) reduced pleural neutrophil migration and reduced exudate volume and plasma exudation. Intrapleural bradykinin-(1-5) and prostaglandin E levels were significantly higher in G-CSF-r than in Vehicle-r. The increased neutrophil migration in G-CSF-r may be atributed to enhanced activation of the complement system facilitated by increased plasma exudation due to bradykinin and prostaglandins. [ABSTRACT FROM AUTHOR]

In anesthetized, mechanically ventilated guinea pigs, infusion of captopril (1 mg/kg/h), an angiotensin converting enzyme inhibitor, significantly enhanced bronchoconstriction induced by intravenous injection of bradykinin (BK; 0.1-30 nmol/kg). Pretreatment of guinea pigs with capsaicin (100 μg/kg) slightly suppressed the bronchoconstriction by BK alone and almost all of the enhancement of BK-induced bronchoconstriction by captopril was suppressed. Intravenous injection of substance P (SP; 0.1-100 nmol/kg), neurokinin A (NKA; 0.1-30 nmol/kg) and neurokinin B (NKB; 0.1-30 nmol/kg) also induced dose-dependent bronchoconstriction but captopril treatment enhanced only the bronchoconstriction induced by SP. BK degradation in bronchoalveolar lavage fluid (BALF) in vitro was significantly suppressed by captopril (p<0.05). Captopril infusion to guinea pigs significantly increased the levels of BK, SP, and NKA in BALF after BK injection (p<0.05). FK224, an NK1 and NK2 receptor antagonist and SR 48968, an NK2 receptor antagonist, significantly suppressed the broncoconstriction induced by BK alone (p<0.01 and p<0.05, respectively) as well as the enhancement by captopril (p<0.01). It can be concluded that the enhancement of BK-induced bronchoconstriction by captopril was attributable to inhibition of the degradation of BK itself and thereby enhanced release of NKA and partly of SP from sensory nerves by BK. [ABSTRACT FROM AUTHOR]