Evaluation of nasal passage patency after antigen and histamine challenge in guinea pigs by acoustic rhinometry

Persistent pain after distal claviculectomy (the Mumford procedure) has been attributed to both inadequate and excessive clavicle resection or incomplete supraspinatus outlet decompression with continued impingement. A retrospective review of twenty glenohumeral arthroscopies done in shoulders with a previous Mumford procedure disclosed 15 cases, (75%) of superior glenoid labrum, long head biceps tendon (SLAP) lesions. Most of the distal calvicle resections 13 out of 15 (86%) had been done for "acromioclavicular arthritis." These patients were young, with an average age of 37 years (range 20 to 50) and most, 14 out of 15, had pain attributable to a specific traumatic event. Most had deep pain referable to the bicipital groove with cross chest adduction of the shoulder with the elbow extended and forearm pronated (thumb down). The discomfort improved with the forearm supinated (thumb up). It is concluded the SLAP lesion to be part of the differential diagnosis of acromioclavicular joint disease. In younger patients with a traumatic history, glenohumeral arthroscopy should be used to rule out SLAP pathology and possibly prevent an unnecessary distal clavicle resection.     

The effect of unilateral nasal patency on the contralateral side

This investigation was designed to verify the possible feed-back mechanism which works to compensate for changes in the nasal volume of one side by the other side. Acoustic rhinometry, with which nasal volume is easily evaluated, was used in this investigation. Acoustic rhinometry was performed at 4 points in time (immediately after, and three, six and nine minutes after, the setting of experimental conditions). This investigation was composed of two studies. In the first study, ten healthy subjects (nine males and one female, 26-49 years of age, mean age 30 years) were evaluated to estimate the effect of decreased unilateral nasal patency upon the other side. In this study, one nasal cavity was occluded with an acryle plug, and the nasal volume of the other side was evaluated by acoustic rhinometry before and after the occlusion. In the second study eight healthy subjects (five males and three females, 24-34 years of age, mean age 29 years) were evaluated to estimate the effect of increased unilateral nasal patency upon the other side. This study covered a period of three days. A small piece of cotton soaked in a vasoconstrictor solution (1/1000 adrenalin or 0.05% naphazolin nitrate) was put in one nasal cavity (the right on the first day, the left on the second day) and the other side was evaluated before and after administration of the solution. On the third day of the control study, a similar piece of cotton soaked in physiological saline solution was put in one nasal cavity, and the other side was evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Participation of leukotriene D4 and tumor necrosis factor on lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs

Partial failure of a free flap can create an unusual dilemma, as guidelines suggesting appropriate further intervention are not well defined. The increased complexity of a second free flap attempt is not necessarily contraindicated, but must be minimized if the same fate as the first is to be avoided. For the unique circumstance where the initial failed flap contained a vascular flow-through, the most distal patent vessels can then secondarily serve in an expeditious manner as the recipient vessels for the second or salvage free flap. The efficacy of this concept has been here validated after limited necrosis occurred in the distal portion of a radial forearm free flap. Following the requisite debridement, the residual flap still maintained a satisfactory arterial and venous flowthrough as a "bridge flap" that supported the attachment of a gracilis muscle free flap, and both flaps in turn preserved a sensate transtarsal amputation stump.     

Late phase response during nasal challenge: effect of astemizole on leukotriene B4 levels

Two conditioned media were prepared by culturing human umbilical artery smooth muscle cells (SMC) in 75 cm2 flasks with minimum essential medium (MEM) under magnesium (Mg) sufficient (900 microM) or deficient (100 microM) conditions for 72 h ([900]- and [100]-MEM), respectively. A third conditioned medium was obtained by adjusting the Mg concentration of half of the [100]-MEM to 900 microM ([100-900]-MEM). SMC in 12-well plates were incubated in one of the three conditioned media and the growth rates of SMC were determined by [3H]-thymidine incorporation and cell counting. The growth rate in [100-900]-MEM was significantly higher than in [900]- and [100]-MEM. When platelet derived growth factor (PDGF) was neutralized by the addition of a mixture of anti-PDGF-AA and -BB antibodies, [3H]-thymidine incorporation in [100-900]-MEM decreased by 23.3 per cent, but only by 7.0 per cent in [900]-MEM. The quantity of PDGF in the Mg-deficient media was greater than in the magnesium-sufficient media at all indicated times, as shown by radioimmunoassay for PDGF-BB or -AB. These results indicate that Mg deficiency increases the secretion of PDGF by SMC.     

Staurosporine inhibits the effects of leukotrienes C4 and D4 in isolated guinea pig heart and trachea

Isolated hearts from guinea pigs were perfused at 37 degrees C with Tyrode's solution according to the technique of Langendorff. Coronary flow, left ventricular pressure amplitude and heart rate were measured. Bolus injection of 30 ng leukotriene C4 caused a long-lasting decrease in coronary flow and left ventricular pressure amplitude while heart rate was not affected. A similar but shorter lasting effect was induced by 100 ng leukotriene D4. The effects of the leukotrienes were completely blocked by 1 microM staurosporine. Staurosporine at concentrations of 100 and 10 nM, in contrast to 1 microM, influenced basic cardiac function slightly or not at all, but antagonized the effects of 30 ng leukotriene C4. In isolated tracheal muscle preparations, leukotriene C4 and D4 induced concentration-dependent contractures. Staurosporine at concentrations of 25-100 nM antagonized the effects of leukotriene C4 and D4 in a noncompetitive manner with inhibitor constants of 47.6 and 75.9 nM, respectively. The results indicate that staurosporine is a potent noncompetitive antagonist of the effects of leukotriene C4 and D4 in smooth muscle.     

Effect of SC-41930, a potent selective leukotriene B4 receptor antagonist, in the guinea pig model of middle ear inflammation

Arachidonic acid metabolites such as prostaglandins and leukotrienes have been shown to play an important role in the pathogenesis of otitis media (OM). Among these mediators, leukotriene B4 (LTB4) is one of the most potent inducers of inflammatory processes. SC-41930 has been shown to be a specific LTB4 receptor antagonist both in vitro and in vivo. In this study, anti-inflammatory effects of SC-41930 were investigated in a guinea pig model of OM induced by middle ear (ME) inoculation of killed Staphylococcus aureus. Outcome of treatment was determined by measurement of myeloperoxidase activity in the samples of ME mucosa, evaluation of temporal bone histopathology, and presence of ME fluids. Myeloperoxidase activity in the SC-41930-treated group was found to be significantly lower than that in the control group. Histopathology of temporal bones indicated decreased inflammation in the treated group as compared to the controls. In addition, ME fluids were absent in four out of six treated animals. These results demonstrate that SC-41930 can produce significant anti-inflammatory effects in this model of OM.     

The effect of IL-4 on human nasal mucosal responses

Interleukin (IL)-4 causes the dose limiting sensation of nasal congestion when administered systematically at doses of 3 micrograms/kg or higher thrice daily to humans. This side effect was observed in a group of patients treated as part of an immunotherapy protocol for cancer management. To determine the source of this congestion, nasal secretions were collected prospectively in a group of patients at baseline and after provocation with normal saline, methacholine (which stimulates glandular secretion), and histamine (which causes increased vascular permeability). Nasal lavages obtained at baseline and after provocation were analyzed for the presence of these glandular and vascular proteins and inflammatory mediators. Washings and provocations were performed before IL-4 administration, after 24 hours of IL-4 treatment, and after 3 days of treatment, at a time when nasal congestion was maximal. Compared with histamine challenge before IL-4 treatment, the secretion of the plasma proteins albumin and IgG were significantly decreased after 3 days of IL-4 treatment. IL-4 treatment had no apparent effect on methacholine-induced responses. Thus systemically administered IL-4 causes the subjective sensation of nasal congestion, increased histamine in nasal lavages, and the development of vascular unresponsiveness to histamine, without affecting parasympathetic responses to histamine. The relationships among increases in nasal lavage histamine, vascular unresponsiveness to histamine, and the sensation of nasal congestion are unclear.     

Development of new chromanol antagonists of leukotriene D4

By addressing the issues of potency and metabolism in 3, a new series of LTD4 antagonists represented by (+)-26 was developed which is equipotent to clinical LTD4 antagonists Zafirlukast (1) and Pranlukast (2).     

The effect of chronic diazepam treatment on hypoxia-induced alterations in functional activity of guinea pig myocardium

The concentration-related sensitization of guinea pig left atrium to adenosine in the presence of diazepam is well established. It was found in our experiments that the cardiodepressive action of hypoxia is significantly enhanced by diazepam in the left atrial myocardium. In atrial preparations obtained from guinea pigs treated with diazepam for 10 days, the hypoxia-induced depression of myocardial contractility was not altered. These results indicate that diazepam-treatment does not impaire the hypoxic tolerance of myocardium.     

Inhibitory effect of tetrahydropalmatine on calcium current in isolated cardiomyocyte of guinea pig

AIM: To study the effect of tetrahydropalmatine (THP) on calcium channels in ventricular single cells of guinea pig heart. METHODS: Patch-clamp technique (whole cell recording) was used to observe calcium current in ventricular myocytes. RESULTS: THP decreased ICa in ventricular myocytes with a dose and frequency-dependent manner. THP (0.1, 1, and 10 mumol.L-1) decreased ICa from 1.15 +/- 0.22, 0.91 +/- 0.18, and 1.60 +/- 0.42 nA (control) to 0.9 +/- 0.21 (P < 0.01), 0.56 +/- 0.21 (P < 0.01), and 0.83 +/- 0.21 nA (P < 0.05), respectively, number of cells is five in each group (n = 5), and the rates of the depression of ICa were 22%, 38%, and 48%, respectively. The effect was easily reduced by washing the cell with the Tyrode's solution. The current-voltage relation curve showed that the potential producing peak value of ICa was 0 mV at which THP had the most markedly inhibited action on ICa. When the stimulating frequency was changed, ICa varied in a frequency-dependent manner 5 min after THP was given, and the inhibition of THP was stronger at 2 Hz than that at 0.1 Hz. CONCLUSION: THP possessed a Ca2+ channel blocking effect.     

Inhibitory effects of tachykinin receptor antagonists on leukotriene C4-induced cardiovascular responses in guinea pigs

This study is to determine whether sensory neuropeptides are involved in the cardiovascular effects of leukotriene C4 (LTC4). LTC4 (0.8 nmol.kg-1, i.v.) caused hypotensive response and increased Evans blue extravasation from the atria and ventricles in anaesthetized guinea pigs. CP-96345 (2.06 mumol.kg-1, i.v.), a tachykinin NK-1 receptor antagonist, and SR-48968 (1.66 mumol.kg-1, i.v.), an NK-2 receptor antagonist, partially inhibited LTC4-induced increase (46.6% and 37.5%, respectively) of dye extravasation from the atria of guinea pigs. Combination of CP-96345 and SR-48968 markedly inhibited LTC4-induced hypotension and increase of microvascular leakage in both atria and ventricles (58.1% and 54.1%, respectively), similar to the inhibition by ONO-1078 (0.06 mumol.kg-1, i.v.), a specific leukotriene antagonist. These results suggest that NK-1 and NK-2 receptors may be involved in the hypotension and the inflammation of heart induced by LTC4.     

The effect of chorion-uterine interaction upon free progesterone metabolism during advanced gestation in the guinea pig

The in vitro fate of [3H]progesterone was studied after incubation with guinea pig tissues at 58/59 days (before pubic symphysis relaxation) and in the final week (post relaxation) of gestation. Buffered steroid was added to the fetal surface of chorion attached to the uterus or to the uterus alone. Neither the amount of recovered progesterone nor its metabolites (6.2% average conversion) differed between the two stages when only uterus was incubated. With chorion present, conversion averaged 28.3% at 58/59 days and 63.4% at the late stage. A 4.6-fold decrease in progesterone concentration, and 3.0-, 2.4- and 3.1-fold increases in the concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one, 3beta-hydroxy-5alpha-pregnan-20-one and 5alpha-pregnane-3,20-dione, respectively, were found in the uterus in the late stage vs 58/59 days. Also, 2.8- and 6.4-fold decreases in progesterone concentration occurred in the myometrium and endometrium, respectively, from 58/59 days to the late stage. In endometrium, the concentrations of the 3alpha- and 3beta-isomers, and 5alpha-pregnane-3,20-dione, increased 2.6-, 2.6- and 5.0-fold, respectively. The above changes were all significant at P < 0.05 or better. Changes in the 3alpha-, 3beta- isomers and dione in the myometrium were not significant. The chorion-uterine interaction and gestation time thus affect the degree of progesterone conversion, and the amounts of metabolites reaching the uterus in the chorion-uterine in vitro system.     

Enhancement effect of tetramethylpyrazine on slow inward current in guinea pig papillary muscles

Tetramethylpyrazine (TMP) could potentiate the force of contraction and increase the action potential duration (APD) of isolated guinea pig papillary muscles in a dose-dependent manner. Similar effects were also observable in BaCl2 or histamine-induced contraction and the accompanied slow action potential (SAP). In fact, contraction and SAP could also be induced by TMP itself at 3.0 mmol/L concentration and antagonized by verapamil (1 mumol/L) within 10 min. In the presence of propranolol or in experiments carried out in catecholamine-depleted (reserpine 2.5 mg/kg, i.p. 15 h prior to the experiment) muscles, TMP was unable to induce SAP and contraction. These results suggested that the effects of TMP on enhancing Isi were mediated by the release of catecholamine in myocardium.     

Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart

BACKGROUND: The local anesthetic bupivacaine is an equal mixture of two optically active isomers known to exert different cardiotoxic profiles in vivo. Enantiomer-specific forms of bupivacaine may have differential effects on cardiovascular function, specifically on cardiac electrophysiology. The authors' aim was to determine if there were any direct functional differences in the cardiac effects of bupivacaine isomers. The isolated heart was used to avoid possible indirect cardiac effects of bupivacaine, such as autonomic nervous and hormonal influences, as well as preload and afterload factors. METHODS: The hearts of 12 ketamine-anesthetized guinea pigs were perfused with Krebs-Ringer's solution (97% oxygen, 3% carbon dioxide) at constant perfusion pressure using the Langendorff technique. Atrial and ventricular bipolar electrodes were placed to measure heart rate (HR) and atrioventricular (AV) conduction time. Left ventricular pressure (LVP), coronary flow, and inflow and outflow oxygen tensions were also measured. Oxygen delivery, oxygen consumption (MVO2), and percentage of oxygen extraction were calculated. Each heart was perfused with increasing randomized concentrations (0.5, 1, 5, 10 microM) of both isomers and the racemate of bupivacaine. RESULTS: Racemic and isomeric bupivacaine equally and dose dependently decreased cardiac function. At 10 microM bupivacaine these changes were HR, -17 +/- 2%; LVP, -50 +/- 3%; coronary flow, -20 +/- 4%; and MVO2, -46 +/- 4%. The (+) isomer significantly prolonged AV conduction compared with the racemate and the (-) isomer at all concentrations. At 10 microM, AV time was 54 +/- 6% longer with the (+) isomer and 30 +/- 4% longer with the (+/-) racemate than with the (-) isomer. The greater delay in AV time with the (+) than the racemate or (-) isomer led to a second-degree AV dissociation in 10 of 12 of hearts treated with (+) bupivacaine. CONCLUSIONS: This study shows that bupivacaine has an enatiomer-specific effect to delay AV conduction and to produce second-degree AV dissociation in the isolated perfused heart. This suggests that bupivacaine isomers probably have differential effects on one or more ion-specific channels regulating AV conduction. Other measured direct cardiac effects of bupivacaine appear to be independent of the isomeric form.     

Subchronic toxicity studies with the leukotriene D4 antagonist RG 12525

Preclinical safety studies with the leukotriene D4 antagonist RG 12525 were conducted by the oral route in mice, rats, and monkeys. Oral administration of RG 12525 was repeated daily in studies up to 6 months in duration. RG 12525 was shown to have limited high-dose toxicity after repeated oral administration. The effects of RG 12525 were strongly dependent upon the species considered. High doses of RG 12525 caused significant increases in liver weight in mice, rats, and monkeys that were associated with diffuse hepatocellular hypertrophy in mice and rats but not in monkeys. No related clinical chemistry changes were observed in any of the species and hepatic activities of peroxisomal enzymes or cytochrome P450 were increased only slightly. Proliferation of brown adipose tissue (BAT) was observed in rats and mice but not in monkeys. The BAT reaction was more pronounced in the interscapular area but it was also observed in other subcutaneous locations as well as in mediastinal and bone marrow fat. In all locations, the RG 12525-induced BAT had some morphological similarities with cold-adapted BAT. Repeated administration of RG 12525 at high doses to female rats resulted in a lack of progression to the luteal phase of the estrous cycle that was reversible after discontinuation of treatment. Finally, RG 12525 was nephrotoxic in mice with males being more sensitive than females.     

Effects of nitric oxide on leukotriene D4 decreased bile secretion in the perfused rat liver

Nitric oxide (NO) and leukotrienes are potent vasoactive agents that are involved in the control of portal blood flow. The present study investigated the role of leukotriene D4 and NO in a non-recirculating constant pressure rat liver perfusion model to analyse their interchanges on portal flow and bile secretion. The addition of leukotriene D4 (20 nM) to the perfusate for 5 minutes resulted in a decrease in portal blood flow (-55.3%), in bile flow (-24.4%) as well as bile acid release (-35.2%). In parallel, leukotriene D4 increased glucose output. The administration of a lower dose of leukotriene D4 (5 nM) reduced the respective parameters to a lesser degree, indicating dose-dependence. The addition of NO via the infusion of sodium nitroprusside (0.05 mM, 1 mM) reduced the effect of leukotriene D4 on portal flow, bile flow and bile acid secretion whereas the leukotriene D4 effects on hepatic glucose output remained unaffected. Correlation coefficient between decrease in portal flow and reduction of bile flow by infusing leukotriene D4 was R = 0.91, while in the presence of sodium nitroprusside R = 0.85. These results suggest that the leukotriene D4-induced cholestasis is dependent on portal flow. In contrast, hepatic vasoconstriction does not contribute to glycogenolysis stimulated by leukotriene D4 in the perfused liver.     

The effect of exchanger inhibitory peptide (XIP) on sodium-calcium exchange current in guinea pig ventricular cells

While the osteopenia associated with oestrogen deficiency is thought to arise from a relative defect in bone formation with respect to resorption, oestrogen administration itself leads to a decrease, rather than an increase, in bone formation. This decrease in bone formation, which arises from oestrogen's inhibitory effect on bone turnover, presumably masks any underlying tendency of oestrogen treatment towards stimulation of bone formation. To investigate this further, we have examined the early effect of discontinuing the administration of oestradiol-17 beta (OE2; 40 micrograms/kg) on bone formation indices in ovariectomized 13-week-old rats, before the turnover-induced increase in formation occurs. Histomorphometric indices were assessed at the proximal tibial metaphysis 0, 7, 10, 13 and 16 days following discontinuation of OE2 treatment. Measurements of body weight, uterine weight and longitudinal growth rate confirmed that there were rapid effects of OE2 deficiency on these parameters. We could detect no significant increase in bone resorption, as measured by osteoclast surface and number, until 16 days after ending treatment with OE2; this was coincidental with a reduction in bone volume. Shorter periods of OE2 deficiency were associated with a marked decrease in bone formation, as assessed by dynamic histomorphometric indices. This inhibition of bone formation was largely due to a reduction in double fluorochrome-labeled trabecular surfaces, which were decreased by approximately 70%. We conclude that ending OE2 administration in ovariectomized rats caused a striking decrease in trabecular bone formation, if such indices are assessed prior to the subsequent turnover-induced increase in formation.(ABSTRACT TRUNCATED AT 250 WORDS)