Comparison of estrogen receptor DNA binding in untreated and acquired antiestrogen-resistant human breast tumors

Preliminary studies have suggested that measuring the ability of immunoreactive 67-kDa estrogen receptor (ER) to bind DNA and form in vitro complexes with its cognate estrogen response element (ERE) might serve to identify breast tumors most likely to respond to antiestrogens like tamoxifen. Data from two different surveys of untreated primary breast tumors confirmed that only 67% (74 of 111) of ER-positive tumors express a receptor capable of forming ER-ERE complexes by gel-shift assay, with tumors of lower ER content having significantly reduced ER DNA-binding frequency (56%) relative to those of higher ER content (82%; P = 0.007). In contrast to these untreated tumors, a panel of 41 receptor-positive breast tumors excised after acquiring clinical resistance to tamoxifen during either primary (n = 26) or adjuvant therapy (n = 15) showed a significantly greater ER DNA-binding frequency, with nearly 90% capable of forming ER-ERE complexes (P < 0.02). To assess experimentally whether ER DNA-binding function is altered during the development of antiestrogen resistance, nude mouse MCF-7 tumor xenografts were analyzed before and after the acquisition of in vivo resistance to either tamoxifen or a pure steroidal antiestrogen, ICI 182,780. Tamoxifen-resistant MCF-7 tumors retained full expression of 67-kDa DNA-binding ER, and despite a markedly reduced ER content in the ICI 182,780-treated tumors, the expressed ER in these antiestrogen-resistant tumors exhibited full ability to form ER-ERE complexes. These findings indicate that breast tumors with acquired antiestrogen resistance continue to express ER of normal size and DNA-binding ability and suggest that the failure of antiestrogens to arrest tumor growth during emergence of clinical resistance results from an altered gene-regulatory mechanism(s) other than ER-ERE complex formation.     

Parallel airways inhomogeneity and lung tissue mechanics in transition to constricted state in rabbits

To investigate whether changes of tissue resistance (Rti) during methacholine (MCh)-induced constriction correspond to an intrinsic mechanism or are an artifact of increased airways inhomogeneity, rabbits were studied after exposure to air (n = 7) or 1.5 parts/million O3 (n = 6). Animals were anesthetized and mechanically ventilated. Tracheal flow and pressure (Ptr) and four alveolar capsule pressures (Pcap) were measured during 3 min after administration of an intrajugular bolus of 0.8 mg/ml MCh. By adjustment of the equation of motion [P(t) = E . V(t) + R . dV(t)/dt + P0] [where P(t), V(t), and dV(t)/dt are pressure, volume, and flow as a function of time, respectively, E is elastance, R is resistance, and P0 is end-expiratory pressure] to Ptr, lung resistance (RL) and dynamic elastance (EL) were determined breath by breath. Rti and airways resistance (Raw) were determined from Pcap in phase with rate of change of pulmonary expansion. Hysteresivity (eta) was calculated. Parallel inhomogeneity was estimated from the coefficients of variation (CV) of every Pcap at end inspiration and end expiration. Increase in CV significantly lagged Rti, RL, and eta. A linear relationship between EL and Raw was observed. Our results suggest that changes in tissue mechanics during the transition to the constricted state are not artifactual.     

Correction of inverted nipple using strut reinforcement with deepithelialized triangular flaps

Mucus hypersecretion is a common characteristic of asthma. Acute severe asthma is often associated with neutrophilic infiltration into airways. Neutrophils contain elastase, a potent secretagogue in airways. Therefore, we hypothesized that instillation of ovalbumin in sensitized guinea pigs causes goblet cell secretion by releasing elastase from recruited neutrophils. When we instilled ovalbumin into the trachea of ovalbumin-sensitized guinea pigs, early recruitment of neutrophils identified by 3,3'- diaminobenzidine staining, and goblet cell degranulation measured with a semiautomatic computer-based imaging system occurred. The Leumedin NPC 15669 (a drug that inhibits leukocyte recruitment) and an antibody to intercellular adhesion molecule-1 (ICAM-1) both prevented neutrophil recruitment and goblet cell degranulation, implicating leukocytes in the response. Using immunofluorescence we showed that the leukocytes recruited early after antigen challenge were CD-16-positive, implicating neutrophils. Pretreatment with the selective neutrophil elastase inhibitor ICI 200,355 also prevented ovalbumin-induced goblet cell degranulation, implicating elastase. We conclude that ovalbumin-induced goblet cell degranulation is due to neutrophil recruitment and elastase release.     

Inhaled ICI 204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma

Three inhalation formulations of ICI 204,219 were compared for antagonism of antigen-induced bronchoconstriction in 16 subjects with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each subject received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204,219 until the forced expiratory volume in 1 s (FEV1) decreased by 20 percent or the maximum allergen concentration (100 micrograms/ml) was reached. The majority of subjects tolerated 100 micrograms/ml of allergen without a 20 percent decrease in FEV1. Inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.     

Methacholine causes reflex bronchoconstriction

To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial artery or as an aerosol via tracheostomy into the lower airways. We then measured the contraction of an isolated, in situ segment of trachealis smooth muscle and determined the effect of vagotomy on the trachealis response. Administering methacholine to the subcarinal airways via the bronchial artery (0.5-10.0 microg/ml) caused dose-dependent bronchoconstriction and contraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased an average of 186% over baseline. Aerosolized methacholine (5-7 breaths of 100 mg/ml) increased trachealis tension by 58% and airways resistance by 183%. As the bronchial circulation in the sheep does not supply the trachea, we postulated that the trachealis contraction was caused by a reflex response to methacholine in the lower airways. Bilateral vagotomy essentially eliminated the trachealis response and the airways resistance change after lower airways challenge (either via the bronchial artery or via aerosol) with methacholine. We conclude that 1) methacholine causes a substantial reflex contraction of airway smooth muscle and 2) the assumption may not be valid that a response to methacholine in humans or experimental animals represents solely the direct effect on smooth muscle.     

Self-reported mental distress under the shifting daylight in the high north

Our knowledge of airways reactivity to inflammatory agonists is derived predominantly from tests dominated by large airway responsiveness. To determine directly, the histamine responsiveness of the smallest airways, eight normal and 11 asymptomatic asthmatic subjects were studied utilizing a wedged bronchoscope technique. A fiberoptic bronchoscope was wedged in the anterior segment of the right upper lobe and a double-lumen catheter was advanced through the working channel to its tip. With a constant flow of gas (5% CO2 in air) through one lumen of the catheter, pressure at the tip of the bronchoscope was measured with the subject breath-holding at FRC. Peripheral airways resistance (Rp) was measured at baseline and after saline, histamine (10, 50, 100 mg/ml) and isoproterenol (2 mg/ml) challenge through the bronchoscope. Baseline Rp of asthmatics (0.041 +/- 0.015 cm H2O/ml/min; mean +/- SE) was significantly greater than normal subjects (0.011 +/- 0.003 cm H2O/ml/min; p = 0.019). The log of the concentration of histamine that caused a 100% increase in peripheral airways response was greater in the normal subjects than in the asthmatic subjects (p = 0.0114) and correlated with whole lung responsiveness to histamine in asthmatics (r = 0.847, p < 0.05). Isoproterenol reversed completely the increase in Rp in normal subjects but not asthmatic subjects. The results of this study demonstrate that the resistance of the smallest peripheral airways, when measured directly, increased when challenged locally with histamine in both normal subjects and asthmatic subjects. However, the peripheral airways responsiveness was significantly enhanced in asthmatic subjects relative to normal controls.     

Review of respiratory mechanics in animals. 4. The diagnostic affirmation ability of research using the impulse oscilloresistometry system (IOS) in calves

Taking methodological and physiological aspects into account (see Part 3), the impulse oscillometry system (IOS) was found to be sensitive to detecting and to quantifying clinically relevant changes in respiratory mechanics in calves. Therefore, the complex respiratory impedance needs to be measured in terms of resistance and reactance within the frequency range between 5 Hz and 20 Hz. The behaviour of resistance and reactance in dependence of frequency allows to differentiate and to localise airway obstructions. Obstructions of upper (extrathoracic) airways were mainly characterised by a frequency independent increase in the resistance. Within the reactance curve, no change in the resonant frequency could be observed. In a peripheral airway obstruction both resistance and reactance changed. The most typical finding concerning resistance was that a negative frequency dependence occurred. The reactance became more negative. Following this, the resonant frequency increased. With progressive obstruction of the peripheral airways, the reactance became more informative than resistance.     

A risk for obstruction of the airways in the parenteral use of levomepromazine with benzodiazepine

Arrhythmogenic effects of phenothiazines appear to be associated with sudden death, whereas respiratory complications have received little attention. In this report we describe 5 cases with accompanying obstruction of the airways after intramuscular injections of levomepromazine (LPZ), a potent sedative phenothiazine, in combination with intravenous injections of benzodiazepine (BZ) during a 3-month period in a psychiatric intensive care unit. Two out of 5 cases were unpredictable because obstruction of the airways occurred 2 hours or more after the last injection. As compared with patients who received parenteral (intravenous or intramuscular) injections during the same period, the dose of intramuscular LPZ was significantly large in the 5 cases with obstruction of the airways. All 5 of these cases received intramuscular LPZ 0.52 mg/kg or more. In contrast, there was no patient with obstruction of the airways who received only intramuscular LPZ, the combination of LPZ and HDL, or BZ and HDL. The occurrence of obstruction of the airways among patients who received both intramuscular LPZ and intravenous BZ was significantly higher than among patients who received other drug regimes. These preliminary results suggest that the intramuscular use of LPZ with intravenous BZ may be a risk for obstruction of the airways.     

Frequency dependence of specific airway resistance in a commercialized plethysmograph

Specific airway resistance (sRaw) measured by body plethysmography has been shown to decrease markedly with decreasing breathing frequency when the inspired air is not conditioned to body temperature, atmospheric pressure and saturation with water vapour (BTPS). The phenomenon has been attributed to noninstantaneous gas warming and wetting in the airways. The aim of this investigation was to assess whether the phenomenon was also present in a commercialized plethysmograph featuring an "electronic BTPS correction". Airway resistance (Raw) and sRaw were measured in 15 healthy subjects at six breathing frequencies ranging 0.25-3 Hz, using a constant volume plethysmograph in which a correction for non-BTPS gas conditions was applied by electronically flattening the box pressure-airway flow loop (Jaeger Masterscreen Body, version 4.0). The temperature and water vapour saturations in the box averaged 26.5 +/- 1.3 degrees C and 59 +/- 6%, respectively. Raw and sRaw exhibited a clear positive frequency dependence in all but one subject. From 0.25 to 3 Hz Raw increased from (mean+/-SD) 0.62 +/- 0.55 to 1.71 +/- 0.76 hPa x s x L-1 (p<0.001), and sRaw from 2.34 +/- 1.90 to 7.55 +/- 3.08 hPa x s (p<0.001). The data are consistent with a simple model, in which gas conditioning in the airways and external dead space occurred with a time constant of 0.39 s. We conclude that the electronic BTPS correction of the instrument was inadequate, probably because it is assumed that gas conditioning in the airways is instantaneous. We recommend that, with similar instruments, airway resistance be measured using as high a panting frequency as feasible.     

Effect of the high-affinity estrogen receptor ligand ICI 182,780 on the rat tibia

We examined the specificity of the steroidal antiestrogen ICI 182,780 (ICI) on bone and reproductive tissues in adult and growing female rats. Using a 1.5-mg/kg dose (s.c.), we evaluated the effects of ICI on the bone, body weight, uterine weight, serum cholesterol, and serum estradiol in either adult and/or growing rats. ICI increased serum estradiol cholesterol in ovary-intact rats, had no effect on uterine weight in ovariectomized rats, and resulted in uterine atrophy in ovary-intact animals comparable with ovariectomy. In contrast, ICI had no effect on body weight. In bone, ICI significantly increased the rate of periosteal bone formation in long bones of growing and mature female rats. In contrast, ICI had no effect on longitudinal bone growth in rapidly growing rats. When ICI was administered to mature rats with or without ovaries, two-factor ANOVA revealed significant interaction (P < or = 0.05) between ovariectomy and ICI treatment for cancellous bone area and labeled bone perimeter. ICI increased skeletal indices of bone turnover in the cancellous bone of ovary-intact rats but reduced these indices of bone turnover in the cancellous bone of ovariectomized rats. The increase in bone turnover was associated with a reduction in cancellous bone area in the ovary-intact rats. A reduction in bone turnover was similarly associated with an increase in bone area in the ICI-treated ovariectomized rats. In summary, ICI exhibited complete estrogen antagonism in cortical and cancellous bone, partial agonism in cancellous bone, and no activity on tibial longitudinal growth rate of growing ovary-intact rats. The effects in adult rats were influenced by circulating levels of estradiol. ICI had no activity on body weight and complete antagonism on uterine weight. These results demonstrate that a ligand with high binding affinity to the estrogen receptor(s) can elicit an array of estrogen-mediated regulation of bone metabolism.     

Fetal unilateral cleft lip and palate: detection of enzymic anomalies in the amniotic fluid

BACKGROUND: Tracheal intubation frequently results in an increase in respiratory system resistance that can be reversed by inhaled bronchodilators. The authors hypothesized that insertion of a laryngeal mask airway would be less likely to result in reversible bronchoconstriction than would insertion of an endotracheal tube. METHODS: Fifty-two (45 men, 7 women) patients were randomized to receive a 7.5-mm (women) or 8-mm (men) endotracheal tube or a No. 4 (women) or No. 5 (men) laryngeal mask airway. Anesthesia was induced with 2 microg/kg fentanyl and 5 mg/kg thiopental, and airway placement was facilitated with 1 mg/kg succinylcholine. When a seal to more than 20 cm water was verified, respiratory system resistance was measured immediately after airway placement. Inhalation anesthesia was begun with isoflurane to achieve an end-tidal concentration of 1% for 10 min. Respiratory system resistance was measured again during identical conditions. RESULTS: Among patients receiving laryngeal mask airways, the initial respiratory system resistance was significantly less than among patients with endotracheal tubes (9.2+/-3.3 cm water x 1(-1) x s(-1) [mean +/- SD] compared with 13.4+/-9.6 cm water x 1(-1) x s(-1); P < 0.05). After 10 min of isoflurane, the resistance decreased to 8.6+/-3.6 cm water x 1(-1) x s(-1) in the endotracheal tube group but remained unchanged at 9.1+/-3.3 cm water x 1(-1) x s(-1) in the laryngeal mask airway group. The decrease in respiratory system resistance in the endotracheal tube group of 4.7+/-7 cm water x 1(-1) x s(-1) was highly significant compared with the lack of change in the laryngeal mask airway group (P < 0.01). CONCLUSIONS: Resistance decreased rapidly only in patients with endotracheal tubes after they received isoflurane, a potent bronchodilator, suggesting that reversible bronchoconstriction was present in patients with endotracheal tubes but not in those with laryngeal mask airways. A laryngeal mask airway is a better choice of airway to minimize airway reaction.     

Regulation of spontaneous activity of the delta-opioid receptor: studies of inverse agonism in intact cells

Adenylyl cyclase activity was measured following labelling of the cellular ATP pool with [3H]adenine in intact Rat-1 fibroblasts that had been stably transfected to express the murine delta-opioid receptor (clone D2). Basal [3H]cyclic AMP accumulation was low and was increased substantially by the addition of the diterpene forskolin. The synthetic enkephalin D-Ala2,D-Leu5 enkephalin (DADLE) produced strong inhibition of forskolin-amplified [3H]cyclic AMP production, whereas the delta-opioid ligand ICI174864 augmented forskolin-amplified adenylyl cyclase activity. Naloxone was unable to mimic the effects of ICI174864, and coincubation of the cells with these two ligands attenuated the effect of ICI174864. The EC50 (9.4 +/- 0.6 x 10(-8) M) for ICI174864 augmentation of forskolin-stimulated adenylyl cyclase was equal to its estimated Ki. Pertussis toxin pretreatment of clone D2 cells prevented both this effect of ICI174864 and the inhibition produced by DADLE. Use of a Cytosensor microphysiometer demonstrated that treatment of clone D2 cells with DADLE increased and that with ICI174864 decreased the basal rate of cellular proton extrusion. By using these two distinct experimental strategies, ICI174864 was shown to function in a manner anticipated for an inverse agonist, demonstrating that such effects can be observed in intact cells and are not restricted to assays performed on membrane preparations.     

Dopexamine attenuates endotoxin-induced microcirculatory changes in rat mesentery: role of beta2 adrenoceptors

OBJECTIVE: To investigate the influence of dopexamine on endotoxin-induced leukocyte adherence and on vascular permeability in postcapillary venules of rat mesentery. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Twenty-seven male Wistar rats, weighing 250 to 350 g. INTERVENTIONS: Rats received one of three treatments: a) infusion of Escherichia coli endotoxin without dopexamine pretreatment; b) infusion of endotoxin with dopexamine pretreatment; or c) infusion of endotoxin after pretreatment with dopexamine and ICI 118,551, a selective beta2-receptor antagonist. MEASUREMENTS AND MAIN RESULTS: Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules were evaluated using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from red cell velocity and vessel diameter. Dopexamine attenuated both the increase in leukocyte adherence and vascular permeability during endotoxemia. The attenuating effect on leukocyte adherence could not be antagonized by the beta2-adrenoceptor antagonist. However, the attenuating effect on vascular permeability was antagonized by ICI 118,551. Dopexamine prevented a decrease in venular wall shear rate during endotoxemia. This effect was not influenced by ICI 118,551. CONCLUSIONS: Dopexamine attenuates endotoxin-induced microcirculatory disturbances in rat mesentery. The attenuating effect on vascular permeability is a beta2-adrenoceptor-mediated process, whereas the beta2-adrenoceptor actions of dopexamine play no significant role in attenuating leukocyte adherence.     

Effect of indomethacin and atropine in experimental asthma in conscious guinea pigs

Pulmonary mechanics were measured in unanesthetized guinea pigs sensitized to horseradish peroxidase (HRP) before and during two aerosolized challenges of this antigen. During the first challenge the pulmonary resistance increased in all animals. Prior to second challenge the animals received either atropine (0.2 mg/kg) or indomethacin (10 mg/kg) intraperitoneally. We found that during the second challenge the indomethacin group had an increase in pulmonary resistance slightly greater or similar to that during the first exposure to the antigen, while the animals treated with atropine had a significantly diminished response (P less than 0.05). In five guinea pigs sensitized to HRP but challenged with a nonspecific aerosal made up of rabbit albumin, we found that pulmonary resistance increased in some animals and that this increase could be partially blocked by atropine. These results show that indomethacin has no effect on this model of allergic airways disease. They also confirm the importance of the vagus nerves in allergic bronchoconstriction and in addition show that nonspecific hyperirritability can be induced in some animals by immunization.     

Stimulation of parabrachial nuclei dilates airways in cats

Stimulation of the parabrachial nuclei has been shown to increase mean arterial pressure as well as to terminate inspiration. Nevertheless, the effect on airway caliber evoked by stimulation of the parabrachial nuclei is not known. Therefore, in chloralose-anesthetized cats, we microinjected DL-homocysteic acid (25 nl; 100 mM) into 44 sites in or near the lateral and medial parabrachial nuclei while calculating breath-by-breath total lung resistance and dynamic compliance. We found that, in 43 of these sites, microinjection of this excitatory amino acid consistently decreased total lung resistance but had no effect on dynamic compliance. The decrease in lung resistance was caused by a withdrawal of cholinergic tone to the airways. We could find no evidence that the decrease in total lung resistance evoked by stimulation of the parabrachial nuclei was caused by activation of either beta-adrenergic or nonadrenergic noncholinergic pathways. The decrease in total lung resistance evoked by stimulation of the parabrachial nuclei was not secondary to the baroreceptor reflex even though microinjection frequently increased mean arterial pressure. In addition, microinjection did not have consistent effects on phrenic nerve activity, although in individual circumstances the effect on this activity was quite large. We conclude that stimulation of cell bodies and dendrites in the parabrachial nuclei dilates the airways of anesthetized cats and that the effect is not secondary to the baroreceptor reflex.     

The protein truncation test (PTT) as a method of detection for choroideremia mutations

The development of endocrine resistance in previously sensitive, estrogen receptor-positive breast cancers is a major limitation in the treatment of breast cancer. Because antiestrogens have a cell cycle-specific action on breast cancer cells and influence the expression and activity of several cell cycle-regulatory molecules, the development of aberrant cell cycle control mechanisms is a potential mechanism by which cells might develop resistance to antiestrogens. We postulated that overexpression of cyclin D1, which is a common feature of breast cancer, may confer antiestrogen resistance. We addressed this question in vitro by testing the ability of ectopic cyclin D1 overexpression to overcome the growth-inhibitory effects of tamoxifen and the pure steroidal antiestrogens, ICI 164384 and ICI 182780, in T-47D and MCF-7 human breast cancer cells. In cells stably transfected with a human cyclin D1 cDNA under the control of a metal-inducible metallothionein promoter, cyclin D1 expression was increased 2-4-fold following treatment with zinc. Despite the continued presence of antiestrogen, cyclin D1 induction resulted in the formation of active cyclin D1/Cdk4 complexes, concurrent hyperphosphorylation of the retinoblastoma protein, and entry into S phase of cells previously arrested in G1. Elevated cyclin D1 protein levels were first detected 3 h after treatment with zinc, and the proportion of cells in S phase began to increase 6 h later. The S-phase fraction increased 2-3-fold from 13 to 17% in cells treated with antiestrogen alone, to a peak of 33-38% 15 h after zinc treatment. Both the cyclin D1 protein level and the proportion of cells in S phase increased with increasing concentrations of zinc. We conclude that the ectopic overexpression of cyclin D1 reverses the growth-inhibitory effect of antiestrogens in estrogen receptor-positive breast cancer cells, providing a potential mechanism for clinical antiestrogen resistance.     

Inhaled procaterol inhibits histamine-induced airflow obstruction and microvascular leakage in guinea-pig airways with allergic inflammation

BACKGROUND: Beta2-adrenoceptor agonists (beta2-agonists) are shown to inhibit airway microvascular leakage in experimental animals. This effect may change in animals with chronic airway inflammation. OBJECTIVE: We examined whether inhaled beta2-agonists inhibit microvascular leakage in guinea-pig airways with chronic allergic inflammation. METHODS: Three weeks after the sensitization with ovalbumin (OA; 6 mg/mL), each guinea pig was challenged with inhaled OA once a day for 1 or 3 weeks. Control animals without sensitization with OA also inhaled vehicle for OA (saline) for 3 weeks. One day after the last challenge, different doses of inhaled procaterol (1, 3 or 10 microg/mL) or vehicle was given to animals for 10 min after an anaesthesia. Fifteen minutes after the end of inhalation, the animals were given i.v. Evans blue dye (EB dye; 20 mg/kg), a marker of microvascular leakage, and then i.v. histamine (3 or 30 microg/kg) or vehicle. Lung resistance, a parameter of airflow obstruction, was measured for 6 min and the lungs were removed to calculate the amount of extravasated EB dye into the airways. RESULTS: A significant increase in eosinophil infiltration into the airways was seen in sensitized and challenged animals compared with control animals without sensitization. Among animals receiving antigenic exposure for either 0 (control), 1 or 3 weeks, 10 microg/mL procaterol significantly inhibited 30 microg/kg histamine-induced increase in EB dye extravasation to a similar degree (ranged from 28.7 to 69.8% inhibition) as well as that in lung resistance (more than 90% inhibition in all groups). The minimal dose of procaterol to inhibit 3 microg/kg histamine-induced microvascular leakage was not different between nonsensitized control animals and those sensitized and challenged for 3 weeks at all airway levels. CONCLUSION: Inhaled beta2-adrenoceptor agonists may be also potent in attenuating microvascular leakage even in the airways with chronic allergic inflammation.     

Lung mechanics in sitting and horizontal body positions

We measured lung compliance, pulmonary flow-resistance, and expiratory reserve volume (ERV) in ten healthy young adults in sitting, supine, and lateral positions. Average lung compliance was 0.21 in sitting, 0.19 in lateral and 0.16 L.cm H2O-1 in supine positions. The change was significant (p less than 0.01) between sitting and supine position. Flow-resistance increased from 1.78 in sitting to 2.5 cm H2O.L-1.s (p less than 0.001) in lateral positions, and did not increase further in the supine posture in spite of a 35 percent decrease in ERV (p less than 0.001). Since it is known that lower airways resistance increases with decreasing lung volume, the lack of change in flow-resistance when shifting from lateral to supine posture suggests that upper airways flow-resistance (larynx and oropharynx) is greater in the lateral decubitus than in the supine positions. The decrease of lung compliance in horizontal postures probably reflects increased pulmonary blood volume and small airways closure.     

Surgical maneuvers placing the sciatic nerve at risk during total hip arthroplasty as assessed by somatosensory evoked potential monitoring

We investigated the influence of hyperthyroidism on relaxant responses of small mesenteric resistance arteries to beta-adrenoceptor agonists and to compounds stimulating the corresponding second-messenger system. Hyperthyroidism was induced by feeding rats for 28 days with 5 mg/kg L-thyroxine (T4)-containing rat chow. This treatment produced a stable hyperthyroid state, as indicated by several biochemical/metabolic and haemodynamic parameters. Preparations of small mesenteric arteries were mounted in an isometric wire myograph. Subsequently, concentration-effect curves were determined for isoproterenol, noradrenaline and salbutamol as well as for forskolin, dibutyryl-cAMP and theophylline. We also determined concentration-effect curves to the beta-adrenoceptor agonists in the presence of ICI 118,551 and CGP 20712A (i.e., in the presence of a selective beta 2- and beta 1-adrenoceptor antagonist, respectively). Apparent pA2-values were calculated to determine which beta-adrenoceptor subtype causes vasodilation. These experiments indicate that beta-adrenoceptor-mediated vasodilation involves both beta 1- and beta 2-adrenoceptors in mesenteric resistance vessels of both hyperthyroid and control rats. In our experiments hyperthyroidism has a sensitizing influence on vascular responses induced by the beta-adrenoceptor agonist isoproterenol and the selective beta 2-adrenoceptor agonist salbutamol. Sensitization to isoproterenol was abolished in the presence of ICI 118,551, whereas it was emphasized in the presence of CGP 20712A. Although this was not fully supported by the results obtained with noradrenaline, these results indicate that the sensitization to beta-adrenoceptor agonists is probably limited to the beta 2-adrenoceptor/G-protein complex and not associated with alterations of the corresponding second messenger system.