Role of ß2-Adrenoreceptors in Adrenergic Anti-Inflammatory Mechanism in Sepsis.

Experiments on random-bred albino mice showed that of ß2-adrenoreceptor agonist hexaprenaline sulfate significantly reduced mortality of mice from experimental sepsis (intraperitoneal administration of E. coli) in 4 and 24 h after modeling by reducing blood levels of proinflammatory cytokines TNFα, IL-1ß, and IL-6. The antagonist of ß2AR ICI-118,551 eliminated this effect.

Importance of the adrenergic nerve system in the response of gases in the arterial blood following the provoked bronchospasm.

INTRODUCTION: This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the beta2-drenergic stimulator-Hexoprenaline and alpha2-adrenergic blocker-Tolazoline in the bronchoconstriction caused by a beta-blocker-Propranolol. MATERIAL AND METHODS: in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin). RESULTS AND DISCUSSION: Following the inhalation of the beta-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2 appeared. This shows that stimulation of beta2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases.

Beta 2-agonist treatment enhances uterine oxytocin receptor mRNA expression in pregnant rats.

The objective of this study was to disclose an interaction between Beta(2)-adrenergic (Beta(2)-ARs) and oxytocin (OT) receptors (OTRs) in the late-pregnant rat uterus. We investigated the level of uterine OTR mRNA expression after the administration of Beta(2)-AR agonists fenoterol and hexoprenaline to rats from day 18 to 22 of pregnancy, and also tested the effect of fenoterol on uterine explants. Hexoprenaline induced a maximum 24% increase of OTR mRNA. Fenoterol in vivo elicited a maximum 125% increase of OTR mRNA, in vitro produced a maximum fourfold increase in OTR mRNA. In fenoterol-treated rats the maximal contractility increasing effect of OT on isolated uterine rings was significantly higher than in intact term pregnant rats, but the EC50 values were not statistically different. It was concluded that the enhanced expression of OTR mRNA induced by Beta(2)-agonists in the late-pregnant rat uterus may be a possible drawback to effective therapy of preterm uterine contractions with Beta(2)-agonists.

[Effects of verapamil and gynipral on the uterine contractile activity in rats]. / Vliianie verapamila i giniprala na sokratitel'nuiu deiatel'nost' matki krys.

Verapamil and gynipral administered to pregnant rats in doses on a clinical level suppress the uterine contractions, which is manifested by a decrease in the amplitude and frequency of the biopotential. The joint administration of gynipral and verapamil (in half doses) resulted in a pronounced tocolytic effect.

[The use of Gynipral (hexoprenaline) in suppression of uterus contractions]. / Zastosowanie gynipralu (hexoprenaliny) w hamowaniu czynnosci skurczowej macicy.

OBJECTIVE: The aim of of this study was to estimate the effectiveness and tolerance of Gynipral (hexoprenaline)-beta-2 sympathomimetic used as oral and intravenous tocolytic. MATERIAL AND METHODS: We analysed 110 pregnant women admitted to the hospital with premature uterus contractions between 17 and 37 week of pregnancy. Pregnant women were divided into two groups. Group I--86 patients with regular uterus contractions. In this group Gynipral was administered to suppress uterus contractions. Group two consisted of 24 patients without regular uterus contractions. In this group women were treated with Gynipral to keep pregnant uterus in maximum relaxation in such cases as IUGR, oligohydramnion, after Strassman procedure before pregnancy or cerclage procedure in current pregnancy. Group I was treated with intravenous Gynipral infusion and after suppression of uterus contractions the way of administration was changed into oral. Group II from the beginning was treated with oral tocolysis with Gynipral. Pregnant women were continually under CTG control and all ailments such as tachycardia, flapping tremor and anxiety were analysed and noted. RESULTS: Gynipral has effectively suppressed premature uterus contractions in 80 cases in group I (93%) and in 24 cases in group II (100%). In 106 cases (96%) patients have not presented any side effects. CONCLUSIONS: Gynipral is an effective tocolytic successfully used in premature labor treatment. Gynipral has a good tolerance administered both intravenously and orally as well and in most cases there was no need to add antiarrhythmic drugs to reduce side effects.

Asthma induced by ice water ingestion in ethnic Chinese asthmatic children: a challenge.

UNLABELLED: The purpose of this study was to investigate the relationship between ice water ingestion and the induction of asthmatic symptoms and signs in ethnic Chinese asthmatic children. Sixty asthmatic children with a positive history of exacerbation of symptoms after drinking ice water were divided randomly into two groups: 34 children were instructed to drink 250 ml of 0-4 degrees C ice water within one minute, and 26 to drink 250 ml of 25 degrees C warm water. All of the asthmatic children were stable when studied. Twenty-three healthy children as controls were asked to drink 250 ml of 0-4 degrees C ice water. The three groups had forced expiratory volume in one second (FEV1) performed at baseline and at 5, 15, 30, 60, and 90 minutes after challenge. After the spirometric test at 90 minutes the patients of the two asthmatic groups received three puffs (0.6 mg) of hexoprenaline MDI and a further spirometric test was performed 5 min after the inhalation. Cough and wheeze were monitored throughout the course of the test. The mean FEV1 after challenge decreased significantly only in the ice-water asthmatic group (p = 0.004). Compared with the baseline data, the mean FEV1 at various periods after challenge was only significantly decreased at 60 min (p = 0.035). After hexoprenaline inhalation the FEV1 significantly increased in the two asthmatic groups (p < 0.001). A significant difference in FEV1 change was noted among the three groups (p = 0.015). Nine cases (26%) from the ice water asthmatic group, three (12%) from the warm-water asthmatic group, and none of the ice-water normal control group showed a decrease of FEV1 greater than 15% (p = 0.018). The greatest difference occurred between the two ice water groups. All six cases who developed symptoms after challenge, accompanied by a simultaneous decrease of FEV1 greater than 15%, belonged to the ice-water asthmatic group. Forty-seven percent of the ice-water asthmatic group and 4% each of the two other groups had cough and/or wheeze after challenge (p = 0.0002). IN CONCLUSION: Ice water ingestion may induce or exacerbate asthma in ethnic Chinese asthmatic children.

Role of the baroreflex in beta 2-sympathomimetic induced tachycardia in male rats.

The aim of the study was to determine whether tachycardia which is associated with the use of beta 2-sympathomimetic tocolytic agents is caused by baroreflex activation or by direct stimulation of cardiac beta-adrenoceptors. In conscious male rats, tachycardiac responses following intravenous injection of hexoprenaline, ritodrine and fenoterol were compared following (i) bilateral sinoaortic denervation (SAD) or (ii) sham-operation, and (iii) ganglionic-blockade using hexamethonium. Dose-ranges were chosen to result in similar reductions in diastolic blood pressure (DAP). Furthermore, following ganglionic blockade, the relative contribution of beta 1-adrenoceptor stimulation was assessed using the selective beta 2-receptor antagonist ICI 118,551. In intact rats, increases in HR induced by all beta-adrenoceptor agonist were comparable. In SAD and ganglion-blocked rats, DAP fell more pronounced at even lower doses. The corresponding increases in HR were approximately 3 times smaller than in intact rats but not different between agents. During ganglionic blockade ICI 118,551 significantly inhibited HR responses to fenoterol and hexoprenaline but not ritodrine. The conclusion is that in intact male rats, baroreflex activation is the major determinant of tachycardia following injection of ritodrine, fenoterol or hexoprenaline. Increasing the beta 2-selectivity of these drugs will not limit the tachycardic effects.

The extrapulmonary effects of inhaled hexoprenaline and salbutamol in healthy individuals.

We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 micrograms of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 micrograms). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation. There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QTc interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.

[Uterine-placental-fetal blood flow and fetal cardiac activity during the ginipral treatment of premature labor]. / Sostoianie matochno-platsentarno-plodovogo krovotoka i serdechnoi deiatel'nosti ploda pri lechenii ginipralom prezhdevremennykh rodov.

Effects of intravenous and oral hinipral on the uteroplacentofetal blood flow and fetal heart work were studied in tocolytic therapy of preterm labor in 27 pregnant women at terms 25-35 weeks. Intravenous infusions of hinipral resulted in a significant reduction of the systolic-diastolic ratio in the umbilical artery, with the blood flow in the uterine arteries persisting stable, and in a significant reduction of the fetal heart rate and increase of fetal heart rhythm variability, as evidenced by cardiotocogram. In oral tocolysis the reduction of the umbilical artery was related to the pregnancy term; fetal heart rate and heart rhythm variability were within the normal range over the course of the investigation. The results evidence no negative effects of the drug on the uteroplacentofetal blood flow and fetal cardiovascular system both in oral and parenteral forms of tocolysis.

Hexoprenaline activates potassium channels of human myometrial myocytes.

Hexoprenaline is a beta-adrenergic agent used for tocolysis after the 26th week of pregnancy. The purpose of the present study was to demonstrate the site of action of hexoprenaline on the membrane of single isolated smooth muscle cells. The main action of beta-mimetics on the cell is hyperpolarization of the cellular membrane, i.e. beta-mimetics have similar effects as K(+)-ions (Standen et al., 1989). Our results indicate a prolonged and significantly enhanced activity of K(+)-channels in the cell membrane, as may also be demonstrated by the use of the K(+)-channel activator Calcitonin-gene related peptide (CGRP). In control experiments under physiological conditions, we observed a large conductance K(+)-channel with 158 pS. The channel was voltage dependent and Ca++ sensitive indicating that it belongs to the class of big conductance Ca(++)-activated K(+)-channels (BKCa). Hexoprenaline and CGRP both increased the open probability (P(o)) of the channel measured with the patch clamp system in the cell attached configuration. Hexoprenaline was also an activator of the BKCa in the presence of Nitrendipine, indicating that the activation of the Ca++ sensitive channel is not an indirect effect of Ca++ currents via L-type Ca++ channels.

Potassium channels and modulating factors of channel functions in the human myometrium.

Hexoprenaline, a beta-adrenergic agonist of clinical importance in preventing preterm labor, and the calcitonin gene-related peptide (CGRP) that is known to have receptors in the plasmalemma of myometrial cells were investigated to ascertain whether in human myometrium K+(Ca++)channels are involved in the relaxant mechanism. Small sections from the fundus and the corpus of vaginal-dissected uteri were isolated under limitation of the operation collective (age of women 35-50 years). Strips of 1-cm length were cut for isometric measurement of contraction. After an equilibration of 60 min under 10 mN tension at 37 degrees C, spontaneous activity occurred and experiments were performed. By enzymatic disaggregation with papain and collagenase single cells were isolated. Electrophysiological experiments were performed using the patch-clamp technique in the cell-attached and excised inside-out configurations. We observed K+ channels with a conductance of 158 pS between -20 and 20 mV in [K+]o/[K+]i of 5.4/140 mM with a reversal potential at about -70 mV. The channel was sensitive to the free calcium concentration on the cytoplasmic side and open probability (Po) increased with membrane depolarization. 0.5 mM ATP facing the cytoplasmic side of the patches (at 40 mV depolarization and pCa of 6) showed no inhibition. Hexoprenaline and CGRP both increased the Po of the K+ (Ca++)channels in the cell-attached mode at steady-state kinetics. Forskolin failed to be an activator of K+ (Ca++)channels. In isometric measurements of human myometrial strips spontaneous activity is suppressed by hexoprenaline 10(-5) M and CGRP 10(-7) M, but these effects are antagonized by 2 mM TEA.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased myometrial beta-adrenoceptors in women receiving beta 2-adrenergic tocolytic therapy: correlation with lymphocyte beta-adrenoceptors.

We have determined simultaneously the density of beta-adrenoceptors in human myometria (by (-)-[125I]iodopindolol binding) derived from 36 women undergoing cesarean section and in the corresponding circulating lymphocytes (by (-)-[125I]iodocyanopindolol binding). In myometrial membranes about 80% to 85% of the beta-adrenoceptors were of the beta 2-subtype. The density of myometrial and lymphocyte beta-adrenoceptors in women treated with the beta 2-adrenoceptor agonist hexoprenaline to prevent preterm labor was about 65% to 70% lower than that in nontreated women. Concomitantly, in hexoprenaline-treated women the 10 mumol/L isoproterenol-evoked increase in lymphocyte cyclic adenosine monophosphate content (as index for lymphocyte beta-adrenoceptor responsiveness) was diminished to a similar extent. Combining all data resulted in a significant positive correlation between myometrial and lymphocyte beta-adrenoceptor densities (r = 0.7303; n = 36; p less than 0.001). It is possible that determination of beta-adrenoceptor function in circulating lymphocytes may be a useful model to monitor myometrial beta-adrenoceptor changes during tocolytic therapy.

Pharmacological characterization of mare uterus motility with special reference to calcium antagonists and beta-2-adrenergic stimulants.

1. Uterine motility was studied in vitro in the myometrial tissue obtained from pregnant and non-pregnant mares. 2. The spontaneous contractions of the preparations were not modified by tetrodotoxin, by anticholinergics, antiadrenergics, histamine H1 and H2 blockers, antiserotoninergic and opioid antagonists; but disappeared in Ca2+ and Na+ free medium. 3. beta 2-adrenergic stimulants like salbutamol and hexoprenaline and the calcium channel blockers nifedipine and verapamil were effective inhibitors of the amplitude of phasic contractions (ID50S for salbutamol and nifedipine were 7.7 nM and 14.6 nM, respectively in oestrus preparations). 4. The above data indicated that the mare myometrium contractility in vitro is very sensitive to the action of beta 2 mimetic compounds and calcium antagonists; nifedipine, in particular, seems to be a very promising alternative to beta 2 stimulants in the tocolytic therapy.

Increase of progesterone production in human and rat luteal cells by beta-adrenergic stimulation.

The effects of the beta 2-adrenergic agonist hexoprenaline were studied on the progesterone production of rat and human corpora lutea and compared to hCG-induced hormone production. Human corpora lutea were obtained from healthy patients, rat corpora lutea were harvested on day 6 of pseudopregnancy. Corpora lutea were digested by trypsin and homogeneous luteal cell suspension (6 X 10(5) cells/ml) was incubated for 2 h. Hexoprenaline and hCG were added to the medium and progesterone production was measured by RIA. Hexoprenaline or hCG dose-dependently increased the progesterone production of rat luteal cells and of human cells in mid- and late luteal phase. Moreover, hexoprenaline further increased the hCG-induced hormone production. The stimulatory effect of hexoprenaline could be prevented by propranolol. It is supposed that beta 2-adrenergic stimulation induces an increase in progesterone production of luteal cells and potentiates the effects of gonadotropic hormones.

Activation of sodium transport in human erythrocytes by beta-adrenoceptor stimulation in vivo.

Beta-adrenoceptor stimulation in vivo shifts potassium into the cells. To examine whether human erythrocytes participate in this process, we measured, along with serum or plasma potassium, the concentrations of potassium and sodium in erythrocytes. Beta-adrenoceptor stimulation was obtained by infusion of either fenoterol or hexoprenaline into 6 volunteers at rest or by endogenous amines provoked in 14 volunteers during ergometric exercise. Metabolic effects were followed at rest on serum insulin, C-peptide, and growth hormone levels, and during exercise on pH on lactate concentration in blood. The potassium concentration (mean +/- S.E.M.) dropped (p less than 0.01) in serum from 4.64 +/- 0.37 to 3.19 +/- 0.43 mmol x l-1 in the first hour at rest and in plasma from 5.70 +/- 0.93 to 4.63 +/- 0.45 in 90 sec directly after exercise. The concentration of erythrocyte sodium dropped (p less than 0.001) from 9.68 +/- 0.73 to 8.81 +/- 0.62 mmol x l-1 in cells and from 9.62 +/- 1.16 to 8.55 +/- 1.24 during exercise for 90 s, respectively. Changes in the concentration ratio of cellular sodium to potassium confirmed this sodium shift. An increased sodium transport in erythrocytes due to beta-adrenoceptor stimulation in vivo appears to complement a shift of serum potassium into the cells and may be mediated by the membrane-bound sodium, potassium ATPase.