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.

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.

Hexoprenaline: a review of its pharmacological properties and therapeutic efficacy with particular reference to asthma.

Hexoprenaline1, N,N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl] hexamethyl-enediamine, sulphate is a selective beta2-adrenoreceptor agonist which is active in man as a bronchodilator by the oral or intravenous routes and by inhalation. It is indicated for use in the treatment of bronchospasm associated with obstructive airways diseases, including asthma, bronchitis and emphysema. Clinical experience and double-blind studies have established that hexoprenaline is an effective bronchodilator. It major advantage over many other many other brochodilators of equal efficacy is its generally low production of side-effects, particularly tremor, palptitations, and tachycardia. In comparative trials, it has generally been rated as superior to orciprenaline or trimetoquinol, but comparisons with salbutamol have provided equivocal results. Oral hexoprenaline was superior to fenoterol as long-term maintenance therapy is asthma, principally because its somewhat lesser bronchodilatory effects were more than compensated for by a lesser incidence of side-effects.

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.

[Hexoprenalin as a tocolytic drug (author's transl)]. / Hexoprenalin als wehenhemmende Substanz.

Hexoprenalin, a betasympathomimetic drug, was tested with respect to tocolytic effect and cardiovascular side effects. The dosage varied according to the obstetrical situation and the resultant indication for tocolysis. "Long-term tocolysis" in the prophylaxis of premature labour was indicated when more or less rhythmical uterine contractions were present without any effect, as yet, on the cervix. The dosage was 0.075 microgram/min hexoprenalin intravenously as long-term infusion using a motor pump. In a collective of 20 patients in the last trimester of pregnancy the tocolytic effect was satisfactory, the mean rise in fetal heart rate being 2.43% and the mean rise in maternal heart rate 4.13%. Massive tocolysis to inhibit effective premature labour was indicated when rhythmical uterine contractions had already exerted an effect on the cervix. The dosage was 0.33 microgram/min hexoprenalin intravenously in form of a long-term infusion using a motor pump. In a collective of 20 patients in the last trimester of pregnancy the tocolytic effect was satisfactory, the mean rise in maternal heart rate being 33% and the mean rise in fetal heart rate 3%.

[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.

[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 role of hexoprenaline in suprapubic amniocentesis during late pregnancy. A pilot study.

Suprapubic amniocentesis is often complicated by the fetal head being fixed in the pelvis, oligohydramnios or a hyperirritable myometrium. These factors limit the success rate associated with the procedure. If the myometrium is relaxed with a beta 2-stimulant, a higher success rate may be achieved. This was investigated in a randomized, prospective, double-blind pilot study using hexoprenaline. When four- or five-fifths of the fetal head was palpable above the pelvis, hexoprenaline (17 amniocenteses) showed no advantage over a placebo (16 amniocenteses). However, when three-fifths or less of the fetal head was palpable above the brim, 4 dry taps were obtained in the control group using a placebo (17 amniocenteses), while none occurred in the study group (19 amniocenteses) (P less than 0,05). Elevation of the fetal head was less difficult in the study group, but this difference was not statistically significant. These results suggest that hexoprenaline is not indicated for routine use during amniocentesis. When a dry tap is obtained or when marked difficulty is encountered in lifting the fetal head from the pelvis, 10 micrograms hexoprenaline administered intravenously 5 minutes before amniocentesis appears to facilitate successful completion of the procedure. However, a larger series is necessary to confirm this observation.

[The influence of beta-mimetics on foetal pulmonary maturing (author's transl)]. / Der Einfluss von beta-Mimetika auf die fetale Lungenreifung.

Amniocentesis was carried out in 99 patients between the 31st to the 32nd gestational week in order to determine lung maturity. We subdivided the patients into 5 groups 11 women were treated with Hexoprenaline, 12 with Ritodrine, 26 with Dexamethason for acceleration of lung maturity, 23 with Dexamethason and beta-mimetics and 27 women were controls. A significant rise of surfactant factor measured by surface tension by means of the Wilhelmy-balance could be demonstrated in the two groups receiving glucocorticoids, whereas in the other groups the rise of surfactant factor corresponded with the usual increase due to age of gestation. But concerning the incidence and intensity of RDS and intensity, the best results were observed in the group with Dexamethason only. Increase of surfactant factor and incidence of RDS in groups with tocolytics and in the controls were similar, therefore we conclude, that beta-mimetics do not have an influence on lung maturity. A relatively high incidence of mild RDS-cases in the group of Dexamethason combined with tocolytics should be a warning to use both drugs routinely together.

[The influence of hexoprenalinsulfate aerosol on the ciliary wave frequency of the respiratory epithelium (author's transl)]. / Die Beeinflussung der Schlagfrequenz der Zilien des respiratorischen Epithels durch Hexoprenalinsulfat als Aerosol.

A report is given on the possible influence of hexoprenalinsulfate on the mucociliary wave frequency of the mucous membrane of the respiratory tract. The object of investigation was native human tracheaL mucosa obtained by tracheotomies. It was shown, that there was a significant decrease in frequency just on account of the usual gas fraction of the aerosol spray. If air was used instead of the gas, hexoprenaline did not influence the ciliary wave frequency.

Reversal of active labour. A case report.

The clinical course of primiparous patient who presented in premature labour at 31 weeks' gestation is described. Cervical dilatation was reversed from 9 cm and pregnancy continued for 6 days. The possible causes and mechanism are discussed and the implications are considered.

The effects of hexoprenaline, a beta 2-sympathomimetic drug, on maternal glucose, insulin, glucagon, and free fatty acid levels.

Hexoprenaline, an adrenergic beta 2-receptor agonist, was administered as a 10 microgram intravenous bolus to 9 women in the third trimester of pregnancy. The maternal plasma glucose, serum immunoreactive insulin, plasma immunoreactive glucagon (IRG 30 K), and free fatty acid (FFA) concentrations rose significantly at different times following the bolus injection. Thc serum insulin level increased first and reached a peak at 10 minutes, before the rise in plasma glucose, which reached a maximum at 30 minutes, suggesting that beta 2-receptor stimulation affects insulin secretion directly and not via a rise in the glucose level. Plasma glucagon and FFA levels also rose despite the rise in glucose levels. We therefore conclude that beta 2-receptor stimulation has direct actions on insulin and glucagon release and on glucose and FFA metabolism. The possible fetal sequelae due to these changes in the maternal metabolic milieu are discussed in relation to the use of a 10 microgram intravenous bolus of hexoprenaline as a measure in the treatment of acute fetal distress.

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.

Potentiating action of hexoprenaline on 14C-aminopyrine uptake by isolated rat parietal cells.

Hexoprenaline potentiated the 14C-aminopyrine uptake (a reliable index of H+ generation) of isolated rat gastric cells stimulated by 10(-6) -10(-4) mol/l carbachol, and inhibited that in response to 10(-4) mol/l histamine without and in the presence of propranolol. It is concluded that hexoprenaline acts as a partial agonist on parietal cell H2-receptors and that beta-adrenoceptor activation may functionally modulate gastric acid secretion.

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)

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.