Inhibition of anti-IgE induced skin response in normals by formoterol, a new beta 2-adrenoceptor agonist, and terbutaline. 2. Effect on the late phase reaction.

Formoterol, a new beta 2-selective long-acting bronchodilator, was compared with terbutaline in terms of ability to inhibit dual phase skin reactions to anti-human IgE in volunteers. Anti-IgE induced an early wheal and flare reaction (WFR) followed by a progressively increasing induration, the late phase reaction (LCR), lasting greater than or equal to 24 h. Intradermal injection of formoterol 20 ng or terbutaline 500 ng 5 min before challenge gave equal inhibition of the WFR. The subsequent LCR was suppressed by formoterol (30%) for the whole 24 h period, while terbutaline only attenuated the first 4 h period. Increasing the dose range of both drugs 25-fold, caused a further analogous reduction of the WFR to anti-IgE. In this higher dose range formoterol (0.5 micrograms) antagonized the following 1-24 h LCR by 50%, while terbutaline (25 micrograms) only attenuated the LCR by an average of 20%, with higher effect in the first 6 h period. The anti-LCR capacity of formoterol was highly superior to that of terbutaline (P less than 0.001). The histamine-elicited wheal response was attenuated by both drugs, but they had no effect on the flare response, favouring an anti-permeability action of both compounds. The data support the concept that terbutaline, given locally in a single dose shortly before challenge, inhibits the mast cell mediator release reaction with limited consequences for the following LCR. In contrast to terbutaline, formoterol exerted a substantial anti-LCR action, probably by interfering with inflammatory mechanisms after the initial mast cell mediator release.

Interactions of cryptosin with mammalian cardiac beta-adrenoceptors.

Cryptosin - a new cardenolide from the leaves of Cryptolepis buchanani R & S was found to be a potent positive inotropic agent. In experiments with dog heart ex vivo, the rise in the cardiac rate associated with an increase in dP/dtmax and left ventricular pressure (LVP) correlated with changes in the beta-adrenoceptor densities as measured by the binding of 3H-Dihydroalprenolol (DHA). A significant change in the beta-adrenoceptor densities was observed when cryptosin was incubated with guinea pig and dog heart sarcolemmal membranes in vitro. Analysis of the binding of 3H-DHA in post-cryptosin treated membranes indicated a non-specific type of interaction of cryptosin with mammalian cardiac beta-adrenoceptors.

Esmolol decreases the adverse effects of acute coronary artery occlusion on myocardial metabolism and regional myocardial blood flow in dogs.

This study was designed to test the hypothesis that beta-adrenergic receptor blockade with esmolol would decrease the hemodynamic and myocardial metabolic impairment produced by left anterior descending coronary artery (LADa) occlusion. Twenty-three anesthetized open-chest dogs underwent direct cannulation of the LADa, its companion vein (LADv), and a distal circumflex vein (CFXv) for blood sampling. All dogs were subjected to two consecutive 15-minute periods of total LADa occlusion; group 1 (n = 11) received an infusion of esmolol (150 micrograms.kg-1.min-1) during either occlusion period (randomly assigned) and group 2 (n = 12) received no intervention during either occlusion period. One hour of reperfusion was interposed between the two periods of LADa occlusion. Hemodynamic measurements were made and blood was sampled from the aorta, CFXv, LADa, and LADv before and during both periods of LADa occlusion. Without esmolol infusion, LADa occlusion was associated with decreases in stroke index, coronary perfusion pressure, and left ventricular stroke work index; with esmolol infusion these hemodynamic decrements did not occur. During both LADa occlusion periods in both groups, lactate extraction became negative, i.e., there was net lactate production. Despite this, the magnitude of lactate production was less with esmolol than without it. Finally, average endocardial-to-epicardial blood flow ratio in the LAD perfusion area was decreased during each LAD occlusion period except when esmolol was infused, during which the baseline value was maintained. Thus, infusion of esmolol during temporary LADa occlusion preserved certain hemodynamic variables, preserved the ratio of endocardial-to-epicardial blood flow, and decreased the apparent magnitude of lactate production.

Effects of stimulation of the ocular sympathetic nerves on IOP and aqueous humor flow.

Ocular sympathetic nerves were stimulated chronically in awake rabbits using electrodes unilaterally implanted on the cervical sympathetic trunk. IOP was measured by pneumatonometry and aqueous inflow was measured by fluorophotometry. In each animal, continuous trains of 1 msec pulses were delivered by means of a portable electrical stimulator. Experiments were spaced by 1 week recovery periods. Stimulation was varied over a range of amplitudes (5-15 V) and frequencies (3-12 Hz). Continuous sympathetic stimulation produced an immediate sharp decrease in IOP followed by a gradual rise to pre-stimulation values which were attained 60-90 min after onset. A rebound increase in IOP occurred when stimulation was terminated. The magnitude of the initial IOP drop, the delay in the return to pre-stimulation IOP, and the rebound rise in IOP subsequent to termination of electrical stimulation were proportional to the stimulation frequency. Maximal effects were observed at 12 Hz, and stimulation with 8-10 Hz for 180 min caused a sustained reduction in anterior chamber aqueous humor flow. Topical 2% phentolamine 1 hr before stimulation markedly reduced IOP and abolished the acute IOP changes observed in untreated stimulated animals. Topical 1% timolol did not affect either the initial IOP drop or the rebound; however, the IOP recovered during stimulation to values greater than pre-stimulation IOP. We conclude that in rabbits the beta-adrenergic effect of prolonged sympathetic nerve stimulation is to decrease aqueous flow. Chronic electrical stimulation in awake animals provides an experimental model for studying the role of the ocular sympathetic nerves.

The effects of beta-adrenergic drugs on the human sperm motility in vitro. I. The effects of propranolol and isoprenaline.

The investigations were carried out on 28 samples of human semen with asthenozoospermia. The experiments were performed in three groups of semen, adding to the first one 0.34 mM of propranolol and 0.025 mM of isoprenaline, to the second one the double dose and to the last one the fivefold dose of the drugs. The lowest concentrations of the drugs applied in our investigations result from the used therapeutic intravenous doses for people. The proportional content of moving sperma was evaluated under the phase-contrast microscope at the 5, 30, 60, 120 and 240 minute of the experiment. The addition of 0.34 mM of propranolol caused a decrease of the sperm motility but only after 60 minutes and for a short period of time. However, the addition of the double and the fivefold doses of the drug led to immediate and significant reduction of the sperm motility. The lowest dose of isoprenaline markedly increased the sperm activity in comparison with the control values but not earlier than 120 minutes after the addition. The further increase in dose showed no effect on the moving sperm percentage increase, merely accelerating this effect.

Impact of beta 1 selectivity and intrinsic sympathomimetic activity on potential unwanted noncardiovascular effects of beta blockers.

Beta-adrenoceptor-blocking drugs are widely used as effective antihypertensive and antianginal agents, but treatment with these agents may be contraindicated in hypertensive patients in whom receptor blockade would interfere with noncardiovascular activities dependent on sympathetic drive. beta blockade impairs pulmonary function in asthmatic patients through antagonism of beta 2 bronchodilation. However, patients with chest problems may be treated effectively with beta 1-selective drugs, including acebutolol, atenolol and metoprolol. The metabolic response to hypoglycemia, which is mediated by beta-receptor stimulation, involves insulin release, gluconeogenesis, tachycardia and increased systolic pressure. Beta 1-selective drugs are preferred in patients who need to increase blood glucose levels because they do not interfere with glycogenolysis. Hypertension induced by pregnancy may be treated with a beta blocker with no apparent adverse effects on the fetus or neonate. Those possessing intrinsic sympathomimetic activity may be preferable.

Da existência de receptores beta-adrenérgicos na glândula lacrimal do cäo / Beta-adrenergic receptors in the lacrimal gland of the dog

Estudo em glândulas lacrimais de cäes, das modificaçöes do fluxo lacrimal, bem como das alteraçöes histológicas induzidas por drogas alfa e ß-adrenérgicas, sem e com bloqueio destes receptores pelo propranolol. Os resultados mostraram que as drogas ß-estimulantes induziram ao aumento do fluxo, lacrimal, bloqueável pelo propranolol. Quanto às drogas estimulantes, aquele efeito näo ocorreu. A administraçäo crônica de drogas ß-estimulantes ocasionou aumento do volume nuclear na glândula lacrimal

Studies on the affinity and selectivity of denopamine (TA-064), a new cardiotonic agent, for beta-adrenergic receptors.

Denopamine is a new orally active cardiotonic agent. The present experiment was carried out to characterize the binding affinity and selectivity of this drug for beta-adrenergic receptor subtypes. Binding studies were performed using 3H-dihydroalprenolol as the radioligand. Binding affinities of denopamine and some beta-agonists for rat heart membranes (KiH), which contain predominantly the beta 1-subtype, were in the order of isoproterenol (Iso, 14.1 nM) greater than prenalterol (158) greater than norepinephrine (Nor, 227) greater than or equal to epinephrine (Epi, 248) greater than denopamine (545) greater than or equal to dobutamine (645) greater than procaterol (1440) greater than terbutaline (6420). In rat lung membranes (predominantly beta 2-subtype), the order of potency (KiL) was Iso (20.6 nM) greater than procaterol (70.2) greater than Epi (136) greater than prenalterol (412) greater than dobutamine (735) greater than or equal to Nor (744) greater than denopamine (2205) greater than terbutaline (2500). The beta 1/beta 2-selectivity as judged from the KiL/KiH values was in the order of denopamine (4.1) greater than Nor (3.3) greater than prenalterol (2.6) greater than Iso (1.5) greater than dobutamine (1.1) greater than Epi (0.55) greater than terbutaline (0.39) greater than procaterol (0.05). Practolol, a beta 1-antagonist, showed a high beta 1-selectivity (KiL/KiH = 15.3). In the presence of guanine nucleotide (GTP), the denopamine radioligand competition curve showed a rightward shift, and its Hill coefficient increased like other agonists, although the degree of the shift was less than that observed with full agonists such as Iso. These results essentially correspond with the pharmacological and biochemical properties of denopamine and confirm the beta 1-selectivity and the agonist property of this compound.

Sistema beta-adrenérgico: II. Seu papel na homeostasia fetal, neonatal e na resposta hemodinâmica à hipovolemia / Beta-adrenergic system: II. Its role in fetal and neonatal homeostasis and in hemodynamic response to hypovolemia

Os autores analisam as informaçöes disponíveis na literatura, bem como aquelas geradas em seus laboratórios, sobre o emprego de drogas ativadoras ou inibidoras do sistema beta-adrenérgico em Perinatologia. Estudam, neste trabalho, os efeitos sobre o concepto, nos períodos intra-útero e neonatal. Em vista do crescente emprego de agonistas beta-adrenérgicos no tratamento do parto prematuro associado com sangramento vaginal, investigam o comportamento do sistema beta-adrenérgico durante hipovolemia induzida por perda sangüínea

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazole class.

A series of 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazoles is described. The compounds were investigated in vitro for beta-adrenoceptor antagonism, and several examples were found to be selective for the beta 1-adrenoceptor. The structure--activity relationship exhibited by this series of compounds is discussed. (S)-2-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]-4-(2 -thienyl)imidazole [(S)-13] was over 100 times more selective than atenolol for the beta 1-adrenergic receptor and has been selected for in-depth studies.

Effects of beta-adrenoceptor agonists and antagonists on thyroid hormone secretion.

The effects of various beta-adrenoceptor agents on radioiodine release from the thyroid were studied in mice pretreated with 125I and thyroxine. The non-selective beta-adrenoceptor agonist isopropylnoradrenaline and the selective beta 2-adrenoceptor agonist terbutaline both, and with the same efficacy, enhanced radioiodine release, whereas the selective beta 1-adrenoceptor agonist prenalterol had no such effect. The non-selective beta-adrenoceptor antagonist L-propranolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 both abolished the radioiodine release induced by isopropylnoradrenaline or by terbutaline. The selective beta 1-adrenoceptor antagonist metoprolol inhibited the radioiodine response to isopropylnoradrenaline, but not that to terbutaline. Neither of the beta-adrenoceptor antagonists influenced the radioiodine release induced by TSH. It is concluded that the beta-adrenoceptors involved in the regulation of thyroid hormone secretion are mainly of the beta 2-subtype, and, further, that beta-adrenoceptor agonists and TSH exert their thyroid hormone secretory effects through different mechanisms.

Modulation by beta-adrenoreceptors of spontaneous contractions of rat urinary bladder.

1 Propranolol (0.1 mg/kg i.v.) but not metoprolol (0.2 mg/kg i.v.) pretreatment increased the spontaneous motility triggered by progressive filling of rat urinary bladder without a concomitant effect on bladder capacity, except at high filling volumes. Compared to controls, the spontaneous motility of urinary bladder in propranolol pretreated rats displayed a higher frequency, indicating the existence of a tonic sympathetic inhibition. 2 beta-adrenoreceptor stimulation by isoprenaline (0.1-10 microgram/kg i.v.) or terbutaline (0.1-1 mg/kg i.v.) in vivo produced a dose dependent inhibition of bladder spontaneous motility which was antagonized by propranolol (0.1 mg/kg i.v.) but not by metoprolol (0.2 mg/kg i.v.). Propranolol (0.2 mg/kg i.v.) pretreatment did not antagonize the inhibition of bladder motility produced by intravenous papaverine (0.5 mg/kg). 3 Propranolol (0.1 mg/kg i.v.) significantly antagonized the isoprenaline-induced tachycardia (beta 1 mediated) and fall in diastolic blood pressure (beta 2 mediated) while metoprolol (0.2 mg/kg i.v.) antagonism was confined to beta 1 mediated responses. 4 Isoprenaline (0.25-1.5 microM) inhibited in a concentration dependent manner field stimulation induced contractions of rat detrusor muscle strips as did tetrodotoxin (0.5 microM). Hexamethonium (50 microM) had no inhibitory effect. 5 Our in vivo findings support the view that beta 2-adrenoreceptors are responsible for modulating bladder motility mainly by suppressing the onset of spontaneous contractions.

Exogenously stimulated gastric secretion in dogs after ganglion and sympathetic blockade and antral acidification.

1 In conscious dogs with gastric fistulae, Heidenhain pouches and in some cases, innervated pyloric pouches, ganglionic blockade augmented Heidenhain pouch acid secretion only if the gastric fistula remained closed in animals receiving pentagastrin. 2 Ganglionic blockade depressed methacholine-stimulated acid and pepsin secretion from the Heidenhain pouch whether or not the fistula was open. 3 Acidification of the antral pouch consistently augmented the acid and pepsin secretion from the Heidenhain pouch when either pentagastrin or methacholine was the stimulus. Ganglionic blockade prevented this.

Constriction of the epicardial coronary artery induced by alpha-adrenergic stimulation.

Effects of alpha adrenergic stimulation on diameter change of the epicardial coronary artery were studied in in-situ canine heart. The diameter of the left circumflex coronary artery (LCX) was continuously measured by 10 MHz PZT crystals applied to the external wall of the LCX. Aortic pressure was measured using high fidelity catheter-tip manometer. Enhanced activity of alpha adrenergic receptor by humoral and/or somatic nerve stimulations caused a reduction of the LCX diameter despite of the systemic pressure rise.

Drugs and the fetus during labour and delivery.

The anaesthetist's potential to favourably influence fetal outcome rests upon a thorough knowledge of perinatal physiology, pathophysiology and pharmacology (pharmacokinetics and pharmacodynamics). The actions of drugs and compounds influencing placental perfusion and exchange are therefore discussed in relation to the concept of intra-uterine resuscitation of the asphyxiated fetus.