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Effects of sympathomimetic agonists and antagonists on mucociliary activity.

The effect on the mucociliary (m.c.) wave frequency of sympathomimetic agonists and antagonists was studied in the maxillary sinus in anesthetized rabbits. The non-selective beta-adrenoceptor agonist isoprenaline (0.005-10 micrograms/kg i.a.) and the selective beta2-adrenoceptor agonist salbutamol (0.01-10 micrograms/kg, i.a.) induced a dose-dependent acceleration of the m.c. wave frequency, whereas the beta1-adrenoceptor agonist prenalterol (1-200 micrograms/kg, i.a.) did not influence the basal m.c. activity. The selective alpha1-adrenoceptor agonist phenylephrine (0.01-20 micrograms/kg, i.a.) and the selective alpha2-adrenoceptor agonist oxymetazoline (0.001-1 microgram/kg, i.a.) both induced a dose-dependent retardation of the m.c. wave frequency. The non-selective beta-adrenoceptor antagonist propranolol (2-200 micrograms/kg, i.a., and 1 mg/kg, i.v.) and the non-selective alpha-adrenoceptor antagonist phentolamine (0.1-1 000 micrograms/kg, i.a.) had no influence on the basal m.c. wave frequency. Propranolol (1-2 mg/kg, i.v.) reduced the effect of isoprenaline and salbutamol (both in the dose range of 0.01-10 micrograms/kg, i.a.) and similarly phentolamine (0.2 and 1 mg/kg, i.a.) reduced the effect of oxymetazoline (0.01-10 microgram/kg, i.a.). It was concluded that during basal conditions in the anesthetized rabbit the m.c. activity functions independently of sympathetic activity and that sympathomimetic agonists acting on beta2-adrenoceptors accelerate the wave frequency, whereas sympathomimetic agonists acting on alpha1 and alpha2-adrenoceptors have a retarding effect, all in a dose-dependent manner.

Albuterol↗

Association of sympathomimetic drugs with malformations.

We observed 2 cases of severe limb defects in infants following the use of sympathomimetic drugs during pregnancy. The mother of I had taken large doses of Primatene (ephedrine, theophylline, phenobarbital) as tablets and mist throughout pregnancy. The infant was born with oligoectrosyndactyly. In the other infant, maternal ingestion of sympathomimetic drugs including Triaminic (pseudoephedrine, phenylephrine, phenylpropanolamine) was associated with distal limb defects. Experimental studies in pregnant rabbits using Primatene in both low and high dosage resulted in limb reduction defects and other malformations in a significant number of the offspring compared with controls. Limb defects in the offspring of chicks following exposure to sympathomimetic drugs had previously been observed. We suggest that these agents may be teratogenic in the human and should be used with great caution or avoided during pregnancy.

Adult↗

Adenosine potentiates sympathomimetic effects of nicotinic agonists in vivo.

We showed previously that circulating adenosine potentiates pressor responses to nicotine in rats, apparently by enhancing the effects of nicotine in sympathetic ganglia. In the present studies, we examined the effects of adenosine (or synthetic adenosine receptor agonists) on a variety of sympathomimetic responses to nicotine (or other nicotinic cholinergic agonists). Indices of sympathetic activity examined were: blood pressure; heart rate; eyelid tension; and vas deferens perfusion pressure. Elevation of arterial plasma adenosine from its basal level (approximately 1.5 microM) to 2 to 3 microM (by i.v. adenosine infusion) had no effect on the basal value of any of these indices, but increased by 2.5 to 4-fold their peak responses to nicotine (40 microgram/kg i.v.). Adenosine also strongly enhanced sympathomimetic responses to inhaled cigarette smoke. The adenosine receptor antagonist caffeine (10 mg/kg) suppressed the ability of adenosine to potentiate these responses to nicotine. Pressor responses to the nicotinic cholinergic receptor agonists dimethylphenylpiperazinium iodide, tetramethylammonium, lobeline and cytisin were also potentiated by adenosine. Low doses (0.25-5 mu/kg) of synthetic adenosine receptor agonists potentiated all four of the tested sympathomimetic responses to nicotine, exhibiting the rank order of potency: N-Cyclopropylcarboxamidoadenosine greater than 2-Chloroadenosine greater than N6-R-Phenylisopropyl adenosine greater than N6-S-Phenylisopropyladenosine. The nonpurinergic vasodilator sodium nitroprusside failed to potentiate responses to nicotine, suggesting that the influence of adenosine on responses to nicotine is not secondary to its direct circulatory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

Arousal and stability: the effects of five new sympathomimetic drugs suggest a new principle for the prevention of space motion sickness.

Sympathomimetic agents are frequent components in antimotion-sickness drug combinations because of their usefulness in counteracting the sedation caused by stressful motion or resulting from the administration of other antimotion-sickness drugs. The noradrenergic neurochemistry of the brain's arousal-attentional systems prompted us to evaluate the efficacy of five new sympathomimetic drugs and to further define the role of arousal in susceptibility to motion. Subjects were orally administered methamphetamine (20 mg), phenmetrazine (25 mg), phentermine (37.5 mg), methylphenidate (20 mg), or pemoline (75 mg) 2 h prior to taking a Staircase Profile Test. All of the drugs increased resistance to stressful coriolis stimulation by 80-120%. Methylphenidate and pemoline showed fewer side effects. These findings, interpreted in conjunction with the documented inefficacy of most anticholinergic and antihistaminergic drugs tested to date, suggest that sympathomimetic drugs or a generalized state of arousal can inhibit the development of motion sickness.

Clinical Trials as Topic↗

Noradrenergic responses in rat hippocampus: electrophysiological actions of direct- and indirect-acting sympathomimetics in the in vitro slice.

The effects of perfusion of postulated direct- and indirect-acting sympathomimetics on evoked potentials in the CA1 region of the in vitro rat hippocampus were examined. A selective alpha agonist, 6-fluoronorepinephrine, produced depressions of population spike amplitude which were antagonized by the alpha antagonist phentolamine, but not by the beta antagonist timolol. The selective beta agonist, 2-fluoronorepinephrine, produced increases in population spike amplitude which were antagonized by timolol but not by phentolamine. Weak and variable responses were seen to the indirect-acting sympathomimetic tyramine, with lower doses producing increases and higher doses producing decreases in population spike amplitude, respectively. As with 2-fluoronorepinephrine, increases in spike amplitude elicited by tyramine were blocked by timolol but not by phentolamine. Another indirect-acting sympathomimetic, d-amphetamine, produced only increases in population spike amplitude which were blocked by timolol. Phencyclidine, an agent which may produce some of its central effects via noradrenergic synapses, was virtually ineffective in producing catecholamine-like responses in this system. Only nonspecific, local anesthetic effects were observed. Taken together with previous studies, these results support the hypothesis that activation of alpha and beta receptors decreases and increases, respectively, pyramidal cell excitability. Furthermore, although both alpha and beta receptors appear to be capable of interacting with endogenously released norepinephrine, the beta response may predominate.

Action Potentials↗

[Use of sympathomimetics in the treatment of asthma].

There are many sympathomimetic products available in treatment of asthma, such as ephedrin, isoproterenol, orciprenalin, salbutamol, terbutalin..., used by oral or injectable route and spray. In the spray form, the sympathomimetic products have immediate and intense activity but the easiness of their use leads to a dose multiplication or overdose ineluctably, and thus involves cardiac and respiratory accidents which can be fatal. Their prescription should be slightly different according to the clinical type of asthma in the patient. On the other hand the oral sympathomimetic products are less inclined to overdose.

Albuterol↗

The glycemic effects of sympathomimetics in stressed mice.

Sympathomimetics are extensively used clinically as decongestants and bronchodilators in cough, cold, and sinus remedies. However, few studies have addressed the glycemic potentials of these drugs. In this study, the glycemic potentials of pseudoephedrine (PSD), ephedrine (EPD), and phenyl-propanolamine (PPA), the three most commonly used sympathomimetics, were evaluated. PSD caused a dose-dependent delayed hyperglycemia. This was attenuated when procedural stress was reduced. EPD and PPA did not increase the hyperglycemia due to procedural stress. EPD and PPA blunted the hyperglycemia in fed mice after a 2 g/kg oral glucose challenge; PSD had no effect. The effects of PPA and EPD on post-challenge glucose levels may be partially explained by increased insulin/glucose ratios at 15 minutes post-challenge. These studies indicate that there are differences in the glycemic effects among the sympathomimetics in stressed mice.

Animals↗

Use of rapid superfusion to differentiate the release of dopamine from striatal tissue induced by sympathomimetic amines from release induced by potassium.

A rapid superfusion system incorporating a continuous amperometric detector has been employed to study the effects of p-tyramine, d-amphetamine and cocaine on K+-stimulated release of dopamine (DA) from striatal tissue. Qualitative identification of the released substances is made by liquid chromatography with electrochemical detection and DA is established to be the principal substance released following exposure of the tissue to 60 mM K+ in the presence of Ca++. At a superfusion rate of 1 ml/min with a 20 microliter volume tissue holder, d-amphetamine and p-tyramine do not elicit detectable release of endogenous substances. These results are in direct contrast to the significant release of DA observed when striatal tissue is incubated with d-amphetamine for the same time period and suggest that the pools susceptible to release by the sympathomimetic amines are removed by superfusion. When striatal tissue is superfused with a buffer containing 60 mM K+ and cocaine or sympathomimetic amines, the effects of uptake blockade are manifested as an increase in the amount and duration of observed release over that obtained with 60 mM K+. In a competitive study of cocaine and p-tyramine with d-amphetamine, it appears that all three of these agents induce blockade at the same site(s). All of these data are in direct accord with the facilitated exchange diffusion mechanism proposed for the actions of sympathomimetic amines at DA nerve terminals.

Animals↗

Arrhythmogenic dose of acetylstrophanthidin unchanged by beta-sympathomimetics in conscious dogs.

The enhanced arrhythmogenic risk of combined treatment with cardiac glycosides and beta-sympathomimetics is referred in some textbooks, but only a few detailed studies on in vivo models are available. We therefore investigated this problem in conscious dogs in an intraindividual study. We determined the dose of acetylstrophanthidin (intravenous infusion of 5 mcg/kg per min), which provoked ventricular premature beats with and without concomitant treatment with the partial beta-agonistic compounds doxaminol (3 mg/kg p.o.), prenalterol (0.4 or 1.0 mg/kg p.o.) or isoprenaline (0.31 +/- 0.100 mcg/kg per min). In some dogs a coronary artery was narrowed in order to reduce the coronary blood supply. The arrhythmogenic dose of acetylstrophanthidin was nearly the same in all the groups investigated (range from 52.1 +/- 5.66 to 59.9 +/- 3.23 mcg/kg). Whereas the arrhythmogenic dose of acetylstrophanthidin was unchanged by beta-sympathomimetics, the combination of the glycoside and each of the beta-agonistic drugs increased the contractile force more than did either single compound. We therefore conclude that the arrhythmogenic risk of the combination of glycosides and beta-sympathomimetics may be--at least in experimental models--less than has been suggested in the past.

Adrenergic beta-Agonists↗

Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated?

The role of bronchodilator regimens combining a sympathomimetic and a methylxanthine in the treatment of acute exacerbations of asthma remains controversial. This report describes the outcome of 157 emergency room visits for asthma in which patients were randomly assigned to single-drug therapy with intravenous aminophylline, subcutaneous epinephrine, or inhaled isoproterenol or to one of three regimens combining a sympathomimetic and a methylxanthine. The increase in one-second forced expiratory volume after one hour of treatment with the two-drug combinations (0.79 +/- 0.07 liter) was significantly greater than for epinephrine alone (0.57 +/- 0.08 liter; p less than 0.05) but did not differ significantly from that occurring with therapy with isoproterenol alone (0.72 +/- 0.09 liter; p = NS). This disparity reflects the greater bronchodilation effected by isoproterenol as a single agent than by epinephrine, in the dosing schedules and routes of administration chosen. Among patients presenting with severe airflow obstruction (one-second forced expiratory volume 35 percent or less of normal), the bronchodilator response to isoproterenol alone was 0.88 +/- 0.14 liter versus 0.51 +/- 0.11 for epinephrine alone (p less than 0.05). It is concluded that the observed benefit derived from use of combination therapy depends on the dosage and potency of the particular sympathomimetic to which a methylxanthine is added, and on the severity of the airflow obstruction at presentation.

Acute Disease↗

Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room.

The effectiveness of nebulized anticholinergic and sympathomimetic regimens was evaluated in a double-blind study of 199 patients with acute airways obstruction. Patients were assigned to one of three treatment regimens according to a randomized schedule: 0.5 mg of ipratropium bromide, 1.25 mg of fenoterol hydrobromide, and 0.5 mg of ipratropium plus 1.25 mg of fenoterol. In 148 patients with acute exacerbations of asthma (mean one-second forced expiratory volume, 1.18 +/- 0.64 liters), all three regimens produced significant improvement in one-second forced expiratory volume (p less than 0.001). The greatest improvement followed treatment with the ipratropium-fenoterol combination (0.53 +/- 0.40 liters at 45 minutes; 0.57 +/- 0.51 liters at 90 minutes) and was significantly greater than that following either ipratropium alone (p less than 0.001) or fenoterol alone (p less than 0.05). In 51 patients with acute exacerbations of chronic obstructive pulmonary disease (mean one-second forced expiratory volume, 0.67 +/- 0.29 liter), each regimen produced significant improvement in one-second forced expiratory volume at both 45 and 90 minutes (for all, p less than 0.05), but there was no significant difference among the three treatment regimens. It is concluded that, in patients with acute asthma, combination therapy with sympathomimetic and anticholinergic agents is more efficacious than either one alone. In patients with acute exacerbations of chronic obstructive pulmonary disease, although either sympathomimetic or anticholinergic therapy provides bronchodilatation, no further benefit could be demonstrated from combination therapy.

Administration, Intranasal↗

Mechanisms of beta sympathomimetic action on neonatal glucose homeostasis in the lamb.

Beta sympathomimetic drugs are used clinically to inhibit premature labor. Significant alterations in glucose homeostasis have been documented in both mother and offspring. To determine the mechanism(s) of beta sympathomimetic drugs on neonatal glucose homeostasis, ritodrine hydrochloride was infused in a newborn term lamb model of glucose kinetics by a crossover design. There was a progressive rise in plasma glucose concentration and plasma insulin concentration during ritodrine hydrochloride infusion compared with the control (saline) infusion. The rise in plasma glucose concentration was associated with a progressive rise in Ra (rate of appearance, production) and Rd (rate of disappearance, utilization). The ritodrine hydrochloride-infused animals had a progressive rise in [insulin/glucose] compared with our prior studies in the newborn lamb, suggesting direct stimulation of pancreatic beta cell secretion. In the neonatal lamb, beta sympathomimetic drugs directly stimulate both hepatic glucose production and pancreatic beta cell secretion. These effects explain, in part, why infants of mothers infused with ritodrine hydrochloride may evidence alterations in neonatal glucose homeostasis.

Adrenergic beta-Agonists↗

Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation.

Beta-adrenergic blocking agents differ considerably in their effects on myocardial excitable properties. The possibility that intrinsic sympathomimetic activity might contribute to such differences has not been adequately explored. This study examined the influence of intrinsic sympathomimetic activity on the electrophysiologic effects of three agents with varying degrees of such activity. Intravenous propranolol (0.5 mg/kg), oxprenolol (0.5 mg/kg) and pindolol (0.05 mg/kg) were administered in 16 anesthetized dogs. The effects of the drugs on ventricular vulnerability were studied over a 2 hour period. Propranolol and oxprenolol raised the ventricular fibrillation threshold by 42 and 56%, respectively. In contrast, pindolol resulted in an elevation of only 25%. After depletion of endogenous norepinephrine stores using reserpine, pindolol led to a decrease of the ventricular fibrillation threshold, which was reversed by propranolol. These data indicate that intrinsic sympathomimetic activity of beta-adrenergic blocking agents substantially alters their ultimate effect on myocardial excitable properties.

Adrenergic beta-Antagonists↗

Intravenous beta-blockade in coronary heart disease: is cardioselectivity or intrinsic sympathomimetic activity hemodynamically useful?

Beta-blocking drugs are increasingly prescribed in coronary heart disease, but controversy surrounds the hemodynamic relevance of their ancillary pharmacologic properties--cardioselectivity and intrinsic sympathomimetic activity. We therefore compared the effects of four intravenous beta-adrenoreceptor antagonists with different ancillary properties on left ventricular function in 24 patients with coronary heart disease. All four drugs depressed the relation between left ventricular filling pressure and cardiac output at rest and during exercise. However, practolol and oxprenolol, which have intrinsic sympathomimetic activity, induced significantly less depression of left ventricular function than either propranolol or metoprolol, which do not have this activity. Cardioselectivity, a property of both practolol and metoprolol, had no discernible hemodynamic advantage. Beta-blocking drugs that have intrinsic sympathomimetic activity appear to be more effective in maintaining cardiac function than drugs without this property, when given intravenously to patients with coronary heart disease.

Adrenergic beta-Antagonists↗

Glucuronidation of morphine and six beta 2-sympathomimetics in isolated rat intestinal epithelial cells.

The metabolism of morphine and six beta 2-sympathomimetics (orciprenaline, terbutaline, fenoterol, salbutamol, ritodrine, and bamethan) in isolated rat intestinal epithelial cells was investigated. Only conjugates with glucuronic acid were detected. With regard to observed Vmax values the beta 2-sympathomimetics can be divided in two groups. The three resorcinols (orciprenaline, terbutaline, fenoterol) have a Vmax value comparable to that of morphine (70-230 pmol/min X mg cell protein). The phenolic beta 2-sympathomimetics (salbutamol, ritodrine, bamethan) exhibit a Vmax value comparable to the Vmax value of 1-naphthol (500-1100 pmol/min X mg cell protein). Calculation of intestinal intrinsic (metabolic) clearance and intestinal first pass extraction ratios from Vmax and Kappm values suggests that most of these drugs may undergo substantial intestinal first pass metabolism after oral administration. The glucuronidation of morphine in isolated mucosal cells could be completely inhibited by addition of 1-naphthol (50 microM), salicylamide (5 mM), or fenoterol (5 mM). Glucuronidation of fenoterol could be partially inhibited by 1-naphthol, salicylamide, and morphine. Preliminary data obtained with microsomes suggest that 1-naphthol and morphine are metabolized by different forms of the intestinal microsomal UDP-glucuronosyltransferase. Fenoterol and ritodrine are probably glucuronidated by the form, which also glucuronidates morphine. The results demonstrate that rat intestinal epithelial cells can be used to predict intestinal metabolism of morphine and other drugs at least qualitatively and that phenolic food constituents (e.g. 1-naphthol) and non-prescription drugs (e.g. salicylamide) may affect the intestinal first pass metabolism of morphine and fenoterol.

Adrenergic beta-Agonists↗

Sympathomimetic-induced effects in the soleus muscle of the guinea-pig.

Sympathomimetic amines reduced the peak tension, time to peak and time to half-relaxation of indirectly elicited twitches of the guinea-pig soleus muscle in vivo. Clonic contractions of the soleus muscle were depressed by the amines. On a molar basis salbutamol and orciprenaline were 5.12 and 80.0 times less potent than (+/-)-isoprenaline in producing these effects. Results obtained with the beta-receptor antagonists propranolol, practolol and H35/25 suggest that the depression in skeletal muscle contractility is due to beta2-adrenoreceptor stimulation. The effects of the amines on twitches and clonic contractions of the guinea-pig soleus muscle are qualitatively similar to those reported previously in the cat soleus muscle preparation, which has been used to assess the possible tremorogenic actions of sympathomimetic bronchodilators. On a quantitative basis the molar dose-ratios of the sympathomimetics used, and the effects of beta-receptor antagonists on the responses, are similar in the two species.

Adrenergic beta-Agonists↗

INHIBITION OF SYMPATHOMIMETIC EFFECTS ON THE HEART.

The adrenaline beta-receptor blocking drug, pronethalol, and the sympathomimetic amines, (-)-ephedrine, (-)-amphetamine, dexamphetamine, (-)-Psi-ephedrine and tyramine, inhibited the sympathomimetic effects of butyrylcholine and tyramine on the guinea-pig isolated atrium. Being reversible and noncompetitive, this antagonism was unspecific and not due to blockade of adrenaline receptors, although pronethalol inhibited the effect of noradrenaline competitively.

Amphetamine↗

Chiral separation of sympathomimetics by ligand exchange capillary electrophoresis.

A rapid and simple approach to the chiral separation of sympathomimetic drugs with amino alcohol structure by ligand exchange capillary electrophoresis is described. An N-(2-hydroxyoctyl)-L-4-hydroxyproline/copper(II) complex is used as chiral selector. Thirteen sympathomimetics were resolved, nine with baseline resolution. The influence of pH and composition of the electrolyte on resolution was investigated. The optimal pH for complexation of these amino alcohols was found to be 12.

Electrophoresis, Capillary↗