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PubMed1970

Actions of some sympathomimetic bronchodilator and beta-adrenoceptor blocking drugs on contractions of the cat soleus muscle.

1. (-)-Isoprenaline, salbutamol, orciprenaline and quinterenol injected intravenously decreased the tension and degree of fusion of incomplete tetanic contractions of the soleus muscle of the anaesthetized cat.2. Under the most sensitive conditions, the smallest effective dose of (-)-isoprenaline was of the order of 0.01 mug/kg intravenously. Salbutamol was usually 6-10 times, orciprenaline 20-30 times and quinterenol about 35 times less potent than isoprenaline. The effects of salbutamol were about 1.6 times, of orciprenaline about 1.8 times and of quinterenol more than 20 times as long lasting as those of (-)-isoprenaline.3. The effects of the sympathomimetic amines were blocked by propranolol, H56/28, H35/25 and butoxamine but not by ICI 50172. The combined results with agonists and antagonists indicate that the receptors involved can be classified as of the beta(2) type.4. The effect of the amines on the cat soleus muscle appears to be analogous to that causing enhancement of physiological tremor in man, which suggests that skeletal muscle tremor may be an occasional unwanted side effect of the use of these bronchodilators.

Acetanilides↗

PubMed1972

Use of cumulative dose-response curves in potency comparisons of sympathomimetic amines on the cat soleus muscle.

The ability of beta-adrenoceptor agonists to reduce the fusion of incomplete tetanic contractions of the soleus muscle of the cat has been used previously as a model to assess the potential tremor producing effect of sympathomimetic bronchodilators. The ability of (-)-isoprenaline, (-)-adrenaline, (+/-)-soterenol and (+/-)-quinterenol to depress incomplete tetanic contractions of the soleus has now been assessed using cumulative administration of the amines. The method quickly produced accurate and reproducible dose-response curves. It is particularly useful for evaluating the potency of long-acting compounds.

Animals↗

PubMed1972

A structure-activity study of sympathomimetic amines on the beta-adrenoreceptors of guinea-pig trachea.

1. The relative activities of a large number of sympathomimetic amines were estimated on the beta-adrenoceptors of the guinea-pig tracheal chain preparation. Concentrations which produced half-maximal responses were measured for each drug and the maximum responses were also noted and expressed as a percentage of that produced by isoprenaline.2. The relative activities of the amines generally decrease with loss of hydroxyl groups from the structure, and amines with less than two hydroxyl groups produce little or no observable response.3. The affinity constants of the partial agonists and antagonists were measured. The hydroxyl group on the beta carbon atom of the side chain, N-alkyl groups and an alpha carbon methyl group increase affinity, whereas the p-phenolic group decreases affinity. The m-phenolic group does not seem to affect affinity.4. By comparing the effects of groups on affinity with their effects on activity, it was deduced that N-alkyl groups, m- and p-phenolic groups and probably also the beta carbon hydroxyl group increase efficacy. Alpha carbon methylation appears to reduce efficacy.

Amphetamine↗

PubMed1973

Some actions of sympathomimetic amines and their antagonists on mouse superfused ileum.

Superfused segments of mouse ileum exhibited spontaneous movement which Mwere inhibited by sympathomimetic amines. Isoprenaline and adrenaline were approximately equipotent and about 15 times more potent than either noradrenaline or phenylephrine. Supersensitivity developed to all these agents when mice had been 'sympathectomized' with NGF-antiserum or 6-hydroxydopamine and it was more pronounced with the latter treatment. Responses to the amines were reduced by phentolamine and propranolol, alone or in combination, with the exception of phenylephrine, the responses to which were simply shortened in duration after,beta-adrenoceptor blockade. No qualitative changes were evident in the effects of the blocking agents after 'sympathectomy'.

Animals↗

PubMed1975

The effect of sympathomimetic amines on the ventricular fibrillation threshold in the rabbit isolated heart.

1 The ventricular fibrillation threshold (VFT) was measured in the isolated heart of the rabbit perfused via the aorta with McEwen's solution at 37 degrees C by applying a single 10 ms pulse of current during the vulnerable period of late systole. The arrhythmia induced was either fibrillation or a rapid tachycardia. 2 The catecholamines adrenaline, noradrenaline and isoprenaline, but not dopamine, when infused at rates which produced similar moderate effects on cardiac rate and force, significantly lowered the VFT; it was reduced slightly more by adrenaline than by the other two. Phenylephrine and methoxamine were ineffective. Only those sympathomimetic amines which lowered the VFT also shortened the vulnerable time, i.e. minimal time after the R-wave of the ECG at which the pulse had to be applied to induce the arrhythmia. 3 The lowering effect of adrenaline on the VFT was not influenced by phentolamine but was blocked by propranolol and pindolol. 4 Chloroform potentiated the lowering effect of adrenaline, but not that of isoprenaline, on the VFT. Carbachol did not alter the effect of adrenaline on the VFT. 5 The results indicate that adrenaline, noradrenaline and isoprenaline lower the VFT by a direct action on the cardiac musculature and that this effect is mediated via beta-adrenoceptors.

Amines↗

PubMed1978

A study of the sympathomimetic action of guanethidine on the isolated anococcygeus muscle of the rat.

Guanethidine, acting on the rat isolated anococcygeus, causes adrenergic neurone blockade (slowly terminated by washing), noradrenaline potentiation and, with higher concentrations, spasm (both rapidly terminated by washing). 2 The spasm is an indirect sympathomimetic action, for it is sensitive to phentolamine and reserpine and shows tachyphylaxis. 3 The concentration of cocaine equieffective with the spasmogenic concentration of guanethidine as an inhibitor of noradrenaline uptake caused much less spasm. Moreover, it did not enhance noradrenaline efflux from anococcygeus loaded with (-)-[3H]-noradrenaline, as guanethidine did. 4 The spasm induced by guanethidine in excess of cocaine is due to guanethidine-evoked noradrenaline release.

Animals↗

PubMed1978

Sympathomimetic effects of pancuronium bromide on the cardiovascular system of the pithed rat: a comparison with the effects of drugs blocking the neuronal uptake of noradrenaline.

1. The effects of pancuronium bromide on the cardiovascular system of the pithed rat were examined. Pancuronium had two effects, a short-lasting cardiovascular stimulation following injection and a longer-lasting potentiation of responses to sympathetic nerve stimulation. 2 The initial effect of pancuronium was compared with that of tyramine. The cardioaccelerator but not the pressor responses to both pancuronium and tyramine were significantly reduced following sympathectomy with 6-hydroxydopamine (6-OHDA). 3 The action of pancuronium in potentiating sympathetic nerve responses was compared with that of known blockers of the neuronal uptake of noradrenaline (NA). Pancuronium (1 mg/kg) and cocaine (0.5 mg/kg) potentiated cardioaccelerator and pressor responses to sympathetic stimulation. These effects of pancuronium could be obtained following adrenalectomy and during neuromuscular blockade with gallamine. Pancuronium and uptake blockers potentiated the cardioaccelerator response to NA, reduced the response to tyramine, but did not affect the response to isoprenaline. Pancuronium and uptake blockers potentiated the pressor response to NA, but did not affect the response to tyramine or clonidine. 4 Following sympathectomy with 6-OHDA, pancuronium failed to potentiate cardioaccelerator and pressor responses to NA. 5 These results are discussed in relation to two main cardiovascular effects of pancuronium; an indirect sympathomimetic action and blockade of the neuronal uptake of NA.

Adrenalectomy↗

PubMed1979

Functional antagonism as a means of determining dissociation constants and relative efficacies of sympathomimetic amines in guinea-pig isolated atria.

1 The positive inotropic and chronotropic responses to sympathomimetic amines were examined in guinea-pig isolated atria. 2 The order of potency measured from EC50 values was isoprenaline greater than orciprenaline greater than salbutamol greater than or equal to fenoterol greater than terbutaline. Terbutaline and salbutamol were partial agonists on rate and together with orciprenaline and fenoterol also on tension responses. 3 Functional antagonism by carbachol caused a rightwards shift of the dose-response curve and depression of the maximum response. The rate maxima for orciprenaline, fenoterol and terbutaline were above that of isoprenaline. All the tension maxima were below isoprenaline. 4 Dissociation constants (KA) and relative efficacies (er) were determined by analogy with irreversible antagonism. 5 The relative orders of affinity (KA) were isoprenaline greater than orciprenaline greater than fenoterol greater than salbutamol greater than terbutaline. Affinities were identical on rate and tension. 6 The relative efficacies were all greater than isoprenaline for rate responses. On tension they were the same or less than isoprenaline. 7 The implications of these results are discussed, in particular the fact that a partial agonist has a greater efficacy than a full agonist.

Animals↗

PubMed1981

The response of the rabbit rectococcygeus muscle to stimulation of extrinsic inhibitory nerves and to sympathomimetic drugs.

1 The effects of stimulating sympathetic or non-adrenergic non-cholinergic (NANC) nerves or of the addition of noradrenaline (NA) or isoprenaline (Iso) were investigated on carbachol-induced tone and on contractions produced by acetylcholine (ACh) and by pelvic nerve stimulation, in the rabbit rectococcygeus muscle.2 Each procedure reduced carbachol-induced tone; sympathetic and NANC nerve stimulation were equipotent but both were less effective than sympathomimetic drugs, of which Iso was the better. Both Iso and NA, but not sympathetic nerve stimulation, inhibited the contractions produced by pelvic nerve stimulation in a concentration-dependent manner. Against ACh-induced contractions, only Iso was effective. The effects of NANC nerve stimulation on the motor responses to pelvic nerve stimulation or to ACh were not investigated.3 The inhibitory effects of sympathetic nerve stimulation, of Iso and of NA were reduced by propranolol (3 x 10(-6) M) but unaffected by phentolamine (3 x 10(-5) M).4 In the presence of high (45 mM) concentrations of KCl, Iso and NA produced a concentration-dependent inhibition of tone that was antagonized by propranolol (3 x 10(-6) M).5 Methoxamine (4 x 10(-7) to 4 x 10(-5) M) and phenylephrine (5 x 10(-7) to 5 x 10(-5) M) which interact mainly with alpha(1)-adrenoceptors, produced only small, transient reductions in carbachol-induced tone which were subject to tachyphylaxis, unlike those produced by Iso and NA. These inhibitory effects were antagonized by phentolamine (3 x 10(-6) M) or azapetine (3 x 10(-6) M).6 Phenylephrine (5 x 10(-4) M) and high doses (3 x 10(-5) M or greater) of NA enhanced the contractile response to pelvic nerve stimulation and, on occasion, produced muscle contraction. These effects were antagonized by phentolamine (3 x 10(-6) M).7 These results suggest that inhibition of the rectococcygeus, a muscle which has no intramural nerve plexus, can be inhibited by stimulation of extrinsic NANC nerves, the transmitter for which is unknown and by sympathetic nerve stimulation via alpha- and beta-adrenoceptors located postsynaptically on the muscle. Excitatory alpha-adrenoceptors may also be present.

Acetylcholine↗

PubMed1989

Inhibition of Ca-spikes in rat preganglionic cervical sympathetic nerves by sympathomimetic amines.

1. Propagated Ca-spikes were recorded from isolated cervical sympathetic nerve trunks of the rat when bathed in a solution containing 5 mM Ca2+, 0.5 or 1 microM tetrodotoxin (to block Na currents) and 1 mM 4-aminopyridine (to reduce K currents). 2. Spikes persisted when external Ca2+ was replaced with Sr2+ or Ba2+, but were blocked by the addition of the following inorganic Ca-channel blockers (in descending order of potency): Cd2+ greater than La3+ greater than Ni2+ greater than Co2+ greater than Mn2+ greater than Mg2+. 3. Ca-spike amplitude was reduced by up to 90% by (-)-noradrenaline (IC50 1.5 microM). The following sympathomimetic amines imitated this effect (in descending order of potency): clonidine greater than or equal to (-)-adrenaline greater than or equal to [(-)-noradrenaline] greater than or equal to dopamine greater than (-)-phenylephrine greater than or equal to (+/-)-amidephrine. 4. Ca-spike inhibition by (-)-noradrenaline was antagonized by phentolamine (pA2 6.5). Yohimbine was about 10 times weaker than phentolamine; (+/-)-propranolol (1 microM) and prazosin (10 microM) had no clear effect. 5. (-)-Noradrenaline reduced the amplitude of the compound action potential recorded from the superior cervical sympathetic ganglion following supramaximal preganglionic trunk stimulation when recorded in normal Krebs solution and hyperpolarized the ganglion with respect to the post-ganglionic trunk. Depression of the transmitted ganglionic action potential was antagonized by phentolamine (5 microM) but not by yohimbine (1 microM); in contrast 1 microM yohimbine completely prevented the ganglionic hyperpolarization. (-)-Noradrenaline did not hyperpolarize the preganglionic cervical sympathetic nerve trunk under these recording conditions. 6. It is suggested that inhibition of transmitter release from sympathetic preganglionic fibres produced by noradrenaline results from a depression of the voltage-gated Ca current in the fibres and/or their terminals, and that this action is mediated by an alpha-adrenoceptor which does not fully conform to either alpha 1 or alpha 2 subtypes.

Action Potentials↗

PubMed1982

Quantitative pharmacological characterization of beta-receptors and two types of alpha-receptors mediating sympathomimetic smooth muscle response in the human Fallopian tube at various cyclic stages.

The dissociation constants for adrenoceptor-antagonist complexes (KB) were determined in vitro in circular and longitudinal smooth musculature from the ampullary and isthmic regions of the human Fallopian tube. High extracellular potassium concentrations were used to eliminate the spontaneous contractile activity. Neuronal and extraneuronal amine uptake mechanisms were blocked. The parallel shift of the log dose-response curves was secured in Arunlakshana-Schild plots. KB for the beta-receptor, mediating sympathomimetic relaxation, were determined during alpha-receptor blockade: the values for propranolol were the same (approximately 10(-6) M) in all preparations and at all cyclic stages, as determined from plasma estradiol and progesterone levels. KB for the complex between the alpha-receptor (mediating contraction) and phentolamine were determined during beta-receptor blockade. The values were the same in all types of smooth musculature, but varied with cyclic stage: they were around 7 x 10(-8) M when plasma estradiol and progesterone were both minimum, and around 2 x 10(-7) M when these steroid levels were moderate to high, suggesting that the properties of the contractile receptors of the human Fallopian tube are modified during the menstrual cycle.

Adult↗

PubMed1978

The indirect sympathomimetic activity of etilefrine--a comparison with tyramine and ephedrine using [3H] noradrenaline.

The indirect sympathomimetic activity of etilefrine has been examined using the ventral caudal artery of the rat. This vessel has a rich sympathetic innervation and lends itself to studies on [3H]noradrenaline efflux from these sites. Etilefrine possessed significant indirect activity on the artery and this action, although less than that of tyramine, was equivalent to that caused by ephedrine. Pretreatment of the vessels with a mixture of iproniazid, doca, cocaine and UO521 (3',4'-dihydroxy-2-methyl propiophenone) significantly enhanced[3H]-noradrenaline efflux from the artery.

Animals↗

PubMed1992

Dispositional study of opioids in mice pretreated with sympathomimetic agents.

Brain and plasma levels of morphine and codeine were determined by an assay method involving solid-phase extraction and ion-pair reversed phase HPLC. Detection was by a variable wavelength UV-detector (for codeine) and an amperometric electro-chemical detector (for morphine) coupled in series. Ephedrine or phenylpropanolamine pretreatment did not interfere with the plasma disposition of morphine, evidenced by overlapping plasma concentration-time profiles. Brain opioid levels were equally unaffected by sympathomimetic pretreatment. The relative ratios of brain to plasma concentrations at the time corresponding to the respective peak anti-nociceptive activity for morphine and codeine revealed no significant differences. It is concluded that single doses of ephedrine and phenylpropanolamine do not affect the disposition of morphine and codeine in mice.

Animals↗

PubMed1972

Inhibition of post-ganglionic motor transmission in vas deferens by indirectly acting sympathomimetic drugs.

1. Using field stimulation with short trains of pulses (< 10 per train), the post-ganglionic motor transmission in the mammalian vas deferens has been further analysed pharmacologically.2. In preparations taken from guinea-pigs, rats and rabbits the effects of the indirectly sympathomimetic drugs, tyramine and cocaine, could be explained entirely on the basis of the actions of released, endogenous noradrenaline.3. Tyramine produced a contraction in vasa taken from normal rats but not from normal guinea-pigs. The tyramine contraction was due to release of endogenous noradrenaline because it was not seen in preparations taken from reserpinized rats and because it was abolished in normal vasa by phenoxybenzamine or phentolamine, thus denying the supposed inaccessibility, to alpha-blockers, of the motor alpha-adrenoceptors activated by endogenous noradrenaline.4. Phenoxybenzamine or phentolamine failed to block post-ganglionic motor transmission in rat and in guinea-pig vasa.5. Tyramine strongly inhibited motor transmission in vasa taken from normal but not from reserpinized guinea-pigs.6. Tyramine produced inhibition of motor transmission in phenoxybenzamine-treated preparations taken from normal but not from reserpinized rats.7. Cocaine inhibited motor transmission in guinea-pig and in rat vasa. This effect was not due to a local anaesthetic or to a smooth-muscle depressant action because it did not occur in preparations taken from reserpinized animals.8. The inhibitory effect of tyramine or cocaine was not abolished by beta-adrenoceptor blockade with propranolol.9. Whereas reserpinization abolished the tyramine- and cocaine-inhibitions, it did not affect the inhibitory actions of noradrenaline or of PGE(2).10. Indomethacin and sodium meclofenamate, which suppress prostaglandin synthesis, did not affect the twitch-inhibiting actions of noradrenaline, tyramine or cocaine.11. These results provide further support for the conclusion that post-ganglionic motor transmission to the vas deferens is non-adrenergic in these species and assign to endogenously released noradrenaline an inhibitory role upon motor transmission.

Animals↗

PubMed2006

Roles of norepinephrine, free Fatty acids, thyroid status, and skeletal muscle uncoupling protein 3 expression in sympathomimetic-induced thermogenesis.

Thyroid hormone (TH) plays a fundamental role in thermoregulation, yet the molecular mediators of its effects are not fully defined. Recently, skeletal muscle (SKM) uncoupling protein (UCP) 3 was shown to be an important mediator of the thermogenic effects of the widely abused sympathomimetic agents 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) and methamphetamine. Expression of UCP3 is regulated by TH. Activation of UCP3 is indirectly regulated by norepinephrine (NE) and is dependent upon the availability of free fatty acids (FFAs). We hypothesized that UCP3 may be a molecular link between TH and hyperthermia, requiring increased levels of both NE and FFAs to accomplish the thermogenic effect. Here, we demonstrate that MDMA (40 mg/kg s.c.) significantly increases plasma FFA levels 30 min after treatment. Pharmacologically increasing NE levels through the inhibition of phenylethanolamine N-methyltransferase with +/-2,3-dichloro-alpha-methylbenzylamine potentiated the hyperthermic effects of a 20 mg/kg dose of MDMA. Using Western blots and regression analysis, we further illustrated that chronic hyperthyroidism in rats potentiates the hyperthermic effects of MDMA and increases levels of SKM UCP3 protein in a linear fashion according to levels of circulating plasma TH. Conversely, chronic hypothyroidism results in a hypothermic response to MDMA that is directly proportionate to decreased UCP3 expression. Acute TH supplementation did not change the skeletal muscle UCP3 expression levels or temperature responses to MDMA. These findings suggest that, although MDMA-induced hyperthermia appears to result from increased NE and FFA levels, susceptibility is ultimately determined by TH regulation of UCP3-dependent thermogenesis.

Animals↗

PubMed1994

Ontogeny of positive inotropic responses to sympathomimetic agents and of myocardial adrenoceptors in rats.

Positive inotropic efficacies (maximal increase in contractile force) and potencies of the alpha-adrenoceptor agonist methoxamine and beta-adrenoceptor agonist isoprenaline were determined on electrically driven (1 Hz) ventricular strips from rats aged 0.5, 1, 2, 3, 6, and 10 (adult) weeks. The inotropic response to methoxamine significantly decreased after 2 weeks of age. The inotropic potency of isoprenaline was slightly but significantly lower at all ages than at 0.5 weeks of age. Up to 2 weeks of age, the maximal inotropic effect of methoxamine was comparable with that of isoprenaline, thereafter it was but markedly less. Phenylephrine behaved like methoxamine, and noradrenaline like isoprenaline. The effect of methoxamine was antagonized by prazosin but not by propranolol; the reverse was true for isoprenaline. Injections at birth of triiodothyronine and dexamethasone exerted minimal effects on the inotropic responses to methoxamine and isoprenaline. Chemical sympathectomy with 6-hydroxydopamine caused supersensitivity to the inotropic effects of isoprenaline but produced subsensitivity to responses to methoxamine at 1 week; effects of methoxamine at 3 and 6 weeks of age were not altered by sympathectomy. No significant differences in alpha 1- or beta 1-adrenoceptor densities or affinities in ventricular membranes from 7-day-old and adult rats were found. It is concluded that the positive inotropic responses to sympathomimetic amines decline with age, the decline is most marked in the case of alpha 1-adrenoreceptor- mediated effects, and these changes do not appear to be due to a decrease in the number or affinity of alpha 1- and beta 1-adrenoceptors.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1982

Effects of inhaled sympathomimetics on obstructive response to respiratory heat loss.

To investigate the influence of inhaled sympathomimetics on the obstructive response to airway cooling, we had six asymptomatic atopic asthmatics perform eucapnic hyperventilation with frigid air at various levels of ventilation after pretreatment with aerosols of metaproterenol or placebo in a random blind fashion. In control experiments, eucapnic hyperventilation produced a progressive decrease in 1-s forced expiratory volume in a stimulus-response fashion as the level of ventilation rose in successive challenges. Metaproterenol did not produce an all-or-none blockade, but rather a parallel shift in the stimulus-response curve so that its protective effects could be overcome by increasing the stimulus. There was no effect on respiratory heat loss. These results explain, in a quantitative fashion, why a treatment schedule that permits a person with asthma to perform a given exercise task without difficulty becomes ineffective as the thermal burden or severity of the task increases.

Adult↗

PubMed1990

Effect of hindlimb suspension on cardiovascular responses to sympathomimetics and lower body negative pressure.

To determine whether hindlimb suspension is associated with the development of cardiovascular deconditioning, male rats were studied before and after undergoing one of three treatment conditions for 9 days: 1) cage control (n = 15, CON), 2) horizontal suspension (n = 15, HOZ), and 3) head-down suspension (n = 18, HDS). Testing included lower body negative pressure administered during chloralose-urethan anesthesia and graded doses of sympathomimetic agents (norepinephrine, phenylephrine, and tyramine) administered to conscious unrestrained animals. Both HDS and HOZ were associated with a small decrease in the hypotensive response to lower body negative pressure. The HOZ group, but not the HDS group, exhibited augmented reflex tachycardia. Furthermore, both HDS and HOZ groups manifested reduced pressor responses to phenylephrine after treatment. These reductions were associated with significantly attenuated increases in mesenteric vascular resistance. However, baroreflex control of heart rate was not altered by the treatment conditions. Collectively, these results indicate that 9 days of HDS in rats does not elicit hemodynamic response patterns generally associated with cardiovascular deconditioning induced by hypogravic conditions.

Animals↗