Nasal trigeminal inputs release the A5 inhibition received by the respiratory rhythm generator of the mouse neonate. (1/12)

Experiments were performed on neonatal mice to analyze why, in vitro, the respiratory rhythm generator (RRG) was silent and how it could be activated. We demonstrated that in vitro the RRG in intact brain stems is silenced by a powerful inhibition arising from the pontine A5 neurons through medullary alpha(2) adrenoceptors and that in vivo nasal trigeminal inputs facilitate the RRG as nasal continuous positive airway pressure increases the breathing frequency, whereas nasal occlusion and nasal afferent anesthesia depress it. Because nasal trigeminal afferents project to the A5 nuclei, we applied single trains of negative electric shocks to the trigeminal nerve in inactive ponto-medullary preparations. They induced rhythmic phrenic bursts during the stimulation and for 2-3 min afterward, whereas repetitive trains produced on-going rhythmic activity up to the end of the experiments. Electrolytic lesion or pharmacological inactivation of the ipsilateral A5 neurons altered both the phrenic burst frequency and occurrence after the stimulation. Extracellular unitary recordings and trans-neuronal tracing experiments with the rabies virus show that the medullary lateral reticular area contains respiratory-modulated neurons, not necessary for respiratory rhythmogenesis, but that may provide an excitatory pathway from the trigeminal inputs to the RRG as their electrolytic lesion suppresses any phrenic activity induced by the trigeminal nerve stimulation. The results lead to the hypothesis that the trigeminal afferents in the mouse neonate involve at least two pathways to activate the RRG, one that may act through the medullary lateral reticular area and one that releases the A5 inhibition received by the RRG.  (+info)

The effects of labetalol (AH 5158) on adrenergic transmission in the cat spleen. (2/12)

1. The competitive alpha- and beta-adrenoceptor blocking agent labetalol, in concentrations up to 10(-4) M, produced dose-dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 and 30 Hz. 2. At concentrations above 10(-4) M labetol produced a pronounced decrease in transmitter overflow. 3. Labetalol (1.5 X 10(-4) M) increased the recovery of 3H label in the venous blood following the close-arterial infusion of [3H]-(-)-noradrenaline indicating that the drug inhibits uptake of the amine. 4. Both labetalol (3.8 X 10(-5) M) and piperoxan (7.4 X 10(-6) M) produced parallel shifts to the right of the dose-response curves to noradrenaline and oxymetazoline in isolated strips of cat splenic capsule. In this preparation both drugs acted as competitive postsynaptic alpha-adrenoceptor blocking agents. 5. Labetalol (3.3 X 10(-5) M) increased the transmitter overflow following stimulation of the splenic nerves with 200 impulses at 10 Hz. The overflow could be further increased by subsequent addition of piperoxan (7.2 X 10(-6 M). Piperoxan (5.7 X 10(-6) M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 X 10(-5) M). Cocaine (1.5 X 10(-5) M) or DMI (5.4 X 10(-5 M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 X 10(-5) M). 6. Labetalol produced a biphasic effect on the responses of the isolated blood perfused spleen of the cat to nerve stimulation. With low doses (up to 10(-4) M) vascular responses were potentiated and with high doses (greater than 10(-4) M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic alpha-adrenoceptor blockade. 7. Labetalol appears to act as a postsynaptic alpha-adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic alpha-adrenoceptors. The moderate elevation of transmitter overflow by the drug is related to the inhibitory effect of the drug on neuronal uptake rather than on presynaptic alpha-adrenoceptors.  (+info)

The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist. (3/12)

1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain. 5. We conclude that fluparoxan is a highly selective and potent alpha 2-adrenoceptor antagonist. The density of rat brain [3H]-dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg- 1 orally twice daily. The down-regulation of beta-adrenoceptors by fluparoxan is consistent with its antidepressant potential.  (+info)

Spinal alpha 1- and alpha 2-adrenoceptors mediate facilitation and inhibition of spinal motor transmission, respectively. (4/12)

The role of descending noradrenergic fibers in the spinal motor systems was investigated using spinal reflexes in acutely spinalized rats. In rats pretreated with the MAO inhibitor clorgyline-HCl (1 mg/kg, i.v.), L-3,4-dihydroxyphenylalanine (L-dopa) (5 mg/kg, i.v.), a precursor of dopamine and noradrenaline, markedly potentiated the mono- (MSR) and polysynaptic reflexes (PSR). Selective blockade of alpha 1-adrenoceptors by pretreatment with prazosin-HCl abolished these facilitatory effects on the MSR and the PSR and revealed the inhibitory effect of L-dopa on the PSR. The depression of PSR was antagonized by the alpha 2-antagonist piperoxan. Clonidine-HCl (0.05 mg/kg, i.v.), a so-called alpha 2-agonist, and tizanidine-HCl (0.1 mg/kg, i.v.) decreased the MSR and the PSR in rats pretreated with prazosin. These inhibitions were antagonized by piperoxan. These results suggest that alpha 1- and alpha 2-adrenoceptors mediate facilitation and attenuation of motor transmission in the rat spinal cord, respectively.  (+info)

Permanent release of noradrenaline modulates respiratory frequency in the newborn rat: an in vitro study. (5/12)

1. Respiratory activity was recorded on ventral cervical roots during in vitro experiments performed on superfused newborn rat brain stem-cervical cord preparations. 2. Eliminating the pontine structures by performing a transection at the level of the ponto-medullary junction resulted in a sustained increase in respiratory frequency, which suggests the existence of a pontine inhibitory drive impinging on the medullary rhythm generator. 3. Noradrenaline (NA) and drugs affecting NA efficiency were added to the bathing medium and the resulting changes in respiratory frequency were analysed. NA decreased the respiratory frequency, and this effect was potentiated by pargyline (an inhibitor of the NA degradation by monoamine oxidases) and blocked by yohimbine (an alpha 2-antagonist). 4. Yohimbine or piperoxane (which blocks the alpha 2-adrenoceptors) increased the resting respiratory frequency to the level reached after ponto-medullary transection, whereas pargyline or desipramine (which potentiates NA efficiency) decreased the respiratory rate. Since these effects were no longer observed after elimination of the pons, it is suggested that a permanent release of endogenous NA by pontine areas may modulate the activity of the medullary respiratory rhythm generator. 5. When alpha-methyltyrosine (an inhibitor of NA biosynthesis) was applied to the pons, the respiratory frequency was increased, whereas when tyrosine (a precursor of NA) was applied, the respiratory frequency decreased. This decrease was enhanced by pargyline, suppressed by alpha-methyltyrosine and blocked by piperoxane. 6. To conclude, it is suggested that the mechanisms underlying NA biosynthesis (i) continue to function under these in vitro experimental conditions and (ii) are responsible for a permanent release of endogenous NA, which slows down the respiratory frequency. These results are discussed as regards the possibility that the medullary respiratory rhythm generator may be modulated via the noradrenergic area A5 in the newborn rat.  (+info)

The antinociceptive action of some beta-adrenoceptor agonists in mice. (6/12)

The antinociceptive actions of several beta-adrenoceptor agonist drugs have been studied in mice by use of a modified abdominal constriction test. All the drugs studied had high antinociceptive activity, with ID50 values in the nmol kg-1 range. (-)-Isoprenaline and (+/-)-isoxsuprine were the most potent, being about ten times more active than salbutamol, the least potent drug studied. All these drugs produced their action very rapidly and appear to act within the peritoneum. (-)-Isoprenaline had about six times the potency of the (+)-isomer. (+/-)-Propranolol caused rightward shifts, usually parallel, of the dose-response curves for (-)-isoprenaline. (+)-Propranolol was more than ten times less potent than the racemic drug. Practolol also caused parallel, rightward shifts of the dose-response curves for (-)-isoprenaline, and was about twice as potent as (+/-)-propranolol, whether given by subcutaneous or intraperitoneal injection. Atenolol and ICI 118551 had intermediate potencies. Propranolol, practolol and ICI 118551 were all considerably less potent in antagonizing the antinociceptive actions of fenoterol and RO363, than (-)-isoprenaline. None of these antagonist drugs showed more than a slight ability to discriminate between the beta 1- and beta 2-selective agonist drugs. No evidence was found for the involvement of opioid, dopamine, or alpha-adrenoceptors in the antinociceptive action of the beta-adrenoceptor agonist drugs. Evidence for and against the involvement of beta-adrenoceptors is discussed, and it is concluded that if these receptors do mediate the antinociceptive action they appear to be atypical.  (+info)

The effects of piperoxan on uptake of noradrenaline and overflow of transmitter in the isolated blood perfused spleen of the cat. (7/12)

1 The competitive alpha-adrenoceptor blocking agent, piperoxan, in concentrations up to 2 x 10(-4) M, produced large dose-dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 hertz. 2 At concentrations greater than 2 x 10(-4) M, piperoxan produced a rise in perfusion pressure, a contraction of the splenic capsule, and a marked dose-dependent decrease in transmitter overflow. 3 Phenoxybenzamine (10(-4) M) and desmethylimipramine (3 x 10(-5) M) produced further increases in transmitter overflow when added after piperoxan. 4 Piperoxan (5.8 to 6.6 x 10(-6) M) had no effect on the recovery of 3H in the venous blood following the close arterial infusion or injection of (3H)-(--)-noradrenaline, indicating that the drug does not inhibit uptake of the amine. 5 Piperoxan produced dose-dependent inhibition of responses of the splenic vasculature to close arterial injection of 1 microgram of (--)-noradrenaline but was much less effective at inhibiting responses to nerve stimulation. At 2 x 10(-6) M piperoxan produced a considerable reduction of the response to injected noradrenaline but potentiated the response to nerve stimulation. 6 In isolated strips of cat splenic capsule, piperoxan produced a shift to the right of the dose-response curve to noradrenaline with no change of the maximum response. There was no evidence of a postsynaptic sensitizing effect of the type observed in the rat vas deferens.  (+info)

Local regulation of transmitter release from rodent sympathetic nerve terminals? (8/12)

1. Electrophysiological techniques were used to observe the release of transmitter from single release sites in the sympathetic neuro-effector junction of the rodent vas deferens. Transmitter release produces transient peaks in the rate of depolarization of the smooth muscle cells, known as 'discrete events'. 2. The amplitude distributions of stimulus-evoked discrete events in both mouse and guinea-pig vas are multi-modal. In the mouse, the distribution fits a Poisson with a 'quantal content' of about two. There are too many zeros in the amplitude distributions of guinea-pig discrete events to fit a Poisson distribution, and it is likely that in this species there is a mechanism preceding the transmitter release process which may occasionally prevent it operating. 3. alpha-adrenoreceptor agonists and antagonists produce, respectively, left and right shifts in the amplitude distributions of discrete events at a single latency, with no change in the amplitudes at the modes. 4. There is, however, no evidence of any inhibitory relationship between either discrete events evoked by successive stimuli, or early and late discrete events following a given stimulus. 5. Transmitter release at this junction is therefore packeted, with few quanta released by each stimulus. Release from single sites is affected in ways compatible with the 'alpha-feed-back' hypothesis by alpha-adrenoreceptor agonists and antagonists, but in the absence of drugs we can find no evidence of any local feed-back inhibition of transmitter release.  (+info)

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