Modification of the effect of cardio-accelerator nerve stimulation in dogs by clonidine and several alpha-adrenolytics]

In dogs anaesthetized with pentobarbital (30 mg. kg -1 i.v.), clonidine (0,01 mg.kg-1 i.v.) reduced the tachycardia induced at low frequencies by stimulation of the cardiac nerve. The effects of some alpha-adrenoceptor blocking agents on this effect have been studied. Small doses of yohimbine (0.3 mg. kg-1 i.v.) or piperoxan (0.3 mg. kg-1 i.v.) increased the effects of the stimulation and in addition antagonized the inhibitory effects of clonidine and reversed the pressor response to adrenaline. Thymoxamine (1 mg.kg-1 i.v.) and prazosin (1 mg.kg-1 i.v.) did not increase the effect of the stimulation of the cardiac nerve, but reduced the effect of clonidine. ARC239 (0.05 mg.kg-1) reversed the pressor response to adrenaline but even at high doses did not increase the effects of the stimulation of the cardiac nerve or the effects of clonidine. These observations afford further evidence for a dissimilarity between pre and post-synaptic alpha-adrenoceptors.     

Action of N-butylnorsympathone on the effects of cardioaccelerator nerve stimulation in the dog]

In Dogs anaesthetized with pentobarbital (30 mg . kg-1), N-butylnorsympathone (20 mg . kg-1 i.v.) reduced the bradycardia induced by stimulating the cardiac nerve (1, 2, 5, 10 Hz). Phentolamine (1 mg . kg-1 i.v.) or yohimbine (0.3 mg . kg-1 i.v.), two potent alpha-adrenoceptor blocking agents known to block presynaptic alpha-adrenoceptor induced a recovery of the effect of cardiac nerve stimulation. Prazosine (0.050 mg . kg-1 i.v.) an alpha-adrenoceptor blocking agent known to be ineffective on presynaptic alpha-adrenoceptors did not induce a recovery. However neither phentolamine or yohimbine were able to prevent the effects of N-butylnorsympathone. Neither haloperidol (0.050 to 2 mg . kg-1 i.v.) or pimozide (0.20 to 1 mg . kg-1 i.v.) induced a recovery or prevented the effects of N-butylnorsympathone. These results suggest that N-butylnorsympathone may stimulate presynaptic receptors which do not resemble classical presynaptic alpha-adrenoceptors or dopamine receptors.     

Influence of clonidine on experimental hypertension induced by cholinergic stimulation

Summary Hypertension may be induced by pharmacologic activation of central cholinergic receptors either indirectly, through the injection i.v. of physostigmine, or directly, through the injection i.v. of arecholine in anesthetized rats. Activation of peripheral preganglionic cholinergic receptors with dimethylphenylpiperazinium iodide (DMPP) also produced a hypertensive response. Pretreatment with various doses of clonidine caused inhibition of the pressor response to central cholinergic stimulation but was without effect on the response to ganglionic cholinergic stimulation.     

Zur peripheren sympathikushemmenden Wirkung des Clonidins

Summary The influences of clonidine, tetracaine and procaine on the effects of electrical stimulation of the postganglionic sympathetic cardiac nerves have been compared in the isolated perfused rabbit heart. Much lower concentrations of clonidine than of tetracaine were necessary to antagonize the output of noradrenaline and the rise of frequency and contractility. Procaine even in the highest concentration tested did not inhibit the effects of nerve stimulation. In addition to its known central depression of sympathetic tone, clonidine exerts a specific inhibitory action on postganglionic sympathetic neurons.     

In vitro characterization of adrenergic receptors mediating extrusion of preformed sebum from preputial gland of rat

Extrusion of preformed sebum from the preputial glands of rat after phenylephrine and adrenaline treatment, and its inhibition by alpha-receptor blocking agents under in vitro conditions, shows that secretory response of the glands is influenced by alpha-adrenergic receptors, and isoproterenol--a beta-agonist--is not effective in elicitation of exudation of secretion from the preputial gland.     

Responses to stimulation of the peripheral end of the right splanchnic nerve in the conscious calf

Summary The ratio at which adrenaline and noradrenaline are released from the adrenal medulla in response to stimulation of the splanchnic nerve has been established in the conscious calf. The proportion of adrenaline: noradrenaline was closely similar to that in which the 2 amines are stored in the gland and released in response to other stimuli in conscious, but not anaesthetized, calves.Acknowledgments. This work has been supported by a grant from the Agricultural Research Council, and we are also indebted to Dr D.M. Burley (Ciba) for his continued support. It is a pleasure to acknowledge the skilled technical assistance provided by Mr P.M.M. Bircham.     

Influence of cervical sympathetic nerve stimulation on carotid sinus baroreceptor afferents

Summary In rabbits and dogs, the response of low-threshold carotid sinus baroreceptor afferent fibres to cervical sympathetic nerve stimulation at various non-pulsatile steady pressures was examined. Fibres which possessed a rhythmic bursting discharge at low pressures increased this activity during sympathetic stimulation; all other low-threshold afferents were unaffected.This work was supported by the Medical Research Council of Canada and the British Columbia Heart Foundation.     

Physiologische Untersuchungen an der innervierten glatten Muskulatur der Vogelfedern (Mm. pennarum)

Summary The tension development of the smooth feather muscles of the pigeon was measured (a) on the wing in situ (b) on an isolated innervated skin preparation and (c) on an isolated muscle preparation. The contraction produced by nerve stimulation is biphasic. The second phase can be blocked by -receptor blocking agents. The mechanism of the first phase is unknown. The preparation seems very suitable for the investigation of neuromuscular transmission in smooth muscle.     

Piroxicam-induced analgesia: Evidence for a central component which is not opioid mediated

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p<0.05) and 50% (p<0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Piroxicam-induced analgesia: evidence for a central component which is not opioid mediated.

Piroxicam is a nonsteroidal anti-inflammatory drug with a potent analgesic effect. In order to establish whether the analgesic action of Piroxicam has a central component, we studied the effect of the drug on the nociceptive orbicularis oculi reflexes evoked by electrical stimulation of the cornea and supraorbital nerve in healthy subjects. Piroxicam significantly suppressed the corneal reflex and R3 component of the blink reflex by 28% (p < 0.05) and 50% (p < 0.01), respectively. This effect was not reversed by the i.v. injection of naloxone. Beta-endorphin levels did not change. Piroxicam administration induces distinct inhibitory changes in nociceptive reflexes, which suggests that the analgesic action of the drug has a central component. The ineffectiveness of naloxone, and the lack of beta-endorphin changes, indicate that this central action is independent of the opioid system; other pain regulatory systems are probably involved.     

Serotonergic and cholinergic interaction in the regulation of pituitary-adrenal function in rats

It has been proposed that the central serotonergic inputs which modulate pituitary-adrenal secretion are mediated by cholinergic neurons. We have tested this hypothesis in intact rats. Male Sprague-Dawley rats were injected with cholinergic and serotonergic agents which enhanced transmitter function and with receptor blocking agents. Agents were injected, singly and in combination, into both unstressed and stressed animals. Since the response to cholinergic agents might be due to changes to vasopressin release, Brattleboro (vasopressin deficient) rats were also injected with cholinergic agents. The level of plasma corticosterone at 1-h post-injection was determined. Results indicate that the serotonin receptor blockade decreased the stimulatory, cholinergic effect of physostigmine. Cholinergic receptor blockers did not significantly reduce the corticosterone rise induced by 5-hydroxytryptophan. These results do not support the hypothesis of cholinergic mediation of serotonergic input. Nicotinic and muscarinic receptors appeared to exert opposing influences on the system. The nicotinic receptor antagonist was able to block the stimulatory effect of physostigmine. The muscarinic receptor antagonist significantly elevated plasma corticosterone levels. No differences were found in the effect of physostigmine on Brattleboro rats as compared to controls. These data are interpreted as suggesting that 1) the acetylcholine-induced stimulation of pituitary-adrenal function is mediated, in part, by serotonergic neurons; and 2) stimulation of nicotinic receptors is facilitatory whereas stimulation of muscarinic receptors is inhibitory to pituitary-adrenal function.     

In vitro characterization of adrenergic receptors mediating extrusion of preformed sebum from preputial gland of rat

Summary Extrusion of preformed sebum from the preputial glands of rat after phenylephrine and adrenaline treatment, and its inhibition by -receptor blocking agents under in vitro conditions, shows that secretory response of the glands is influenced by -adrenergic receptors, and isoproterenol — a -agonist — is not effective in elicitation of exudation of secretion from the preputial gland.Acknowledgements. We are thankful to Prof. R.V. Shah, for providing the facilities to conduct this work. D.M. V. is grateful to the Indian Council of Medical Research for the award of a Senior Research Fellowship during the tenure of which this work was conducted.     

Forskolin inhibits tension development in detergent-treated cardiac muscle fibers

Summary In detergent-treated cardiac muscle fibers, forskolin, a potent activator of adenylate cyclases, inhibits tension development elicited with submaximal [Ca²⁺] and increases incorporation of³²P into troponin-I. A similar reduced tension development has been observed after treatment with cAMP or the catalytic subunit of the cAMP-dependent protein kinase. It is concluded that these fibers still contain much of the enzyme cascade involved in evoking a contractile response to \-adrenergic stimulation.Acknowledgment. The authors thank Dr H. Metzger, Hoechst AG, Frankfurt (FRG) for the gift of forskolin. The excellent technical assistance of Mrs Doris Eubler and the support by the Deutsche Forschungsgemeinschaft (SFB 90) are gratefully acknowledged.     

Juvenilizing effect of ecdysone mimic RH 5849 inGalleria mellonella larvae

The response of the final instar larvae ofG. mellonella to topical application of the non-steroidal ecdysone mimic, RH 5849, was age-related as well as dose-dependent. In young final instar larvae, moderate doses of RH 5849 induced perfect supernumerary larval moults, but doses equal to and higher than 8.5 μg per larva caused premature formation of larval cuticle and were lethal. Application of RH 5849 significantly increased allatotropic activity of the brain, and also activated synthesis of juvenile hormone (JH) by the corpora cardiaca/corpora allata complex. Simultaneous application of RH 5849 and FMev, a potent inhibitor of JH synthesis, to young final instar larvae lowered the incidence of perfect supernumerary larval moults. We conclude that the effect of RH 5849 on the developmental programme inG. mellonella is mediated by the corpora allata.     

A new approach to analysis of human sweating

In human skin transplanted to the back of 3 strains of immuno-deficient mice the functin of the eccrine sweat glands of the human transplant was tested by topical intradermal application of pilocarine, adrenaline and atropine+pilocarpine. Sweat responses were observed in pre-selected fields of observation by means of video macroscope. The iodine strarch reaction served as an indicator for the appearance of seat sport and permitted the evaluation of areas wetted by sweat in the field of observation. Among 9 animals tested, the hybrids between the CB-17-scid mouse and the BALB/cA-nu mouse (BALB/cA-nu,scid) seemed to exhibit the most consistent seweating response to local pharmacological stimulation. According to histological examination, eccrine sweat glands were preserved in human skin trasplanted into the back skin of the BALB/cA-nu,scid mouse strain. the heterologous, human skin graft provides a novel model permitting, independent of the normal sweat gland innervation, the analysis of moecular receptors of sweat gland cells by which the actions of natural transmitters and pharmacological agents are transduced.     

Osservazioni preliminari,chimiche e farmacologiche,sulla murexina

Summary (1) Murexine, a new choline derivative found in the hypobranchial body ofMurex trunculus, Murex brandaris, andTritonalia erinacea, was isolated as picrate, picrolonate, styphnate, flavianate, and reineckate. Some preliminary characteristics of these salts are given.(2) The murexine content of the median zone of the hypobranchial body ofMurex trunculus is extremely high: murexine picrate equivalents of 45–70 mg per g fresh tissue are commonly observed.(3) Murexine manifests intense nicotinic and curariform actions, but is practically wanting in any muscarinic activity.The central nervous system is strongly affected by the substance: at first stimulation seems to prevail, but later on, with larger doses, a deep depression regularly develops.In decapitated cats and dogs murexine causes a significant rise in blood pressure, which is due, at least partially, to a liberation of epinephrine from the adrenal medulla and from the adrenergic nerve terminals.On the enucleated eye of frogs andOctopoda the substance acts to cause mydriasis and expansion of the iris chromatophora.

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V. Erspamer eF. Dordoni, Arch. int. Pharmacodyn.74, 263 (1947).     

Cephalopod myocardial receptors: Pharmacological studies on the isolated heart ofSepia officinalis (L.)

Summary This paper presents a synopsis of the information available about the pharmacological action of various substances on the cephalopod heart, with special emphasis on the central heart ofSepia officinalis. Threshold concentrations, EC₅₀ values and maximum effective concentrations have been experimentally determined. Studies with various transmitter substances, analogous compounds and antagonists have led to the following picture: Acetylcholine is the natural inhibitory transmitter substance; it acts via receptors with nicotinic properties which can be blocked by d-tubocurarine and -bungarotoxin. The probable excitatory transmitter system is represented by a noradrenergic innervation. Noradrenaline has a positive inotropic and a positive chronotropic action on in vitro heart preparations. A positive inotropic response can also be evoked by serotonin (5-HT); this effect is not due to stimulation of the catecholamine receptor, as is shown by cross-over experiments with specific blocking agents. Furthermore, a peptidergic receptor system has been described which reacts with the molluscan cardioactive peptide FMRF amide most effectively. It is assumed that cardioactive peptides may reach the central heart in the circulating blood; the sites of synthesis and release are still unknown. Possibly the NSV-layer of the vena cava is involved in hormonal cardiovascular regulation processes.     

Insulin can induce the expression of a memory-related synaptic protein through facilitating AMPA receptor endocytosis in rat cortical neurons

Learning and memory depend on long-term synaptic plasticity including long-term potentiation (LTP) and depression (LTD). Activity-regulated cytoskeleton-associated protein (Arc) plays versatile roles in synaptic plasticity mainly through inducing F-actin formation, underlying consolidation of LTP, and promoting AMPA receptor (AMPAR) endocytosis, underlying LTD. Insulin can also induce LTD by facilitating the internalization of AMPARs. In neuroblastoma cells, insulin induced a dramatic increase in Arc mRNA and Arc protein levels, which may underlie the memory-enhancing action of insulin. Thus, a hypothesis was made that, in response to insulin, increased AMPAR endocytosis leads to enhanced Arc expression, and vice versa. Primary cultures of neonatal Sprague–Dawley rat cortical neurons were used. Using Western-blot analysis and immunofluorescent staining, our results reveal that inhibiting AMPAR-mediated responses with AMPAR antagonists significantly enhanced whereas blocking AMPAR endocytosis with various reagents significantly prevented insulin (200 nM, 2 h)-induced Arc expression. Furthermore, via surface biotinylation assay, we demonstrate that acute blockade of new Arc synthesis after insulin stimulation using Arc antisense oligodeoxynucleotide prevented insulin-stimulated AMPAR endocytosis. These findings suggest for the first time that an interaction exists between insulin-stimulated AMPAR endocytosis and insulin-induced Arc expression.