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PubMedDate not supplied

Interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat.

With pithed normotensive rats we studied the interaction between beta 2-adrenoceptor-mediated vasodilation and alpha 1-adrenoceptor-mediated vasoconstriction. The selective beta 2-adrenoceptor agonist salbutamol was used to elicit vasodilatation. To induce alpha 1-adrenoceptor-mediated vasoconstriction, the selective alpha 1-adrenoceptor agonists cirazoline, St 587, and methoxamine were used. Furthermore, the alpha 1-adrenoceptor-mediated vasopressor effects of intravenously administered (--)-norepinephrine, and (--)-norepinephrine released from neurons by the nicotinic agonist 1,1-dimethyl-4-phenylpiperazine iodide (DMPP), the muscarinic ganglionic stimulant McN-A-343, electrical stimulation of the spinal cord, and the indirect sympathomimetic agent tyramine, were studied. By using the selective beta 2-adrenoceptor antagonist ICI 118,551, the interaction between the alpha 1-adrenoceptor-mediated vasoconstriction of (--)-epinephrine and alpha-methylnorepinephrine with their intrinsic beta 2-adrenoceptor agonistic effects was investigated. Two types of interaction between alpha 1-and beta 2-adrenoceptor-mediated vascular effects were found. Cirazoline and McN-A-343 activated alpha 1-adrenoceptors, inducing a vasoconstriction not affected by beta 2-adrenoceptor-mediated vasodilation. However, methoxamine at low doses, St 487, DMPP, electrical stimulation, intravenously administered (--)-norepinephrine, (--)-epinephrine, and alpha-methylnorepinephrine activated alpha 1-adrenoceptors, and their effect was attenuated by vasodilation. At low doses, tyramine stimulated alpha 1-adrenoceptors that were not sensitive to beta 2-adrenoceptor-mediated vasodilation, in contrast to the population of alpha 1-adrenoceptors activated at high doses of tyramine. It is hypothesized that there exist two different populations of alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Studies on bethanidine and meobentine: direct and indirect effects of antifibrillatory drugs.

The electrophysiological effects of bethanidine and meobentine were studied on isolated canine cardiac tissues and the in situ dog heart using standard techniques. The "direct" electrophysiological effects of bethanidine (in the beta-adrenergic-blocked Purkinje fiber) resemble the effects of meobentine in the normal canine Purkinje fiber; both drugs produce use-dependent decreases of the maximum rate of depolarization of phase 0 and action potential amplitude. In addition, meobentine prolongs action potential duration (100%) of Purkinje fibers. In ventricular muscle cells, the only significant effect of meobentine is a decrease in the maximum rate of depolarization. In studies of ouabain-induced tachycardias and 24-h infarct-induced ventricular arrhythmias, bethanidine tends to increase heart rate and/or exacerbate the ectopic activity (due to its sympathomimetic effects), whereas meobentine tends to reduce heart rate and restore normal sinus rhythm. Both bethanidine and meobentine increase ventricular fibrillation threshold. This increase is evident following bethanidine injection after the subsidence of the sympathomimetic effects. Finally, moderate increases of ventricular fibrillation threshold following treatment with meobentine are accompanied by partial cardiac sympathetic blockade, as indicated by reduced chronotropic responses to stellate ganglion stimulation. The antiarrhythmic and antifibrillatory effects of bethanidine and meobentine may be explained by the use-dependent effects of these drugs on phase 0 of the action potential and by their sympatholytic actions on the autonomic nervous system. Meobentine may, in addition, exert antiarrhythmic effects by decreasing automaticity in partially depolarized cells.

Action Potentials↗

PubMed1996

Potent antifibrillatory effect of combined blockade of calcium channels and 5-HT2 receptors with nexopamil during myocardial ischemia and reperfusion in dogs: comparison to diltiazem.

The need for novel antifibrillatory therapy is underscored by clinical trials indicating that the incidence of sudden cardiac death is increased by sodium or potassium channel blockade and is only partially reduced by beta-blockade. We examined the efficacy of nexopamil, which possesses the unique combination of calcium channel and 5-HT2 receptor blockade, in preventing ventricular tachycardia (VT) and fibrillation (VF) and reducing T-wave alternans magnitude during coronary artery occlusion and abrupt reperfusion in dogs. The results were compared with L-type calcium channel blockade alone with diltiazem. The effect of nexopamil was tested during a 10-min period of left anterior descending (LAD) coronary artery occlusion and release in chloralose-anesthetized dogs. T-wave alternans magnitude was assessed by complex demodulation. The drug reduced the incidence of VT during occlusion (from 5 of 6 to 0 of 6, p < 0.03) and VT/VF during abrupt reperfusion (from 5 of 6 to 0 of 6, p < 0.03) and suppressed the T-wave alternans magnitude increase induced by occlusion (from 14.62 +/- 3.96 to 1.39 +/- 0.34 mV x ms, p < 0.01) and reperfusion (from 17.33 +/- 4.67 to 2.34 +/- 0.77 mV x ms, p < 0.01). When 30-s left stellate ganglion stimulation (10 V, 5-ms pulses, 10 Hz) was superimposed on occlusion, nexopamil reduced the VT/VF incidence (from 8 of 11 to 4 of 11, p < 0.05) and T-wave alternans magnitude (from 24.80 +/- 5.05 to 15.81 +/- 5.09 mV x ms, p < 0.05). Calcium channel blockade alone with diltiazem decreased the incidence of ventricular tachyarrhythmias (from 5 of 10 to 1 of 10, p < 0.05) and T-wave alternans magnitude (from 16.75 +/- 3.06 to 2.87 +/- 1.23 mV x ms, p < 0.05) during coronary artery occlusion. During reperfusion, diltiazem's reduction in arrhythmia incidence (from 5 of 8 to 2 of 8) was not statistically significant, although the decrease in T-wave alternans (from 28.60 +/- 3.43 to 8.27 +/- 3.73 mV x ms, p < 0.05) was significant. Therefore, nexopamil was superior to diltiazem in protecting against reperfusion-induced arrhythmias. Nexopamil's significant antifibrillatory effect during both coronary artery occlusion and abrupt reperfusion is reliably tracked by T-wave alternans magnitude. Because the major component of the protection could be reproduced by blockade of the L-type calcium channel with diltiazem, nexopamil's antiarrhythmic action appears to be due mainly to blockade of this channel. Nexopamil's antiplatelet action through blockade of 5-HT2 receptors may confer additional protection against reperfusion arrhythmias.

Animals↗

PubMed1988

Pulmonary function of haplotype-matched and mismatched allografts in dogs treated with total-body irradiation, autologous marrow transplantation, methotrexate, and donor blood.

Seven beagle recipients surviving 2-11 years after allotransplantation of a left lung were available for study of pulmonary function. Significant reductions of ventilation and perfusion to the transplanted lung were documented by radionuclide scanning. These reductions in function were well-matched, however, and allowed relatively normal gas exchange, as measured by VD/VT, arterial PO2 and shunt fraction. The vasoconstrictor response of the transplanted lung to both hypoxia and stellate ganglion stimulation was comparable to that of the native lung. An abnormal rise in graft pulmonary vascular resistance and fall in PaO2 when the normal lung was made hypoxic suggest an inability of the transplanted lung to vasodilate and recruit blood vessels normally in response to increased blood flow. The animals were sacrificed at the conclusion of the pulmonary function testing. Pathologic study of the transplanted lungs showed minimal changes of rejection in spite of the fact that these recipient animals received no immunotherapy after the second posttransplant week.

Animals↗

PubMedDate not supplied

The effects of sympatholytic drugs on the cardiovascular response to tilting in anaesthetized cats.

1. Using cats anaesthetized with chloralose and urethane, comparison was made of the abilities of several antihypertensive and sympatholytic drugs to lower systemic blood pressure, and to depress the compensatory cardiovascular responses to bilateral carotid occlusion and to 45 degrees head-up tilting. Similar comparisons were also made of the effects of these drugs on the perfusion pressure of the vascularly isolated autoperfused hindquarters, and the response of this to carotid occlusion and tilting. The effects of bilateral vagotomy and haemorrhage on these responses were also studied. 2. It was found that hypotensive doses of both bretylium and guanethidine (3.0 mg/kg, i.v.) markedly depressed the ability of cats to restore their systemic blood pressure and to constrict their hindquarters vasculature during tilting. Both drugs depressed the carotid occlusion reflex in the systemic, but not in the hindquarters, circulation. Neither propranolol, 2.0 mg/kg, i.v., nor bilaterial vagotomy had any effect on these parameters and haemorrhage sufficient to cause marked hypotension was without effect on the systemic responses to carotid occlusion or tilting. 3. Clonidine (1.0, 5.0 and 25 microgram/kg, i.v.), xylazine (62.5, 125 and 250 microgram/kg, i.v.) and reserpine (0.5 and 2.0 mg/kg, i.v.) all caused considerable hypotension but had no effect on the response to tilting of the systemic circulation, apart from somewhat prolonging recovering time. The highest dose of clonidine moderately depressed the hindquarters perfusion pressure, and the response of this to tilting. 4. Clonidine (5.0 and 25 microgram/kg, i.v.) and xylazine (125 and 250 microgram/kg, i.v.) depressed the systemic pressor responses elicited by the ganglion stimulants DMPP and McN-A-343. This may indicate that the ability of clonidine to prolong the pressure recovery during tilt may be due to impaired peripheral sympathetic transmission. 5. It is concluded that drugs which significantly reduce the compensatory pressure reponses to tilting in anaesthetized cats may also cause postural disturbances in man, whilst drugs which merely prolong the period required for pressure compensation seem much less likely to cause serious clinical impairment of orthostatic reflexes. It appears that the cardiovascular response to bilateral carotid occlusion may not provide a good index of the integrity of orthostatic reflexes.

Animals↗

PubMedDate not supplied

The nature of the pressor response to carotid artery occlusion in the hexamethonium-treated rat.

1. The blood pressure monitored from the cannulated right carotid artery and heart rate responses to occlusion of the intact left carotid artery were investigated in rats. 2. Hexamethonium abolished the response to ganglion stimulants but not that to carotid occlusion, although the time course and nature of the response were altered. 3. The pressor response to carotid occlusion in the presence of hexamethonium was not abolished by carotid sinus denervation, vagal section, tubocurarine, atropine, ethyl alcohol or an angiotensin II antagonist, but it was abolished by high doses of phenoxybenzamine. In six out of eight experiments the response was not abolished by cervical cord section. 4. It was concluded that the pressor response to carotid occlusion in the presence of hexamethonium in the rat involves an adrenergic mechanism which is at least in part independent of the autonomic ganglia, and which is mediated by an agent liberated from the brain, possibly under conditions of cerebral ischaemia.

Angiotensin II↗

PubMed1987

Sensitivity changes of the perfused hindquarters' vasculature in rats with alloxan-induced diabetes mellitus.

1. Arachidonic acid (AA, 0.125-1.0 mg/kg) injected via the aorta into the autoperfused hindquarters caused dose-dependent increases in perfusion pressure. This effect was reduced after intravenous administration of the thromboxane receptor antagonist AH23848 (5 mg/kg) or indomethacin (5 mg/kg). 2. Responses to AA (0.125-1.0 mg/kg) were reduced markedly in the Krebs-perfused hindquarters when compared with those occurring in the blood-perfused preparation. 3. Doses of guanethidine (1 mg/kg) and pentacynium (1 mg/kg) blocking pressor responses to intravenous administration of the ganglion stimulants McN-A-343 and DMPP, respectively, did not affect responses to AA. 4. Constrictor responses to AA (0.5-1.0 mg/kg) in blood-perfused hindquarters were increased in 14 day alloxan-diabetic rats but those to the thromboxane A2-mimetic U46619 (0.5-8.0 micrograms/kg, i.a.) were reduced when compared with non-diabetic controls. 5. In 14 day alloxan-diabetic rats vasoconstrictor responses to noradrenaline and methoxamine were potentiated but those to 5-hydroxytryptamine were reduced compared with non-diabetic animals. 6. It is concluded that AA causes constriction in the blood-perfused hindquarters by release of a product of cyclo-oxygenase acting on thromboxane A2-receptors. A constituent of blood, perhaps the platelet, appears necessary for this effect. Conversion of AA to the constrictor metabolite is augmented during experimentally induced diabetes.

Alloxan↗

PubMed1983

Sustained elevation of hippocampal cyclic 3'-5' adenosine monophosphate levels after medial septal lesions.

The cyclic 3'-5' adenosine monophosphate (cyclic AMP) content of the rat hippocampal formation doubles during the week following a medial septal lesion and remains elevated for at least 1 month, the longest time period studied. This elevation in cyclic AMP does not result from sympathetic ingrowth, as neither superior cervical ganglion stimulation nor ganglionectomy influences hippocampal cyclic AMP content after lesions. Interruption of the cholinergic septohippocampal pathway in the fornix did not elevate hippocampal cyclic AMP content. Further, treatment of septal-lesioned animals with oxotremorine or of normal animals with atropine did not influence hippocampal cyclic AMP content. Finally, neither locus ceruleus lesions nor treatment with propranolol affected hippocampal cyclic AMP content. We believe this to be the first report of a sustained elevation in hippocampal cyclic AMP content. Like other long-term events, it is likely to have profound effects on hippocampal function and represents a remarkable brain adaptation to remote injury.

Animals↗

PubMed1958

Some pharmacological properties of murexine (urocanoylcholine).

Murexine (urocanoylcholine, [2-beta-imidazol-4(5)-ylacryloyloxyethyl] trimethylammonium bromide) has been shown to possess ganglion stimulating and neuromuscular blocking actions in cat, dog and rat. The blockade has been shown to be of the depolarizing type both on the basis of the resemblance of the pharmacological properties of the substance to that of known depolarizing blocking agents, and also directly by recording the depolarization produced in the endplate region of the gracilis muscle of the rat.

Animals↗

PubMed1958

Pharmacological properties of betabeta-di-methyl-acryloylcholine and some other beta-substituted acryloylcholines.

The mammalian pharmacology of a new naturally occurring ester of choline, betabeta-dimethylacryloylcholine (DMAC), has been studied, mainly in the cat, together with that of two synthetic beta-substituted acryloylcholines, crotonoylcholine and pent-2-enoylcholine. Comparisons have been made with the reduced form of DMAC, isovalerylcholine, with another naturally ocurring beta-substituted acryloylcholine, murexine (urocanoylcholine), and with suxamethonium. DMAC has been shown to be a ganglion stimulating and neuromuscular blocking agent generally similar, in potency and properties, to murexine. It is also a powerful respiratory stimulant. The other unsaturated esters behaved similarly but were less potent.

Animals↗

PubMed1959

Increased urinary excretion of adrenaline and noradrenaline after phenoxybenzamine.

In dogs anaesthetized with pentobarbitone sodium phenoxybenzamine greatly increased the urinary excretion of adrenaline and noradrenaline. This was associated with a transient increase in the volume of urine excreted and a fall in blood pressure. Hexamethonium prevented the effects on the urinary amines and on the blood pressure. Methacholine hypotension induced an increased adrenaline excretion, but no change in noradrenaline. The excretion of adrenaline released following ganglionic stimulation by acetylcholine did not appear to be affected by phenoxybenzamine, but that of noradrenaline was increased. During infusions of adrenaline or noradrenaline, phenoxybenzamine increased the excretion of both adrenaline and noradrenaline.

Acetylcholine↗

PubMed1962

Dual action of nitroparaffins on the guinea-pig ileum.

Nitroparaffins act on the guinea-pig ileum by several mechanisms. They produce contraction partly by ganglionic stimulation and partly by direct liberation of transmitter from the nerve endings. They also inhibit the response to acetylcholine and nicotine, but interfere less with the action of histamine, serotonin or bradykinin. The two opposite effects of the nitro compounds are independent of each other. Within the homologous series of normal nitroparaffins, the excitatory action diminishes and the inhibitory effect increases with the lengthening of the carbon chain.

Acetylcholine↗

PubMed1970

Acceleration of noradrenaline biosynthesis in the guinea-pig vas deferens by potassium.

1. Increasing the concentration of KCl in Krebs-Henseleit bicarbonate solution enhanced the formation of (14)C-noradrenaline ((14)C-NA) from (14)C-tyrosine in the guinea-pig vas deferens. In 52 mM KCl Krebs-Henseleit solution the specific activity of the newly formed (14)C-NA was double that of controls.2. The rate of synthesis of (14)C-NA from (14)C-tyrosine was constant for up to 2 h in 52 mM KCl Krebs-Henseleit solution and for 4 h in unmodified Krebs-Henseleit solution.3. There was no increase in NA formation in the presence of KCl rich Krebs-Henseleit solution if (14)C-DOPA was used as the starting substrate instead of (14)C-tyrosine.4. The specific activity of (14)C-tyrosine in the high KCl treated vas deferens was 80% of that of control tissues. Thus the enhanced synthesis of (14)C-NA in high KCl Krebs-Henseleit solution did not arise from an increase in the specific activity of precursor.5. The effect of K(+) on NA synthesis was not mimicked by ganglionic stimulants nor blocked by tetrodotoxin.6. Removal of Ca(2+) ions or increasing the concentration of Mg(2+) ions abolished the increase in synthesis of NA seen in high KCl Krebs-Henseleit solution but left the basal rate of NA synthesis in unmodified Krebs-Henseleit solution unaltered.7. The spontaneous release of newly synthesized catecholamines ((14)C-labelled) or tritiated noradrenaline ((3)H-NA) from vasa deferentia was increased in 52 mM KCl Krebs-Henseleit solution. Removal of Ca(2+) ions reduced the increased efflux of newly synthesized amine in high KCl media to that seen in unmodified Krebs-Henseleit solution. The efflux of (3)H-NA was reduced to one-third of its former rate in the absence of Ca(2+).8. High KCl Krebs-Henseleit solution caused a substantial contraction of the vas deferens which was not abolished by tetrodotoxin. Release of (3)H-NA paralleled the contractile response, and was likewise unaffected by tetrodotoxin.9. No evidence was obtained for any alterations in the activity of tyrosine hydroxylase, the rate limiting enzyme in the formation of NA from tyrosine, in homogenates of vas deferens which had been treated with 52 mM KCl Krebs-Henseleit solution.10. These results support the hypothesis that acceleration of NA synthesis occurs when tyrosine hydroxylase is freed from end-product inhibition by the release of noradrenaline, brought about in this case, by high concentrations of KCl.

Animals↗

PubMed1970

The pharmacological basis of coronary and systemic vasodilator actions of diazepam (Valium).

1. The effects of alpha and beta-adrenoceptor blockade, depletion of catecholamine stores, vagotomy, atropine, and ganglionic blockade on diazepam-induced vasodilatation were investigated in forty-six anaesthetized dogs.2. Coronary blood flow was measured by timed collections of coronary venous efflux from fibrillating, decompressed ventricles; coronary and systemic vascular resistances were determined during total cardiopulmonary bypass under conditions of normothermia and constant aortic (coronary artery) pressure.3. No significant alteration in the vasodilatation produced by diazepam was observed following either vagotomy or alpha-adrenoceptor blockade; partial inhibition of vasodilatation occurred after beta-adrenoceptor blockade or catecholamine depletion, and nearly total inhibition was observed after small doses of atropine or ganglion-blocking agents.4. The results suggest that diazepam may act as a specific ganglion-stimulant, causing active sympathetic and cholinergic vasodilatation.

Animals↗

PubMed1974

An analysis of the peripheral effects of l-DOPA on autonomic nerve function.

1 The ability of intravenous L-DOPA to block sympathetic and parsympathetic nerves has been studied in cats and dogs pretreated with a monoamine oxidase inhibitor.2 L-DOPA inhibited positive chronotropic and pressor responses to dimethylphenylpiperazinium (DMPP) and McN-A-343 in dogs, and contractions of the nictitating membrane produced by these ganglion stimulants in cats.3 Responses of the cat nictitating membrane to preganglionic stimulation were inhibited by L-DOPA to a greater extent than those to postganglionic stimulation of the cervical sympathetic chain.4 In dogs, L-DOPA had no vagolytic action, but depressed vasoconstrictor responses elicited in the perfused hind-limb by electrical stimulation of the lumbar sympathetic chain.5 The degree of lumbar sympathetic chain inhibition correlated with the pressor response following L-DOPA, and both effects were prevented by prior decarboxylase inhibition.6 These results suggest that the decarboxylation products of L-DOPA do not impair parasympathetic nerve activity but depress sympathetic nerve function predominantly by inhibiting both muscarinic and nicotinic sites of sympathetic ganglia.

Animals↗

PubMed1984

The effect of gallamine, gallopamil and nifedipine on responses to acetylcholine and carbachol in the taenia of the guinea-pig caecum.

The effects of gallamine, gallopamil and nifedipine on isotonic contractions of the isolated taenia of the guinea-pig caecum produced by acetylcholine (ACh) or carbachol (CCh) were investigated. Gallamine (0.1 to 0.3 mM) inhibited contractions produced by CCh more than those produced by ACh. The difference was still present after pretreatment of the tissue with paraoxon (10 microM for 20 min) to inhibit cholinesterases or in experiments carried out in the presence of tetrodotoxin (0.3 microM) to exclude possible ganglionic stimulation by the agonists. Gallopamil or nifedipine selectively inhibited the tonic response to ACh in the absence or presence of paraoxon. The phasic response to ACh or the tonic response to CCh (0.1 or 1 microM) was much less affected. Reduction of the Ca2+ content of the bath medium reduced phasic and tonic responses to ACh more than the tonic response to CCh. These results suggest that there are differences in the interaction of ACh and CCh with muscarinic receptors in this muscle.

Acetylcholine↗

PubMed1988

Quantitative effects of some muscarinic agonists on evoked surface-negative field potentials recorded from the guinea-pig olfactory cortex slice.

1. The effects of muscarinic receptor agonists on the electrically-evoked surface-negative field potential (N-wave) were measured in the guinea-pig olfactory cortex slice maintained in vitro. 2. Bath-superfusion of (+/-)-muscarine, acetylcholine (ACh), carbachol (CCh), or methacholine (MCh) (10-200 microM) produced reversible, dose-dependent depressions of the N-wave (ACh and MCh effects were observed in the presence of 10 microM neostigmine). The order of potencies (based on agonist dose causing 50% field depression: IC50) was: ACh greater than or equal to muscarine greater than CCh greater than MCh. All four agonists depressed the field potential by 100% at doses greater than 500 microM. 3. Pilocarpine and bethanechol were weak agonists and only produced measurable effects at high doses (1-2 mM). Neither agonist evoked a maximum response at doses up to 10 mM. 4. The muscarinic ganglion stimulant, McN-A-343 yielded inconsistent results, depressing the field potential in some slices, but having no effect in others. Pre-application of a conditioning dose (100 microM) of McN-A-343 reduced subsequent responses to CCh, suggesting possible partial agonist properties. 5. Oxotremorine (up to 100 microM) did not depress the field potential, but it reversibly antagonized the effects of CCh. 6. It is concluded that reproducible, quantifiable responses to muscarinic agonists can be evoked in the olfactory cortex slice. We suggest this preparation may be useful for conducting pharmacological studies of 'intact' central muscarinic receptors.

Acetylcholine↗

PubMed1989

Prejunctional modulation of acetylcholine release from the skeletal neuromuscular junction: link between positive (nicotinic)- and negative (muscarinic)-feedback modulation.

1. Presynaptic receptor-mediated modulation of stimulation-evoked [3H]-acetylcholine[( 3H]-ACh) release from the neuromuscular junction was studied in the region of the mouse hemidiaphragm which contains the motor endplates, and which can easily be loaded with [3H]-choline. This method made it possible to detect exclusively the [Ca2+]0-dependent, quantal release of [3H]-ACh in response to axonal stimulation. 2. Atropine enhanced, and non-depolarizing muscle relaxants [+)-tubocurarine, pancuronium and pipecuronium) reduced, the release of [3H]-ACh evoked by high frequency trains of stimulation (50 Hz, 40 shocks) of the phrenic nerve. The effect of (+)-tubocurarine was frequency-dependent as at 5 Hz (40 shocks) it was less effective than at 50 Hz. The resting release of [3H]-ACh was not affected by these compounds. These findings indicate that ACh released into the synaptic gap by axonal firing reaches a concentration sufficient to influence its own release by a prejunctional effect. 3. The anticholinesterase, physostigmine sulphate, enhanced the release of [3H]-ACh in a concentration-dependent manner. This effect was mediated via prejunctional nicotinic receptor stimulation: (+)-tubocurarine, pancuronium and pipecuronium completely prevented the effect of physostigmine. 4. When the prejunctional nicotinic and muscarinic receptors were stimulated by a high concentration of extracellular ACh which had accumulated in the junctional gap in the presence of physostigmine, atropine did not influence the evoked release of [3H]-ACh. However, when the effect of endogenous ACh on nicotinic receptors was prevented by (+)-tubocurarine, atropine enhanced the release. 5. It is concluded that quantally-released ACh from motor endplates is subject to prejunctional automodulation: (a) ACh facilitates its own release via an effect on prejunctional nicotinic receptors (positive feedback), (b) ACh release is reduced by an action on muscarinic receptors. When the nicotinic receptor-mediated facilitation is fully operative, the muscarinic receptor-mediated negative feedback is much less effective. It is supposed that there is a link between the two feedback mechanisms possibly at the level of the second messenger system(s).

Acetylcholine↗