Adrenergic Inhibition in Mammalian Parasympathetic Ganglia

SINCE the discovery¹ that adrenaline depressed sympathetic ganglionic transmission, there has been an extensive study of the actions of the catecholamines in autonomic ganglia^2,3. It has been shown that administered catecholamines produce two types of ganglionic response: inhibition and facilitation; the former associated with ganglionic hyperpolarization and blocked by alpha adrenergic blocking agents, the latter accompanied by ganglionic depolarization and blocked by beta adrenergic blocking agents^3–5. The naturally occurring amines, adrenaline, noradrenaline and dopamine, have predominantly alpha-inhibitory actions.     

Pharmacological effect of beta toxin of Clostridium perfringens type C on rats

The biological effect of purified beta toxin of Clostridium perfringens type C in vivo was investigated. After intravenous injection of the purified beta toxin into rats, a rise in blood pressure and a simultaneous fall in heart rate were observed. After the blood pressure reached a maximum, the heart rate recovered gradually, and electrocardiographic and respiratory changes began. The rise in blood pressure induced by beta toxin tended to be proportional to the amount of toxin. The latent period between the injection of toxin and the onset of the increase, and also the time between the injection and the maximum pressure induced by the toxin decreased with increasing concentration of the toxin. A good correlation was found between the factor producing the rise in blood pressure and beta toxin. Alpha adrenergic and ganglionic blocking agents reduced blood pressure levels elevated by beta toxin. The data suggest that the toxin causes a release of catecholamines, and that the increase in blood pressure was induced by released catecholamines.     

Studies on rat sympathetic neurons developing in cell culture. III. Cholinergic transmission.

Principal neurons were dissociated from the superior cervical ganglia of newborn rats and grown in culture with several types of non-neuronal cells. As described in the second paper of this series, the neurons in such mixed cultures formed two types of excitatory synapses with each other, electrical and chemical. Evidence is presented here that transmission at the chemical synapses was cholinergic. Four nicotinic ganglionic blocking agents (curare, hexamethonium, tetraethylammonium, and mecamylamine) strongly attenuated or eliminated the excitatory postsynaptic potentials (e.p.s.p.'s) at moderate concentrations; atropine at relatively high concentrations also blocked transmission. Iontophoretic application of acetylcholine (ACh) to the surface of the neurons gave rise to depolarizations that could be made to resemble the e.p.s.p.'s in size and time course; the ACh potentials and the e.p.s.p.'s were then similarly affected by nicotinic blocking agents. The sensitivity to ACh was often distributed nonuniformly on the neuronal surface; it was common to find small, sharply localized regions of high sensitivity. Catecholamines (norepinephrine, epinephrine, and dopamine) had only inhibitory actions; in a few experiments adrenergic blocking agents (phenoxybenzamine, propranolol) were found to have no effect on the e.p.s.p.'s. These observations leave no doubt that the neurons released ACh and had ganglionic, nicotinic ACh receptors on their surfaces. The significance of the fact that a high proportion of the sympathetic neurons in mixed cultures formed cholinergic synapses is discussed.     

Trapping of an open-channel blocker at the frog neuromuscular acetylcholine channel.

At the ganglionic nicotinic acetylcholine channel (Gurney, A. M., and H. P. Rang, 1984, Br. J. Pharmacol., 82:623-642) and on some cholinergic neuromuscular synapses of Crustacea (Lingle, C., 1983a, J. Physiol. (Lond.), 339:395-417; Lingle, C., 1983b, J. Physiol. (Lond.), 339:419-437), some agents that block cholinergic currents by an open-channel block mechanism appear to become trapped within the channel when it subsequently closes. It is unknown whether trapping of some open-channel blockers might also occur at the neuromuscular nicotinic acetylcholine channel. Here we show that the long-lived cholinergic blocking action of chlorisondamine, a ganglionic nicotinic blocker, can in part be most simply explained by an open-channel block mechanism followed by a subsequent trapping of the blocking molecule within the closed ion channel. Unique structural characteristics of the chlorisondamine molecule place several provocative constraints on the mechanism by which trapping may be occurring.     

A study of the origin of altered pharmacological reactivity of synaptic structures caused by diabetes and pretreatment with contrainsular agents

The effect of membrane-stabilizing ganglionic blocking agents was found to be decreased in the ganglia of diabetic cats. Similarly, the sensitivity to membrane-stabilizing muscle relaxants of motor endplates in diabetic rats was also diminished, while the effectivity of depolarizing agents was augmented. Analysing the mechanism of action of these phenomena, it was shown that in diabetes developing as a result of pancreas removal or contrainsular treatment, a factor appeared in the blood of the experimental animals which was heat labile and facilitated the transmission process in the cholinergic synapses. In higher concentration, it produced ganglionic excitation and muscle twitching. This factor influenced the effect of drugs acting at the ganglionc synapses and motor endplates.     

On the transmission of signals in vertebrate retina in the presence and absence of impulses

The ability to transmit signals in the retina in the absence of impulses was tested by means of two agents (tetrodotoxin and procain) blocking the impulse transmission of stimuli. The slow potential (SP) and impulse discharge were recorded simultaneously from the optic nerve of the frog. Tetrodotoxin (0.5 µg/cm³) and procain (0.5–1%) introduced into the eye cup completely blocked impulses but had little effect on SP. Therefore, signals from the photoreceptors to the ganglionic cells can be transmitted in the absence of impulses. These data confirm also a conclusion drawn earlier that the SP originates as a result of electrotonic spread of the postsynaptic potentials (PSP) of ganglionic cells along the optic nerve. The agents blocking the impulse transmission of stimuli broke down the lateral inhibition between the "slow bipolars." Consequently, lateral inhibition spreads by means of the impulse mechanism in the transmission of signals. It is supposed that the interneurons participating in this spread are amacrine cells which possess the ability to generate impulses.Institute of Problems of Information Transmission, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 2, No. 5, pp. 536–543, September–October, 1970.     

Basic properties of beta adrenergic receptors mediating melanosome dispersion of melanophores in a cyprinid fish, Zacco temmincki

In melanophores of a cyprinid fish, Zacco temmincki, receptor mechanisms of melanosome dispersion induced by catecholamines were examined. While possessing a melanosome-aggregating action in higher concentrations, isoproterenol and epinephrine in lower concentrations acted to disperse melanosomes. Norepinephrine, epinine and dopamine altered their action from melanosome aggregation to melanosome dispersion after alpha adrenergic blockade. The catecholamine-induced melanosome dispersion was inhibited by beta adrenergic blocking agents. Mediation of dispersion is regulated through beta adrenergic receptors. The beta adrenergic responses were unaffected by mersalyl, a sulfhydryl inhibitor. A prospective substance acting in dispersing melanosomes appears to be adrenaline, but not noradrenaline.     

Distinct muscarinic mediation of suspected dopaminergic activity in sympathetic ganglions

The competitive neuromuscular blocking agents, gallamine and pancuronium, enhanced the nictitating membrane contraction, in the cat, resulting from muscarine ganglionic transmission. Inhibition of ganglionic muscarinic hyperpolarization, in response to short tetanic bouts of preganglionic cervical sympathetic stimulation, was an associated event and is considered by us to be causally related. The neuroleptic drug, haloperidol, enhanced ganglionic hyperpolarization under similar stimulatory conditions, and reduced the nictitating membrane contraction elicited via ganglionic muscarine pathways, effects opposite to those produced by the skeletal muscle relaxants. Apomorphine reduced both ganglionic hyperpolarization and the ganglionic muscarinic-induced nictitating membrane contractions. The action of gallamine and pancuronium conforms to a speculative cholinergic antagonism at the specific muscarinic receptors, termed Mi, on the ganglionic dopaminergic interneuron. Haloperiodol and apomorphine are anticipated to be exerting distinct antagonistic and agonistic actions, respectively, on prejunctional dopamine receptors of the ganglionic interneuron. Ganglionic slow depolarization mediated through the muscarinic receptors, termed Me, was unaltered by any of the agents studied.     

Ganglionic blocking effect of some antibiotics on isolated rat sympathetic ganglion.

It was shown on the isolated superior cervical ganglion of the rat that some antiobiotics exerted a blocking effect nearly as potent as that exhibited by hexamethonium or d-turbocurarine. The ganglionic blockade thus induced proved to be non-specific and due to the local anaesthetic effect of the tested drugs.     

Mechanism of neurotensin-induced pressor effect and tachycardia in guinea pigs

Neurotensin (NT) was found to produce a dose-dependent increase of the systolic and diastolic blood pressure, and of the heart rate in anesthetized guinea pigs when injected intravenously (i.v.) as a bolus, or when infused i.v. over a 15 min period. In a small percentage (20%) of animals, bolus injections of NT evoked triphasic variations (e.g. increase followed by a decrease and a further increase) of the blood pressure associated with unpredictable changes of heart rate. The pressor effect of NT was consistently reduced by prior treatment of the animals with pentolinium, a ganglion blocking agent, a mixture of alpha and beta adrenergic receptor blocking drugs, reserpine, a drug known to deplete adrenergic neurons of their neurotransmitters, or guanethidine, a drug known to paralyse adrenergic neurons. NT-induced tachycardia was either unchanged or slightly potentiated following the administration of the latter autonomic blockers. Neither the pressor effect nor the tachycardia evoked by NT was affected by antihistaminics, antiangiotensin or by indomethacin, an inhibitor of prostaglandin synthesis. These results suggest that the pressor effect of NT in anesthetized guinea pigs is likely the result of an interaction (most likely an activation) between the peptide and the sympathetic nervous system. The increase of heart rate induced by NT appears to be due to a direct effect on the heart.     

Influence of adrenergic neuron blocking agents on the adrenaline-induced platelet reactions

Adrenaline causes aggregation of human blood platelets through stimulation of alpha-adrenoceptors resembling the alpha 2-type. Alpha-adrenoceptor blocking agents inhibit specifically the adrenaline-induced platelet reactions. The adrenaline-induced aggregation of human blood platelets was inhibited specifically by adrenergic neuron blocking agents such as guanoxan, guanclofine and guanethidine. Guanoxan (I50 = 0.6 mu mol/l) was about three orders of magnitude more effective than guanethidine, guanclofine occupied a median position. The compounds tested inhibited the ADP- and collagen-induced aggregation at relatively high concentrations. This is probably due to non-specific membrane effects. The known alpha-adrenolytic effect of guanoxan is believed to be mediated mainly by alpha 2-adrenoceptors.     

Effect of parathyroid hormone on plasma renin activity in humans

The effect of PTH infusion on PRA was evaluated in 22 normotensive subjects. Intravenous infusion of PTH produced an increase in PRA in studied subjects. This increase in PRA was dose dependent from 1.505 +/- 0.226 to 2.500 +/- 0.346 nmol/l/hour after administration of 100 units of PTH and from 1.648 +/- 0.189 to 4.294 +/- 0.614 nmol/l/hour after 200 units of PTH and was markedly decreased by a beta blocking drug from 1.660 +/- 0.259 to 2.498 +/- 0.485 nmol/l/hour. These responses were observed without any significant changes in plasma calcium and blood pressure. From our results we can conclude that PTH increases PRA in normotensive controls. This effect is partly blocked by beta adrenergic blockers.     

Pharmacological evidence for adrenergic activation of hyperthermic responses associated with psychosocial stimulation

1. Brief social encounters between strange voles living adjacent compartments of a population cage lead to rapid increases of more than 1 degrees C in their core temperatures. 2. Socially induced core temperature responses remain elevated for more than 1 hr following social contact, and are of greater amplitude and duration than can be elicited by handling, noise or exercise. 3. Pretreatment of opponents with adrenergic blockers reduces the amplitude and duration of hyperthermic response proportional to drug intake; both alpha and beta blocking effects are completely reversed within 24 hr. 4. The dynamics of the hyperthermic response and effects of the drugs suggest that the rapid rise in core temperature is due to both vasoconstrictor (alpha) heat conservation and metabolic (beta) heat generating mechanisms, and that the protracted elevation of core temperature is primarily due to (beta) metabolic activation.     

Alpha and beta adrenergic sensitivity in trained and untrained albino rats.

The effects on the blood pressure and heart rate responses of different adrenergic stimulants (norepinephrine, sympathomim, epinephrine and isoproterenol) and blocking agents (phenoxybenzamine and propranolol) were studied in control (N=55) and exercising (N=52) albino rats under anaesthesia. The test rats exercised by regular swimming for 10-14 weeks. Alpha stimulation and beta blocking produced smaller responses while alpha blocking and beta stimulation were followed by greater changes after training as compared with the control animals. The assumption of a modified adrenergic receptor sensitivity could not be substantiated by the results; the observations indicate rather a complex change in the autonomous regulation following regular physical exercise.     

Nervous system regulation of exocrine pancreatic secretion in the chicken

Acute assays were carried out using broiler chickens in which a reentry catheter had previously been placed chronically in the main pancreatic duct. Samples of pancreatic juice were collected after manoeuvres of blockage and stimulation with different neurotransmitters and blocking agents, both cholinergic and adrenergic, as well as electrical stimulation of the left vagosympathetic trunk. Stimulation of the vagus nerve induced a marked increase in the pancreatic flow but with no changes in the enzyme content. Acetylcholine was seen to cause a slight but significant increase in pancreatic flow and a non-significant increase in amylase activity. The drop in the flow of pancreatic juice in response to adrenaline was not very sensitive to adrenergic blockers. The effect of adrenaline on pancreatic secretion cannot be attributed to vascular changes.     

Ion channel topography of the neuronal nicotinic acetylcholine receptor : pharmacochemical approaches

Forty-three bisammonium ganglionic blockers were synthesized to study the structure of the ion channel of nicotinic acetylcholine receptor. The conformational parameters of these blockers were studied, and their effects toward the ganglionic transmission in situ on the sympathetic feline upper cervical ganglions and in vitro on the parasympathetic guinea-pig small intestine ganglions were determined. A model of the binding site for the bisammonium ganglionic blockers in the neuronal ion channel was proposed.     

Cyclic AMP-independent relaxation of depolarized rat ileal smooth muscle by isoproterenol.

Isoproterenol brings about a rapid transient relaxation of depolarized ileal smooth muscle as well as a longer lasting decline in tension. Only the latter effect is mimicked by dibutyryl cyclic AMP or by phosphodiesterase inhibitors. Beta adrenergic blocking agents cause a rapid transient contraction in preparations relaxed by isoproterenol but not in preparations relaxed by the other agents, and this effect persists when influx of Ca²⁺ from the extracellular space is prevented. The transient component of the isoproterenol-induced relaxation is therefore attributed to sequestration of Ca²⁺ at intracellular sites, and the contraction which follows the subsequent addition of beta blocking agents is due to release of Ca²⁺ from these sites.     

Ion Channel Topography of the Neuronal Nicotinic Acetylcholine Receptor: Pharmacochemical Approaches

Forty-three bisammonium ganglionic blockers were synthesized to study the structure of the ion channel of nicotinic acetylcholine receptor. The conformational parameters of these blockers were studied, and their effects toward the ganglionic transmission in situ on the sympathetic feline superior cervical ganglia and in vitro on the parasympathetic guinea-pig small intestine ganglia were determined. A model of the binding site for the bisammonium ganglionic blockers in the neuronal ion channel was proposed.     

Effect of ganglionic stimulating and blocking agents on the fast components of colonic myoelectrical activity in the rat

The presence of two types of fast myoelectrical activities, medium fast activity and fast activity, has been demonstrated previously in the electromyogram of colon in normal children and in the rat by the authors. An absence of medium fast activity in Hirschsprung's disease and in experimental aganglionosis of colon in the rat has also been described. In the present study the fast components of colonic myoelectrical activity were analysed during the procedures affecting ganglionic transmission. It was observed that ganglionic stimulants, such as balloon inflation, and intra-arterial injections of acetylcholine and small amounts of nicotine, increased the spike activity and the frequency of medium fast activity without affecting fast activity. The intra-arterial injections of ganglionic blocking agents, such as nicotine in large amounts and pentolinium tartrate, completely abolished the medium fast activity. These observations suggest that the ganglionic activity is responsible for the genesis of medium fast activity and that the absence of cholinergic ganglionic transmission is the most important single factor for the reported altered electromyogram pattern in aganglionosis.     

Propranolol induces acute natriuresis by beta blockade and dopaminergic stimulation.

dl-Propranolol (0.8-1.6 mg/kg - h for 1 h) produced a transient two- to three-fold increase in sodium excretion in nondiuretic rats infused with Pitressin and aldosterone and in water diuretic rats. Sodium excretion increased more in rats depleted of renin by chronic Doca and salt administration than in rats maintained on a low salt diet. An angiotensin inhibitor (1,sarcosine-8,valine angiotensin II) decreased sodium excretion. Therefore the natriuresis was not mediated by antidiuretic hormone, aldosterone, or renin-angiotensin. d-Propranolol did not produce a natriuresis. Prior treatment with phenoxybenzamine did not prevent the natriuretic response but chlorisondamine pretreatment did. The natriuresis is produced by beta blockade and requires post ganglionic nerve function but is independent of alpha receptors. dl-Propranolol decreased heart rate and cardiac output but systemic pressure did not fall and renal blood flow increased. This suggests a dopamine-mediated renal vasodilation and natriuresis. Haloperidol and pimozide, both dopamine blocking agents with minimal beta blocking effects, prevented the natriuretic response. We conclude that propranolol may increase sodium excretion directly by blocking beta receptors in the distal nephron and indirectly by dopamine-mediated renal vasodilation.