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Publisher Summary This chapter discusses the role of cyclic nucleotides in promoting the trans-synaptic induction of tyrosine hydroxylase. An increase of activity at synapses impinging on either sympathetic ganglia or adrenal chromaffin cells results in an induction of tyrosine hydroxylase. This induction is termed trans-synaptic and occurs after time latency from the termination of the stimulus. Such latency implicates intermediate steps in transforming the increase of synaptic activity into a change of protein synthesis. The chapter also discusses the molecular nature of the events that transform stimulation of synaptic receptors located in the membrane of post junctional cells into an intracellular effector stimulus that increases the number of molecules of the inducible TH. The studies have identified three phases in the sequence of intracellular events which cause the induction of TH in adrenal medulla and superior cervical ganglia of demedullated rats after cold exposure. The cAMP/cGMP concentration ratio increases as a result of the extraordinary high rate of transmitter release. This increase persists for about 90 min and during the subsequent 10 to 18 hours a series of biochemical events occur, including de novo synthesis of specific messenger RNA.

Summary Pretreatment with methiothepin or chlorpromazine prevents catalepsy, prolongs duration of anesthesia and recovery, prevents apneustic respiration, and favors disappearance of limb-withdrawal and jaw reflexes in dogs injected intramuscularly with a minimum anesthetic dose of ketamine. These effects relate to degree of sedation produced by the neuroleptics, and therefore may be nonspecific. A subsedative dose of pimozide antagonizes ketamine anesthesia and potentiates catalepsy, respiratory apneusis, and emergent delirium. Sedative doses of pimozide are less effective in these regards. Mecamylamine enhances ketamine catalepsy and respiratory apneusis, and lightens (but does not shorten) anesthesia. Atropine prevents ketamine catalepsy and antagonizes respiratory apneusis, but potentiates muscle jerking, prolongs recovery time, and greatly prolongs emergent delirium. The results seem to implicate dopaminergic, nicotinic cholinoceptive, and muscarinic cholinoceptive mechanisms in a complex system of mediation and modulation of canine responses to ketamine. This system is different from one previously proposed for the cat. Weingarten (1972) postulated that ketamine catalepsy might be due to stimulation of the monoaminergic component of a balanced cholinergic-monoaminergic system in the brain. In rabbits, the anticholinergic agent procyclidine enhanced ketamine catalepsy ( Authier & others, 1972 ). In cats, the antiserotonergic neuroleptic agent methiothepin ( Monachon & others, 1972 ) prevented ketamine catalepsy, but pimozide 9an antidopaminergic neuroleptic, Anden & others, 1970 ) and chlorpromazine 9a neuroleptic of mixed antimonoamine activity) did not affect ketamine catalepsy ( Hatch, 1973 ). Thus, it appeared that ketamine catalepsy may indeed relate to a cholinergic-monoaminergic imbalance, and that the monoamine of interest in this regard might be serotonin. The purpose of the present study was to examine the validity of the proposed cholinergic-serotonergic mechanism of ketamine catalepsy in dogs. This species is particularly susceptible to the cataleptic and deliriant effects of ketamine.

Pharmacologic studies upon the active bronchial anaphylactic response considered to be mediated primarily by reagin-type antibodies were carried out in rats. Inhibition of the response by pharmacologic-mediator antagonists at maximally active doses were methysergide > mepyramine = atropine, but burimamide, indomethacin, mecamylamine, and bilateral vagotomy were ineffective. This suggests that 5-hydroxytryptamine is the major pharmacologic mediator involved in the response, histamine acting upon H1 receptors is contributory, involvement of prostaglandins and vagal reflexes are minor, and atropine probably exerts a moderate direct bronchial smooth-muscle relaxant effect. Activation of β-adrenergic receptors with isoproterenol is also inhibitory whereas sub-maximal bronchoconstrictor responses are enhanced by β-adrenergic blockade with propranolol. A dose-related bell-shaped inhibition was observed after disodium cromoglycate and dexamethasone was active only with pretreatment over a 3-day period. However, ineffective doses of either disodium cromoglycate or dexamethasone given alone become markedly effective when combined, indicating marked synergistic drug action. The data suggest that the active bronchial anaphylactic rat used in the present study provides an animal model similar to that of the immediate (type I) reagin-mediated asthmatic reactions in man. This model could therefore provide a greater index of predictability for clinical drug utility in human asthma than exists at present.

When tissue metabolic changes like those of hypoxia were induced by intra-aortic infusion of cyanide in dogs, cardiac output began to increase after 3 to 5 min, reached a peak (220% of the control value) at 15 min, and returned to control in 40 min. This pattern of cardiac output rise was not altered by vagotomy with or without atropine pretreatment. However, this cardiac output response could be differentiated into three phases by pretreating the animals with agents that block specific activities of the sympatho-adrenal system. First, ganglionic blockade produced by mecamylamine or sympathetic nerve blockade by bretylium abolished the middle phase of the cardiac output seen in the untreated animal, but early and late phases still could be discerned. Second, beta-adrenergic receptor blockade produced by propranolol shortened the total duration of the cardiac output rise by abolishing the late phase. Third, when given together, propranolol and mecamylamine (or bretylium) prevented most of the cardiac output rise that follows the early phase. When cyanide was given to splenectomized dogs, the duration of the cardiac output response was not shortened, but the response became biphasic, resembling that seen after chemical sympathectomy. A similar biphasic response of the cardiac output also resulted from splenic denervation; sham operation or nephrectomy had no effect on the monophasic pattern of the normal response. Splenic venous blood obtained from cyanide-treated dogs, when infused intraportally, caused an increase in cardiac output in recipient dogs; similar infusion of arterial blood had no effects. These results suggest that the cardiac output response to cyanide infusion consists of three components: an early phase, related neither to the autonomic nervous system nor to circulating catecholamines; a middle phase, caused by a nonadrenergic humoral substance released from the spleen by sympathetic stimulation; and a late phase, dependent upon adrenergic receptors but not upon sympathetic transmission.

The effects of oxotremorine and other cholinomimetics on the concentration of homovanillic acid (HVA) in the striatum was studied in rats. Oxotremorine, arecoline, nicotine, and physostigmine increased the concentration of striatal HVA. The increase in striatal HVA induced by oxotremorine was counteracted by atropine but it was unaffected by atropine methylbromide, mecamylamine or hemicholinium-3. These results suggest that oxotremorine increases the concentration of HVA in the striatum of the rat via a direct action on muscarinic receptors in dopamine neurons.

The actions of the nicotinic drug suberyldicholine (SDC) on carotid baroreceptors and chemoreceptors in the cat have been examined. Suberyldicholine has a direct stimulant effect on chemoreceptors, followed by a small delayed effect which is probably not due to SDC stimulating the superior cervical ganglion, since the effect is also present when the ganglio-glomerular nerves are cut. The direct stimulant effect on chemoreceptors was reduced by mecamylamine or tubocurarine, but not by moderate doses of atropine. Suberyldicholine thus affects chemoreceptor activity via actions at a nicotinic site. There was no evidence of a direct action of SDC on carotid baroreceptors, even with high doses. Delayed increases in baroreceptor activity occurred with high doses of SDC, but these were secondary to the sizable changes in systemic blood pressure evoked by SDC.

This study investigated the stimulus property of nicotine in the rat. The primary objectives of the study were 1. to determine the time course of the nicotine stimulus and its relationship to brain levels of the drug and 2. to determine whether the nicotine stimulus is dependent upon the integrity of specific neurotransmitter systems. A lever choice discrimination was used. After injection of nicotine, depression of one lever in an operant test chamber resulted in food reinforcement according to a variable interval schedule of 15 sec. When saline was administered, the opposite lever was reinforced. A high degree of discriminated responding was observed when either 400 Μg/kg or 200 Μg/kg of nicotine was used as a discriminative stimulus. The degree of discrimination decreased as the length of the time period between the injection of nicotine and the test of discrimination was increased. This decline in discrimination was similar to the decline in brain levels of nicotine suggesting that nicotine discrimination is directly related to the concentration of nicotine in the brain. Atropine, mecamylamine, dibenamine, propranolol and α-methyl-para-tyrosine (AMPT) were all tested, in a range of doses, for effects upon nicotine discrimination. Of these, only mecamylamine antagonized the nicotine stimulus. These results indicate that the stimulus effect of nicotine is mediated specifically through nicotinic-cholinergic receptors and not muscarinic-cholinergic or adrenergic receptors.

1 Periodic stimulation (every 10 min) of the cervical sympathetic nerve increased the ganglionic block by low concentrations of chlorisondamine (CHL) in the superior cervical ganglion of the cat when compared to the contralateral unstimulated side. 2 Periodic stimulation of the postganglionic nerve was ineffective in increasing the block. 3 Ganglionic block by low concentrations of mecamylamine had the same stimulus dependency, but ganglionic block by any dose of hexamethonium was not influenced by nerve stimulation. 4 Physostigmine infused together with CHL increased the rate of onset of block produced by CHL. Atropine had no apparent effect on the development of ganglionic block by CHL. 5 Repeated intra-arterial injections of 1,1-dimethyl-4-phenylpiperazinium into the circulation of the superior cervical ganglion increased the magnitude of block produced by CHL. Similar injections of methacholine had no effect on ganglionic block produced by CHL. 6 The results are interpreted to indicate that activation of ganglionic nicotinic receptors increased the affinity of receptors for CHL and mecamylamine.

In the cat superior cervical ganglion in situ volleys in the preganglionic nerve are capable to evoke hyperpolarizing (P-waves) and depolarizing synaptic responses (LN-waves) which are mediated by muscarinic receptors. In the unblocked and unconditioned ganglion a repetitive stimulation by brief trains of shocks is required to produce a LN-wave; a discharge of ganglionic action potentials is only exceptionally seen during this slow synaptic potential. Single shocks evoked no detectable muscarinic effect. After various procedures (tetanic conditioning, anticholinesterases, slight depolarization by nicotinic agents, KCl and isoprenaline), all known to enhance the responsiveness to exogenous muscarinic agents, a ganglionic transmission of impulses through muscarinic receptors was demonstrated both in the presence and absence of an intact nicotinic transmission. The LN-wave is the postsynaptic event mediating the muscarinic pathway. It is best seen during desensitization of nicotinic receptors by high doses of nicotine.

The effects of several i.p. administered, centrally active cholinergic agonists and antagonists on the naloxone-induced jumping behavior of morphine tolerant and dependent mice were studied in an effort to differentiate muscarinic and nicotinic modification of the withdrawal jumping behavior. Nicotine, tremorine, oxotremorine, arecoline and physostigmine significantly inhibited jumping, whereas atropine, benzotropine, pempidine and mecamylamine significantly potentiated jumping. Quaternary cholinergic drugs did not modify jumping. These drug effects were obtained generally without an alteration of the amount of naloxone or morphine in the brain. Cholinergic drugs also modified the jumping incidence in mice undergoing abrupt morphine abstinence. It is concluded that the inhibition of withdrawal jumping in morphine dependent mice by both muscarinic and nicotinic agonists and its enhancement by muscarinic and nicotinic antagonists reflect cholinergic modifications of the jumping response by a central mechanism(s).

The coronary vasoconstrictor properties of digitals were evaluated in 61 anesthetized, openchest dogs after coronary sinus cannulation and under conditions of a constant heart rate (atrioventricular pacing) and near-constant blood pressure. The contribution of alpha adrenergic receptor stimulation to the digitalis-induced increase in coronary vascular resistance (CVR) was examined. With Na pentobarbital anesthesia (16 dogs), intravenous acetylstrophanthidin (0.5 mg) caused a significant (P

The ganglion-blocking properties of atropine, atropine methyl nitrate, oxyphenonium, poldine, methantheline and propantheline have been examined and compared with those of hexamethonium, mecamylamine, pentolinium and tetraethylammonium. The ganglion-blocking activity was assessed by stimulating the preganglionic nerve to the superior cervical ganglion and recording directly the percentage depression in the postganglionic action potentials. In this way any ambiguity due to the peripheral actions of the drugs was removed. As a group the atropine-like compounds are not markedly less potent than the ganglion-blocking agents, but their action is relatively transient. This work suggests that the ganglion-blocking action of atropine-like substances plays no part in their therapeutic effects.

Chlorpromazine was administered to normal rats placed at 30° and 20° C and to cold acclimated rats exposed to 30° and 2°. Treatment of the animals at 30° produced no increase in catecholamine excretion. However, rats placed at either 20° or 2° significantly increased their noradrenaline excretion, and to a lesser extent their adrenaline excretion, following chlorpromazine. These increases, also noted in adrenalectomized rats and associated with hypothermia, could be prevented by pretreatment with a ganglionic blocker. It is concluded that the increase in noradrenaline excretion is a result of a temporary hypothermia produced by chlorpromazine and originates from sympathetic nerve endings.

Hexamethonium is shown to produce neuromuscular block in cats previously given mecamylamine. Trimetaphan camphorsulphonate is shown to have a similar but less marked action at the motor endplate under the same conditions. The mechanism by which mecamylamine modifies the action of these ganglion blocking agents is discussed. Attention is drawn to the potential risk if similar influences prevail in man.

Rats were trained to respond differentially conditonal upon whether they were injected s.c. with nicotine, 0.4 mg/kg, or arecoline, 0.5 mg/kg, in a shock-escape apparatus. The specific cueing effects of these two cholinergic agonists suggests the presence of distinct C.N.S. receptor sites of action for m- and n-cholinergic drugs. Pretreatment with mecamylamine, 0.5 mg/kg, inhibited the nicotine-induced cue but had no effect on the arecoline response.

Adverse pulmonary reaction to systemically administered drugs is a common occurrence. The roentgen patterns produced by adverse drug reactions can be grouped into five major categories. Agents known to cause pleuropulmonary complications are listed. A careful drug history should be as much a part of the evaluation of a patient with disseminated or recurrent pulmonary disease as is the occupational history.

The content and release of acetylcholine (ACh) from cat brain and ACh content of rat brain was measured using the frog rectus and leech muscle bioassays before and after physostigmine 100 μg kg i.v. or i.p. The drug elevates steady state levels of brain ACh of awake animals especially in the neocortex, caudate nucleus and hippocampus but much less so in the lateral geniculate and superior colliculus. Physostigmine was shown to produce neocortical release of ACh through a subcortical mechanism in brainstem transected cats and to decrease ACh neocortical content in pentobarbital anesthetized cats and rats. The neocortical release of ACh seems to be mediated primarily through a subcortical brain mechanism which is activated by physostigmine. It is postulated that the ascending reticular formation is involved. Local application of scopolamine (1 μg ml ) into the collecting cup did not antagonize the effects of 100 μg kg of physostigmine i.v. as much as l mg kg of scopolamine i.v. On the other hand, 2 mg kg of mecamylamine given i.v. not only did not antagonize physostigmine-induced neocortical release of ACh, but seemed to enhance it. The results indicate a complex action of physostigmine on the cholinergic system of the brain.

It is known that the administration of 3-acetylpyridine (3-AP) to rats induces hyperglycemia. Experiments designed to study the mechanism of this action of 3-AP on blood glucose levels are reported. The hyperglycemia produced by the administration of 3-AP to adult rats was accompanied by a decrease of hepatic and muscular glycogen. The hyperglycemic effect of 3-AP was significantly less in 8-day-old rats than in adult rats. The simultaneous administration of the ganglionic blocking agent mecamylamine inhibited the hyperglycemic effect of 3-AP. Small doses of 3-AP injected intracisternally produced hyperglycemia in short periods of time. The i.p. injection of the same dose of 3-AP did not exhibit such effect. Hyperglycemia was also produced by the intracisternal administration of the analogue of NAD, 3-AP-NAD, at a dose 100-fold less than the intracisternal dose of 3-AP which induced hyperglycemia. The epinephrine content in the adrenal glands did not change significantly after the administration of a hyperglycemic dose of 3-AP. It is concluded that the hyperglycemic effect of 3-AP is due to a release of cathecholamines from the adrenal medulla and that this release is probably secondary to the lesions observed in brain after 3-AP administration. It is also concluded that 3-AP probably acts by forming the analogue 3-AP-NAD in brain.

The effects of nicotine on bar-pressing behaviour in the rat are blocked by mecamylamine. The depressant phase of the effect is blocked by atropine, supporting the conclusion that this depression is mediated by released acetylcholine. The quaternary compounds chlorisondamine and atropine methylnitrate also antagonise the behavioural effects of nicotine but the doses required for this are far in excess of those which are effective peripherally, suggesting that the sites of interaction are central.

The ultrastructural effects of acute and chronic stress in vivo on jejunal microvilli were studied in rats, in order to investigate factors which control microvillous organization. Rats were subjected to one of the following six conditions of stress: ischemia (15 min), hypothermia (20 min), lactose-induced diarrhea (3 days), mecamylamine-induced malabsorption (3 days), protein malnutrition (3 wk), or protein-calorie malnutrition (3 wk). At the end of each period of stress, the jejunum was fixed and prepared for electron microscopy. All six agents caused the appearance of abnormal microvilli, defined as “twinned”, involving up to 9.1% of the mucosal surface. The twinned microvillus consists of two cytoplasmic projections stemming from a base which is continuous with the cortical cytoplasm of the absorptive epithelial cell. Longitudinal filaments run from the apex of each branch, through the base, to the terminal web. In addition, another type of microvillous anomaly was observed, which was defined as “composite.” In the composite microvillus, three or more filamentous axes from the terminal web come to lie within a single enlarged microvillus. Contact of filaments with the apical membrane did not correlate with the presence of subapical dense material in either type of anomaly. Both abnormalities probably represent a stage of suppression of the microvillous border, rather than its regeneration, since they were observed during the period of stress.

Myocardial necrosis was produced in rats by the following regimen: daily injections of dexamethasone and desoxycorticosterone acetate, and gavage with a solution of monobasic sodium phosphate for 5 days, followed by 712 hours of restraint on the sixth day. Separate groups given the above-described treatment were concomitantly administered 0.14, 0.57, and 2.28 mg. per kilogram per day of nicotine alkaloid in the drinking water. Either phenelzine, 1 mg. per kilogram, or mecamylamine, 12.5 mg. per kilogram, was administered daily to separate groups given the steroid-salt-stress treatment and to other groups also administered 2.28 mg. per kilogram per day of nicotine. Reserpine, 1 μg per animal per day, was injected alternately 3 or 7 days prior to, and also during, steroid-salt-stress treatment, both with and without the administration of 2.28 mg. per kilogram per day of nicotine. The two higher doses of nicotine significantly (P Treatment with mecamylamine or phenelzine did not reduce the response to the steroid-salt-stress treatment, but significantly (P

1. Stimulation of the thoracic sympathetic nerve trunk caused a rise in arterial blood pressure and heart rate which was reduced but not abolished during the infusion of hexamethonium chloride, pentolinium tartrate, mecamylamine or tetraethylammonium chloride.2. Preganglionic stimulation no longer elicited a synchronous sC elevation in the post-ganglionic nerves. The persistent blood pressure and heart rate response was associated with an asynchronous discharge in these nerves.3. Both the persistent response and the asynchronous discharge were abolished by the intravenous injection of atropine sulphate in doses of 30 mug/kg.4. Atropine had no effect on spike amplitude or shape, conduction velocity or frequency response in either the pre- or post-ganglionic nerve trunks. Nor did it affect the rise in blood pressure and heart rate evoked by stimulation of the post-ganglionic cardiac sympathetic nerves.5. It is concluded that atropine partially blocked synaptic transmission in cardiac sympathetic adrenergic pathways.

1. 1. Bretylium tosylate has been employed alone or in combination in the treatment of 100 patients with arterial hypertension. 2. 2. It does not lead to significant parasympathetic side effects, such as dry mouth, constipation, or impotence; it occasionally causes looseness of the bowels, which is probably due to lowered orthosympathetic activity. 3. 3. Most patients prefer bretylium tosylate to ganglionic blocking drugs. 4. 4. The main disadvantages are: (a) a peculiar visual blurring which subjectively differs from that which follows the use of ganglionic blocking drugs, (b) the large dose which is needed in some patients, (c) occasional unpredictability of absorption, (d) occasional indigestion, and (e) facial pain on eating. 5. 5. Bretylium tosylate may be combined advantageously with rauwolfia alkaloids or hypotensive diuretics such as hydrochlorothiazide. In patients requiring large doses of bretylium tosylate, potent ganglionic blocking drugs, such as pempidine, M & B 5409A, M & B 4500, or mecamylamine, in appropriate doses, may be used to replace a proportion of the bretylium tosylate, without causing parasympathetic side effects.

The depressing action of a number of α-sympathomimetic agents on the central nervous system was studied in chickens and mice. Clonidine, 2-(2,6-dimethylphenylamino)-2-Δ2-oxazolidine 1–3, tetryzoline, naphazoline, tramazoline xylazine and oxymetazoline induced a loss of the righting reflex in chickens and prolonged the sleeping time induced by chloral in mice. These effects were dose-dependent and much more potent for the two former drugs. The actions in chickens and mouse were antagonized by previous treatment with four α-adrenergic blocking drugs (tolazoline, phentolamine, piperoxane, dibenamine) but not phenoxybenzamine. In chickens, chlorpromazine and imipramine also antagonized the action, but haloperidol was an antagonist only for naphazoline and tetryzoline. In mice, but not in chickens, atropine and mecamylamine were strong antagonists. These results suggest that activation of α-adrenergic receptors in the brain induces sedation and the involvement of cholinergic pathways in mice for this effect.

1. A preparation is described whereby the responses of the two anococcygeus muscles can be recorded in vivo in the pithed rat and the autonomic outflows to the muscle selectively stimulated in the spinal canal.2. Motor responses are obtained from stimulation at two levels; an upper extending from T 11 to L 3 and a lower from L 6 to S 2. Stimulation between these levels, i.e. between L 3 and L 6, produces no response. The response to stimulation at both upper and lower levels is abolished by phentolamine. The response to stimulation in the upper region is abolished by hexamethonium and is, therefore, presumably preganglionic; the response to stimulation at the lower level is resistant to hexamethonium and presumably post-ganglionic. Stimulation at levels above T 11 causes contraction after a delay, by liberating catecholamines from the adrenal medulla. This effect is blocked by both phentolamine and hexamethonium.3. If the adrenergic motor nerves are blocked and the muscle tone raised by a combination of guanethidine and tyramine, stimulation between L 5 and S 2 produces inhibition. The inhibitory outflow, therefore, overlaps the motor outflow but extends one segment more rostral (L 5). Stimulation restricted to this L 5 segment even in the presence of a normal unblocked motor innervation causes inhibition. The inhibitory response is blocked by hexamethonium or mecamylamine but desensitization and ;escape' occurs. This desensitization is less than that observed in the vas deferens when its motor nerves are similarly stimulated in the spinal cord.4. It is concluded that inhibitory fibres to the anococcygeus arise in the spinal cord and are organized in the pattern of the autonomic nervous system with a peripheral synapse. The site of origin of these inhibitory fibres is different from the motor adrenergic fibres to the muscle.

Pylorus ligation significantly increased gastric acid concentration over that found in nonligated acute fistula rats. Ligating the stomach on the antrum did not change the gastric secretory pattern from that obtained by pylorus ligation. Local administration of atropine, mecamylamine, and cocaine into the lumen of a pylorus sac inhibited gastric secretion. Atropine was four times as potent and mecamylamine three times as potent locally as when given orally, indicating direct effects on nerve structures in the submucosa.

Nicotine, given by i.v. or right intra-atrial injection in doses of 10–40 μg/kg, depressed the “spontaneous” electrical activity and tone in both extensor and flexor muscles of cats rendered rigid by intercollicular decerebration and in intact preparations under light chloraloseurethane anaesthesia. The latent periods of this action following intra-atrial injection varied from 1 to 2 sec, indicating that it must have originated from receptors located between the right atrium and the pulmonary capillary bed. The onset of the reflex motor depression frequently coincided with the onset of the vagovagal cardiodecelerator-hypotensive response, suggesting that both effects arose from the same type of receptor. These brief latency effects were dependent on vagal afferents. After vagotomy a motor depressant effect with delayed onset was seen. Instances of differential abolition, or absence, of the effect of nicotine and phenyldiguanide under varying conditions of decerebration and anesthesia suggest that the motor depressant effect of nicotine does not arise from the pulmonary deflation receptors, responsible for the effect of phenyldiguanide, but is initiated at the pulmonary arterial baroreceptors which have earlier been implicated in the hypotensive reflex response to nicotine. The motor depressant effect of nicotine was duplicated by the quaternary nicotinic agent sebacylcholine and also by acetylcholine, and was blocked by hexamethonium, confirming the peripheral reflex nature of the effect. Neuromuscular transmission was not impaired in the doses used. Dihydro-β-erythroidine, blocking the nicotinic synapse at the Renshaw interneuron, reduced or abolished the inhibition by nicotine of the knee jerk but had little influence on the reflex motor depression, while hexamethonium had the reverse effect. Thus, Renshaw inhibition was responsible for much of the depressant action of nicotine on the knee jerk but played only a minor part in the reflex motor depression. In several experiments hexamethonium itself depressed motor activity by an as yet unexplained mechanism.

In experiments on decerebrated cats a study was made of effects of azamethonium, hexamethonium, heptamine, and mecamylamine on the functional mobility of the glossomandibular reflex centers. Mecamylamine and, to a lesser extent, heptamine, depressed the lability of the corresponding centers in conditions of supramaximal stimulation. Azamethonium and hexamethonium in the same conditions did not change the course of the glossomandibular reflex. It is presumed that this difference is connected with a varying capacity of gangliolytics to penetrate into the central nervous system.

Preceding investigations have demonstrated, in general, a decrease in cardiac output and an increase in peripheral resistance after the administration of ganglionic blocking agents. 1–3 Mecamylamine has been shown to have hemodynamic effects similar to ganglionic blocking agents used previously. 4 It has not been established, however, whether the effects of these agents are due purely to the reduction in cardiac filling pressure secondary to peripheral pooling of blood, 3–5 or whether additional factors, such as a decreased discharge from the sympathetic nervous system, are significant as a mechanism of the decreased output. 6 Submersion of the human subject in water after the administration of hexamethonium bromide restored the arterial blood pressure nearly to control values, but no data on cardiac output was recorded during this experiment. 7 In the dog heart-lung preparation or isolated papillary muscle strip, hexamethonium produces an increased force of myocardial contraction; hence, it seems that a direct depressant effect on the myocardium is not likely from this agent. 8,9 Mecamylamine, on the other hand, is reported to decrease contractility of heart muscle strips in vitro. 10 The present report describes a series of experiments designed to test the hemodynamic effect of increasing the central venous pressure after the production of ganglionic blockade.

In a majority of experiments on both dogs and cats, hypotensive doses of tetraethylam-monium chloride or mecamylamine caused no change or moderate increase in efferent electric activity in the largely preganglionic thoracic portion of the splanchnic nerve, and caused complete and prolonged elimination of efferent activity in the postganglionic inferior cardiac and renal nerves. Both drugs failed to suppress changes in splanchnic nerve activity that were elicited refiexly. These results imply strongly that both ganglion-blocking drugs, in dosage used intravenously to induce hypotension, act mainly through their peripheral effects rather than through one on central vasomotor synapses. In both dogs and cats, reserpine caused slowly progressive and marked diminution in efferent splanchnic nerve activity, which supports the hypothesis that the central action of this agent contributes to its hypotensive effect.

The motor response of 5-hydroxytryptamine (5-ht) on the distal part of the isolated rat colon was investigated by constructing dose: response curves to 5-ht, acetylcholine and nicotine; these were repeated in the presence of different antagonists and an anticholinesterase. Hyoscine abolished the responses to acetylcholine, almost completely blocked the effect of nicotine, but reduced the contractions to 5-ht only to about half of the original level. The anticholinesterase NN’-diisopropylphosphorodiamidic fluoride (mipafox) potentiated the responses to acetylcholine, 5-ht or nicotine. Procaine and cocaine inhibited to the same extent the large doses of 5-ht, but had no effect on the small doses. Both drugs reduced the contractions with nicotine. Three ganglion-blocking agents were used. Hexamethonium had no effect on acetylcholine or 5-ht, but antagonised nicotine. Mecamylamine had no effect on acetylcholine; it blocked the responses to nicotine and reduced the large doses of 5-ht. The action of dimethylphenylpiperazinium on the three agonists was similar to that of mecamylamine. 2-Bromolysergic acid diethylamide had no effect on the responses to acetylcholine, but reduced equally the contractions due to 5-ht and nicotine. It was concluded that 5-ht acted indirectly by stimulating the intramural parasympathetic ganglia and directly by an action on the muscle fibres. The direct action was pronounced with small doses, the indirect action with higher doses of 5-ht.

Experience with the neuromuscular preparation of the chick, previously described, has been extended: 1. a) A contracture was evoked by a variety of nicotinergic receptor stimulants shown in tables 1–3. 2. b) Many compounds with known activity on cholinergic receptors were able to antagonize the effects of the contracture-evoking drugs. These substances are listed in table 4. 3. c) A clear-cut facilitative effect of TEA on the height of the twitch response was demonstrated. TMA, TMEA a TMPA did not have this effect in this preparation. 4. d) The results of the experiments indicate that a nicotinic type of receptor is probably concerned in the action of cholinergic drugs on this preparation.

Intestinal peristalsis has been stated to be an important factor regulating small bowel bacterial flora. We studied the midintestinal flora in rats under conditions of altered propulsion. Our results failed to confirm the striking changes in flora and histological appearance produced by a ganglion-blocking agent reported in another study. Agents which moderately retarded propulsion (mecamylamine, chlorisondamine, and morphine) produced only a slight increase in some organisms, in comparison to the gross overgrowth associated with the extreme stagnation from ileal obstruction. Treatments which mildly accelerated propulsion (tolazoline, neostigmine, and fasting) reduced the population of only a few organisms. We found an overgrowth of bacteria in two situations where propulsion was actually accelerated, indomethacin-induced ulceration and whole body X-irradiation. Marked morphological mucosal changes were present in both of these situations. It appears that extreme forms of stagnation are necessary to produce significant bacterial overgrowth in the small intestine of rats, and striking bacterial overgrowth can occur in the absence of retarded small intestinal propulsion, especially if there is mucosal damage.

The anticurare activity of some guanidine derivatives has been studied using the fowl sciatic nerve-gastrocnemius muscle preparation and the cat sciatic nerve-gastrocnemius and tibialis anterior muscle preparations. Among the compounds tested, and in decreasing order of potency, were NN-dimethylguanidine, N-methylguanidine, guanidine and N-aminoguanidine which antagonized or prevented tubocurarine or gallamine triethiodide-induced paralysis. None of the derivatives antagonized the effects of suxamethonium or decamethonium. NN-Dimethylguanidine, N-methylguanidine and guanidine antagonized or prevented the curare-like effects of magnesium without altering the activity of hemicholinium. At high doses NN-dimethylguanidine induced a decamethonium-like spastic paralysis in the fowl sciatic nerve-gastrocnemius muscle preparation. NN-Diethylguanidine, however, induced a tubocurarine-like flaccid paralysis. The derivatives possessing anticurare activity were also studied using the cat superior cervical ganglion-nictitating membrane preparation to check their possible effects against ganglionic blocking agents. Only guanidine antagonized or prevented the effects of hexamethonium, pentolinium and mecamylamine; it had no effect on the actions of pempidine and chlorisondamine. NN-Diethylguanidine was the only compound in the series to show a ganglionic blocking action.