bluuebunny/crossref_metadata_2025 huggingface dataset:
RELATIONSHIPS BETWEEN CHEMICAL STRUCTURE AND AFFINITY FOR POSTGANGLIONIC ACETYLCHOLINE RECEPTORS OF THE GUINEA‐PIG ILEUM
Authors: ABRAMSON F.B. , BARLOW R.B. , FRANKS FIONA M. , PEARSON J.D.M.
Published: July 2012

Some phenylacetyl, diphenylacetyl, benziloyl and (±)‐cyclohexylphenylglycolloyl esters have been made with 2‐ and 3‐hydroxymethylpyrrolidines, 3‐hydroxymethyl‐N‐methylpiperidine, piperidin‐3‐ols, piperidin‐4‐ols, 2,2,6,6‐tetramethyl‐N‐methylpiperidin‐4‐ol, tropine, pseudotropine and quinuclidin‐3‐ol, and the affinity of these compounds and of their metho‐ and etho‐ derivatives has been measured for postganglionic acetylcholine receptors of the guinea‐pig isolated ileum.

Some of the compounds were very active indeed; the benziloyl esters of N‐methylpiperidin‐4‐ol methiodide, tropine methiodide, and quinculidin‐3‐ol, and the (±)‐cyclohexylphenylglycolloyl esters of N‐methylpiperidin‐4‐ol and its methiodide had affinity constants greater than 1010.

The effects of inserting an additional methylene group onto the nitrogen were extremely variable, ranging from a decrease in log K of 1.64 units to an increase of 0.97 units. The effects of replacing hydrogen by phenyl in the acid portion ranged from an increase of 1.04 units to an increase of 3.06 units and of replacing hydrogen by hydroxyl from a decrease of 0.09 units to an increase of 1.94 units.

The extent of the variation in the effects of a particular change in structure on affinity does not appear to be any different in these relatively rigid compounds from that observed with the same changes in open‐chain aminoalcohols.

Reasons for the variable effects of groups on affinity are discussed. If differences in effects on preferred conformations of these particular compounds in solution are of secondary importance, the effect of a group on affinity will be the net result of what it could contribute to binding, offset by the disturbance it causes to existing binding. The maximum effect observed in a large number of comparisons may indicate the contribution in the absence of disturbance and for groups containing only carbon and hydrogen it appears to be related to size, assessed from the increments in apparent molal volume at infinite dilution. The variation in the effects of these groups also appears to be related to size. Changes involving groups containing oxygen can produce bigger contributions to binding, and a bigger variation in contribution, than would be expected from their size.

It is difficult to predict the extent to which groups may fail to produce their maximum effects. Variation is greatest with groups which could produce the biggest changes and so are of the greatest interest.

The relevance of the results to the successful prediction of biological activity is discussed.
BLOCKADE OF PERIPHERAL VASCULAR RESPONSES TO ISOPRENALINE BY THREE β‐ADRENOCEPTOR ANTAGONISTS IN THE ANAESTHETIZED DOG
Authors: HAINSWORTH R. , KARIM F. , STOKER J.B.
Published: July 2012

A dog's hind limb was vascularly isolated by strong nylon snares and its sympathetic nerve supply interrupted. Blood was perfused at constant flow into the femoral artery and drained from the femoral vein. In some dogs the cardiac nerves were cut.

Isoprenaline infused intravenously caused an increase in heart rate and a decrease in arterial resistance.

Practolol (2 mg/kg) effectively blocked heart rate responses to isoprenaline infused at up to 10 μg/min but was relatively ineffective in blocking arterial responses. ICI 66082 (2 mg/kg) reduced vasomotor responses and propranolol (0.5 mg/kg) abolished vasomotor responses.

Small cumulative doses of β‐adrenoceptor antagonists were given to some dogs. Practolol blocked heart rate responses in lower doses than were required to block vasomotor responses. Propranolol preferentially blocked vasomotor responses and ICI 66082 was intermediate between the other two in its effects.
COMPULSIVE GNAWING IN RATS AFTER IMPLANTATION OF DRUGS INTO THE VENTRAL THALAMUS. A CONTRIBUTION TO THE MECHANISM OF MORPHINE ACTION
Authors: BERGMANN F. , CHAIMOVITZ M. , PASTERNAK(NA'OR) V. , RAMU A.
Published: July 2012

Implantation of morphine into various parts of the corpus striatum of rats evokes only weak gnawing responses.

Deposition of apomorphine, morphine or methadone in the region of the nucleus ventralis thalami produces a biphasic response, i.e. general excitation, followed by a period of intense gnawing.

The effect of both apomorphine and morphine is blocked by chlorpromazine, haloperidol and pimozide. However, pretreatment with α‐methyltyrosine methyl ester or α‐methyldopa prevents only the gnawing response to morphine, but not to apomorphine.

Systemic nalorphine, morphine or pethidine suppress the gnawing response, evoked by thalamic implants of apomorphine or morphine.

Systemic amphetamine potentiates the effect of thalamic deposits of morphine.

Compulsive gnawing, following implantation of morphine into the ventral region of the thalamus, probably results from enhanced production and release of catecholamines.
THE EFFECTS OF INTRAVENTRICULAR 6‐HYDROXYDOPAMINE ON BODY TEMPERATURE AND ARTERIAL BLOOD PRESSURE IN CATS AND RABBITS
Authors: LEWIS P.J. , RAWLINS M.D. , REID J.L.
Published: July 2012

In unanaesthetized cats, the administration of 6‐hydroxydopamine (6‐OHDA), 750 μg, via the lateral cerebral ventricle produced a pronounced fall in rectal temperature but only a slight fall when repeated 7 days later. At this time hypothalamic noradrenaline concentration had diminished to 4% of control.

In these animals, the hypothermic response to exogenous noradrenaline, 100 μg, given via the same route was uninfluenced by pretreatment with 6‐OHDA.

In unanaesthetized rabbits, intraventricular noradrenaline, 100 μg, produced a rise in rectal temperature and a biphasic effect on arterial pressure, a rise lasting 30 min followed by a fall.

Intraventricular 6‐OHDA, 750 μg, in unanaesthetized rabbits produced a rise in body temperature and a rise in arterial pressure. The same dose given to rabbits depleted of central noradrenaline with central 6‐OHDA produced rises in body temperature and arterial pressure of similar magnitude, but of slower onset.

These results suggest that intraventricular 6‐OHDA releases noradrenaline from central neurones and that these neurones subserve thermoregulatory functions in both species. In the rabbit, central noradrenergic neurones can raise arterial pressure.
CAN THE ACTIONS OF ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON PENTAGASTRIN‐INDUCED GASTRIC SECRETION BE DUE TO THEIR EFFECTS ON HISTAMINE FORMATION?
Authors: CURWAIN B.P. , HOLTON PAMELA , McISAAC R.L. , SPENCER JAN
Published: July 2012

The effects of some adrenoceptor agonists and antagonists which have been reported to affect histamine formation in leucocytes (Assem & Feigenbaum, 1972) have been investigated on gastric secretion in conscious dogs with Heidenhain pouches.

Submaximal secretion in response to pentagastrin was enhanced by propranolol (0.1–1.0 mg/kg i.v.) and phenylephrine (1.0 μg kg−1 min−1 i.v. for 20 min), which increase histamine formation, and was decreased by phentolamine (2 mg/kg i.v.) and isoprenaline (0.05–0.2 μg kg−1 min−1 i.v. for 30 min), which decrease histamine formation. Practolol (2 mg/kg i.v.), which has no effect on histamine formation, had no effect on secretion.

Acid secretion in response to histamine was either unaffected or affected in the opposite direction by these drugs.

The effects of the drugs on pentagastrin‐induced secretion were not secondary to changes in mucosal blood flow (radioactive aniline clearance).

The results are consistent with the hypothesis that acid secretion in response to pentagastrin involves the formation of endogenous histamine.
DISSOCIATION OF CARDIAC INOTROPIC AND ADENYLATE CYCLASE ACTIVATING ADRENOCEPTORS
Authors: BENFEY B.G. , KUNOS G. , NICKERSON M.
Published: July 2012

At higher temperatures, near the physiological range for mammals and nonhibernating frogs, the adrenoceptors for both inotropic responses to adrenaline and noradrenaline and for cyclic 3′,5′‐adenosine monophosphate (cyclic AMP) production in rat and frog isolated heart preparations, had typical β characteristics. Phenoxybenzamine potentiated the inotropic response and the accumulation of cyclic AMP; conversely, propranolol inhibited the two responses.

When the ambient temperature was reduced, the adrenoceptors mediating cyclic AMP production changed very little; they were blocked as effectively as at the higher temperature by propranolol and were not blocked by phenoxybenzamine. However, the adrenoceptors mediating the inotropic response were markedly changed by the decrease in temperature; phenoxybenzamine now inhibited this response and the inhibitory activity of propranolol was reduced about tenfold.

These results indicate that the adrenoceptors that mediate cardiac inotropic responses at physiological temperatures are distinct from those that mediate the production of cyclic AMP, and that the activation of adenylate cyclase and the accumulation of cyclic AMP are probably not intermediate steps in cardiac inotropic responses to catecholamines.
EVIDENCE FOR PARTICIPATION OF CATECHOLAMINES IN CARDIAC ACTION OF OUABAIN: POSITIVE CHRONOTROPIC EFFECT
Authors: SEIFEN E.
Published: July 2012

The shortening of cycle length (=positive chronotropic effect) by ouabain produced in isolated spontaneously beating atria of the guinea‐pig was analyzed.

The action of ouabain was dose‐dependent; threshold response was seen at 1 × 10−7 m, and maximal response occurred at 4 × 10−7 M. The half‐time of the ouabain effect was about 20 minutes.

The positive chronotropic effect of ouabain was reduced to 40% by β‐adrenoceptor blockade (3.3 × 10−9 M propranolol) or by reserpine‐depletion of catecholamines. Incubation of reserpine‐treated atria with noradrenaline partially restored the action of ouabain.

The effect of ouabain was greatly dependent upon the calcium concentration. The optimal calcium level was 2.5 × 10−3 M. Calcium and ouabain acted synergistically.

Increasing calcium concentrations inhibited the positive chronotropic effect of noradrenaline in a manner similar to increasing ouabain concentrations.

A hypothesis is proposed which explains the chronotropic effect of ouabain on the basis of two mechanisms: (1) increase of the catecholamine concentration affecting the pacemaker; (2) mobilization of calcium, i.e. increase of the biologically effective intracellular calcium level.
CORTICAL POTENTIALS EVOKED BY NOCICEPTIVE STIMULI: THEIR DEPRESSION BY A FACTOR RELEASED DURING SAPHENOUS NERVE STIMULATION IN THE RAT
Authors: LEME J. GARCIA , LICO MARIA
Published: July 2012

The amplitudes of the first positive and the first negative waves of cortical potentials evoked by electrical stimulation of the dental pulp in the rat were decreased following electrical stimulation of the peripheral cut end of the saphenous nerve.

This effect was greatly diminished when the stimulation of the saphenous nerve was performed with the saphenous or femoral veins ligated.

During stimulation of the saphenous nerve of a donor rat, the subcutaneous tissue in the area supplied by the nerve was perfused; when the perfusate (in which a permeability‐in creasing factor was detected) was injected intravenously into a recipient animal, a decrease in the amplitude of the evoked cortical potential of the recipient rat was also observed.

Intravenous injections of 5‐hydroxytryptamine, histamine, bradykinin, prostaglandins or adenosine‐triphosphate produced no effect on the evoked cortical potential, whereas large doses of acetylsalicylic acid caused a decrease.

It is suggested that a humoral factor, released during sensory nerve stimulation, may help to modulate the processing of afferent inputs from pain receptors.
EFFECTS OF CATECHOLAMINES ON THERMOREGULATION IN PIGEONS
Authors: CHAWLA NARESH , JOHRI M.B.L. , SAXENA P.N. , SINGHAL K.C.
Published: July 2012

In unanaesthetized pigeons, kept at room temperature (20–23°C) the effects on cloacal temperature were examined of catecholamines, phenoxybenzamine and propranolol, injected into the cerebral ventricles.

Noradrenaline, adrenaline, dopamine and isoprenaline caused a fall in cloacal temperature.

Phenoxybenzamine produced a long‐lasting small rise in cloacal temperature. This rise is attributed to removal of the hypothermic effect of noradrenaline released continuously from adrenergic neurones ending in the anterior hypothalamus. Propranolol produced a slight fall in cloacal temperature.

The hypothermic effects of noradrenaline, adrenaline and dopamine were prevented by phenoxybenzamine but not by propranolol. They are therefore attributed to activation of α‐adrenoceptors.

The hypothermic effect of isoprenaline was not prevented by either phenoxybenzamine or propranolol. The effect can therefore not be attributed to activation of either α or β‐adrenoceptors. Propranolol actually accentuated the isoprenaline‐induced hypothermia.
INHIBITORY EFFECT OF A PYRROLIDINE ALKALOID, CROTALABURNINE, ON RAT PAW OEDEMA AND COTTON PELLET GRANULOMA
Authors: GHOSH M.N. , SINGH H.
Published: July 2012

The anti‐inflammatory activity of crotalaburnine (=anacrotine) was investigated against increased vascular permeability and oedema produced by formalin, carrageenin, hyaluronidase, 5‐hydroxytryptamine, dextran, bradykinin and prostaglandin, and against formation of granulation tissues by cotton‐pellet in rats. The effect was compared with the activity of hydrocortisone, phenylbutazone, sodium salicylate and cyproheptadine against different types of inflammation.

Crotalaburnine (40 mg/kg s.c. × 5 alternate days) had no significant inhibitory effect against formalin‐induced arthritis, while hydrocortisone (40 mg/kg s.c. × 10 days) was effective from the fifth day onwards.

Against carrageenin‐induced oedema both crotalaburnine (10 mg/kg s.c.) and phenylbutazone (100 mg/kg oral) produced a similar degree of inhibition. Hydrocortisone (10 mg/kg s.c.) produced slightly greater inhibition.

In normal rats crotalaburnine (10 mg/kg s.c), phenylbutazone (100 mg/kg oral) and sodium salicylate (500 mg/kg i.p.) inhibited hyaluronidase‐induced oedema. However, in adrenalectomized rats, there was a reduction of the inhibitory effect of sodium salicylate but not of phenylbutazone or crotalaburnine.

Crotalaburnine (40 mg/kg s.c. and 30 mg/kg i.p., respectively) was ineffective against 5‐hydroxytryptamine‐ and dextran‐induced oedema but against bradykinin‐ and prostaglandin‐induced oedema (in a dose of 20 mg/kg i.p.) it was quite effective. In a parallel series cyproheptadine (10 mg/kg oral and i.p., respectively) produced significant inhibition of 5‐hydroxytryptamine‐ and dextran‐induced oedema, while phenylbutazone (100 mg/kg i.p.) failed to produce any significant inhibition of prostaglandin‐induced oedema.

Against cotton‐pellet granuloma crotalaburnine, in half the dose of hydrocortisone, produced similar inhibition while phenylbutazone produced much greater inhibition in five times the dose of crotalaburnine given orally.

The possible mode of action of crotalaburnine as an anti‐oedema agent is discussed.
THE FACILITATORY ACTIONS OF 5‐HYDROXYTRYPTAMINE AND BRADYKININ IN THE SUPERIOR CERVICAL GANGLION OF THE RABBIT
Authors: WALLIS D.I. , WOODWARD B.
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) on ganglionic transmission and on intrinsic modulation of transmission have been re‐examined and compared with the effects of bradykinin by means of electrophysiological techniques.

Early facilitation, which is maximal 40–75 ms after a conditioning stimulus, was considerably enhanced by 5‐HT. This enhancement was concentration‐dependent, the threshold concentration lying between 0.1 and 1 μm. With concentrations of 5‐HT 10 μm or greater, there was some depression of the Sa response to the conditioning stimulus.

5‐HT reduced or abolished the inhibition of a test response induced by a conditioning response 100–300 ms earlier. Facilitation was observed at these intervals at concentrations of 5‐HT of 25 μm or greater.

Late facilitation, which is maximal 700–2000 ms after a conditioning stimulus, was increased by 5‐HT, but the effect was not as great as on early facilitation and was not always seen with a concentration of 1 μm.

Bradykinin reduced early facilitation but increased the amplitude of the transmitted action potential in response to a single stimulus. The threshold concentration producing these effects was between 1 and 2 μm.

5‐HT produced a rapid depolarization of the ganglion cell membrane which was followed by an after‐hyperpolarization.

Bradykinin either produced no measurable change in ganglion cell resting potential or only very small, transient depolarizations.

The depression of transmission, enhancement of intrinsic facilitation and the depolarization of the ganglion cell membrane induced by 5‐HT may indicate more than one mode of action of this amine at the ganglionic synapse.
A MODULATING ROLE OF PROSTAGLANDINS IN CONTRACTIONS OF THE GUINEA‐PIG ILEUM
Authors: KADLEC O. , MAŠEK K. , ŠEFERNA I.
Published: July 2012

The role of prostaglandins in contractions of the guinea‐pig ileum evoked either directly by acetylcholine or indirectly by angiotensin and by coaxial stimulation has been investigated.

Prostaglandin E2 in low concentration (6 Nm) slightly augmented both types of contraction. Indomethacin, an inhibitor of prostaglandin synthesis, markedly reduced the indirectly evoked contractions but did not affect contractions in response to acetylcholine. The addition of prostaglandin E2 to the preparation treated previously with indomethacin restored the effect of indirect stimulation.

The pretreatment of the preparation with guanethidine or α‐methyl‐p‐tyrosine prevented the inhibitory effect of indomethacin on indirectly evoked contractions. Prostaglandin E2 addition to such preparations considerably augmented both types of contraction.

The stimulation of non‐cholinergic, non‐adrenergic inhibitory nerves in the taenia coli and ileum preparations evoked hyperpolarization and relaxation of the preparations followed by action potentials and contraction. These responses were not changed by indomethacin pretreatment and prostaglandin E2, but rebound contraction was sometimes augmented by the prostaglandin.

Two mechanisms for the effects of prostaglandin E2 are suggested: a direct effect on smooth muscle, and an indirect action through the sympathetic nerves which by release of noradrenaline affect the acetylcholine release from parasympathetic nerve endings.
PULMONARY MECHANICAL EFFECTS OF EXPERIMENTAL LUNG EMBOLISM AND THEIR MODIFICATION BY BRONCHODILATOR DRUGS IN THE GUINEA‐PIG
Authors: DALY M.J.
Published: July 2012

In the anaesthetized guinea‐pig micro‐embolism induced by barium sulphate causes marked increases in pulmonary resistance and decreases in pulmonary compliance. Bronchodilator drugs prevent these changes with salbutamol showing much greater activity on pulmonary resistance changes than compliance changes. The results are discussed with regard to the site of action in the respiratory tree and potential clinical use.
A VASODILATOR INNERVATION TO THE CENTRAL ARTERY OF THE RABBIT EAR
Authors: KALSNER S.
Published: July 2012

The possibility of a vasodilator innervation to the isolated and perfused central artery of the rabbit ear was examined.

Stimulation of the periarterial nerves in the presence of noradrenaline or other agonist used to maintain a partial constriction of the ear artery, led to a decrease in intraluminal flow followed after the cessation of stimulation by an increase in flow beyond the pre‐stimulation level.

After blockade of adrenergic transmission with bretylium or guanethidine or of the α‐ and β‐adrenoceptors with phentolamine and propranolol, stimulation of the periarterial nerves in the presence of a background tone, led to a clearly detectable vasodilatation. This dilatation was not blocked by treatment with atropine or mepyramine; nor was it enhanced by physostigmine.

Pretreatment of rabbits with reserpine (2 mg/kg) to deplete catecholamine stores, eliminated both the vasoconstrictor and vasodilator responses to nerve stimulation. However, a lower dose of reserpine (0.2 to 0.5 mg/kg) selectively eliminated the vasoconstrictor component of periarterial nerve activation.

The ear artery dilated in response to low concentrations of prostaglandin E1, and E2, in the presence of noradrenaline, but treatment with inhibitors of prostaglandin synthesis, indomethacin, aspirin or eicosa‐5,8,11,14‐tetraynoic acid did not reduce the vasodilator response. Attempts to extract a prostaglandin in the bathing medium were unsuccessful.

The involvement of a purine nucleotide appeared unlikely since the ear artery dilated only in response to fairly high concentrations of adenosine 5′‐triphosphate (ATP), adenosine 5′‐diphosphate (ADP) and adenosine 5′‐monophosphate (AMP). Furthermore, dipyridamole, an inhibitor of adenosine uptake, enhanced dilatation due to exogenous ATP but not to periarterial nerve stimulation.

It is concluded that the central artery of the rabbit ear has a vasodilator innervation but the identity of the transmitter remains to be established.
EFFECTS OF DIPYRIDAMOLE ON NEUROGENIC AND NON‐NEUROGENIC DILATOR RESPONSES OF ARTERIAL SMOOTH MUSCLE
Authors: BELL C.
Published: July 2012

In the isolated, perfused parametrial artery of the guinea‐pig dipyridamole (10–100 ng/ml) potentiated dilator responses to adenosine 5′‐triphosphate (ATP), glyceryl trinitrate and non‐cholinergic, non‐adrenergic inhibitory nerve stimulation to similar extents. In contrast dilator responses to acetylcholine were generally unaffected or reduced.

These results support previous electro‐physiological evidence that in this preparation cholinergic vasodilatation is mediated by a cellular mechanism different from that involved in the response to non‐cholinergic dilator nervous activation.

The results also suggest that potentiation of a neurally‐mediated inhibitory response of smooth muscle by dipyridamole does not necessarily implicate ATP as the transmitter involved in this response.
AN ANALYSIS OF THE PERIPHERAL EFFECTS OF l‐DOPA ON AUTONOMIC NERVE FUNCTION
Authors: ANTONACCIO M.J. , ROBSON R.D.
Published: July 2012

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.

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.

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.

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.

The degree of lumbar sympathetic chain inhibition correlated with the pressor response following l‐DOPA, and both effects were prevented by prior decarboxylase inhibition.

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.
MUSCARINIC EXCITATION: A MICROELECTROPHORETIC STUDY ON CULTURED SMOOTH MUSCLE CELLS
Authors: PURVES R.D.
Published: July 2012

Acetylcholine was applied iontophoretically to smooth muscle cells cultured from taeniae coli of new‐born guinea‐pigs. Responses were recorded with intracellular microelectrodes.

Acetylcholine induced depolarization, spike generation and contraction. Large conductance increases could be measured during the action of acetylcholine.

Injection of depolarizing currents through the recording electrode reversed the sign of potential responses. The reversal potential was −5 to −25 mV.

Minimum latencies of responses to acetylcholine were 120–500 ms. These values were not attributable to diffusion time.

Attention is drawn to the long latencies of a variety of muscarinic responses, and the suggestion made that muscarinic mechanisms as a class may be characterized by a long activation time.
THE SELECTION OF ARYLAMIDINOUREA ANTIMALARIALS BY THEIR PREDICTED PHYSICOCHEMICAL PROPERTIES
Authors: CRANFIELD R. , GOODFORD P.J. , NORRINGTON F.E. , RICHARDS W.H.G. , SHEPPEY G.C. , WILLIAMS S.G.
Published: July 2012

A small group of arylamidinoureas for which the predicted physicochemical properties were widely spaced and uncorrelated was selected for study.

The antimalarial activity of each compound was measured against three species of plasmodium. Three corresponding regression equations were calculated relating the potency of each compound to its predicted physicochemical properties.

The potency of further test compounds was forecast for each species, by using the corresponding regression equation. These forecasts were compared with the measured activity of the test compounds, and were better than would be expected by chance.

It is suggested that only a few compounds in a series need be studied initially in order to derive regression equations with worthwhile predictive properties, if the compounds are selected according to appropriate criteria.
CENTRAL α‐ AND β‐ADRENOCEPTORS MODIFYING ARTERIAL BLOOD PRESSURE AND HEART RATE IN CONSCIOUS CATS
Authors: DAY M.D. , ROACH A.G.
Published: July 2012

In conscious unrestrained cats noradrenaline, α‐methylnoradrenaline and clonidine, infused into the lateral cerebral ventricles (i.c.v.) caused dose‐related falls in blood pressure and heart rate; both effects were abolished after i.c.v. phentolamine.

In 12 out of 20 cats, i.c.v. isoprenaline and salbutamol when given caused dose‐related pressor responses and tachycardias. These effects were abolished after i.c.v. β‐adrenoceptor blocking drugs but were unaffected by α‐adrenoceptor blocking agents.

In 5 out of 20 cats, i.c.v. isoprenaline regularly produced dose‐related falls in blood pressure with associated tachycardias; both effects were abolished after i.c.v. β‐adrenoceptor blocking agents.

Intracerebroventricular dopamine produced cardiovascular responses which were qualitatively similar to those produced by i.c.v. isoprenaline.

Intracerebroventricular adrenaline produced complex responses in untreated animals but typical α‐effects were obtained after prior i.c.v. treatment with a β‐adrenoceptor blocking agent and typical β‐effects after i.c.v. pretreatment with an α‐adrenoceptor blocking agent.

The cardiovascular changes produced by i.c.v. β‐adrenoceptor agonists were abolished after systemic administration of hexamethonium or bethanidine.

The results are discussed in the light of the mode of action of β‐adrenoceptor stimulants and β‐adrenoceptor blocking agents in the treatment of hypertension.
EFFECTS OF NICOTINE GIVEN INTO THE BRAIN OF FOWLS
Authors: MARLEY E. , SELLER T.J.
Published: July 2012

The effects of nicotine, given into the IIIrd ventricle of adult conscious fowls (Gallus domesticus) or infused into various brain regions of conscious young chicks, were tested on behaviour, electrocortical activity, respiratory rate and body temperature. Its effects given intraventricularly or applied externally to the brain‐stem of anaesthetized fowls were also examined.

After intraventricular nicotine, fowls squatted for 3 to 5 min with eyes closed, electrocortical activity resembling that during sleep but with superimposed spike activity. Following this, fowls reawakened and tachypnoea developed, together with partial abduction of the wings from the trunk, the back becoming horizontal and the tail flexed. These effects were prevented by pempidine.

Intraventricular nicotine suppressed or, less commonly, reduced operant key‐pecking, an effect unrelated linearly to dose.

Intraventricular nicotine given to fowls anaesthetized with chloralose produced brief apnoea, followed by increased amplitude of respiratory excursion for about 5 minutes. Respiratory rate accelerated slightly but tachypnoea did not develop. Nicotine applied directly to the ventral brain‐stem increased respiratory amplitude in three out of seven fowls.

In anaesthetized fowls, intraventricular nicotine raised blood pressure for 2 to 3 min, an effect prolonged up to 70 min by acute bilateral vagotomy, whereas pressor effects of intravenous nicotine were extended merely two to three fold. Dividing the spinal cord at C2 prevented pressor effects of intraventricular nicotine; those of intravenous nicotine were unaltered.

In young chicks, nicotine infused into the diencephalon, telencephalon and myelencephalon induced effects similar to those observed immediately after intraventricular nicotine, i.e. chicks squatted with closed eyes but recovered within 3 to 5 minutes. Simultaneously, electrocortical activity changed from an alert to the sleep pattern, usually with superimposed ‘spike’ activity. Tachypnoea and associated postural changes did not develop. Pempidine prevented the behavioural and electrocortical effects of nicotine.
EFFECTS OF CHOLINOMIMETIC AGENTS GIVEN INTO THE BRAIN OF FOWLS
Authors: MARLEY E. , SELLER T.J.
Published: July 2012

Effects of cholinomimetic agents, given into the IIIrd ventricle of adult fowls (Gallus domesticus) or infused into the hypothalamus of young chicks, were tested on behaviour, respiratory rate and body temperature.

Carbachol evoked behavioural and electrocortical arousal but lacked postural and respiratory effects. Contrariwise, pilocarpine increased respiratory rate and induced postural changes, i.e. abduction of the wings, but lacked other behavioural effects and did not alter electrocortical activity. Benzoylcholine induced tachypnoea, postural changes and brief electrocortical arousal. Acetylcholine was ineffective unless given with physostigmine, when electrocortical arousal, postural changes and tachypnoea developed. Methacholine induced tachypnoea and postural changes.

Effects of carbachol and pilocarpine were prevented by hyoscine and those of benzoylcholine by pempidine; hyoscine and pempidine were required together to prevent the effects of methacholine and to attenuate those of acetylcholine with physostigmine.
THE EFFECTS OF BRETYLIUM AND GUANETHIDINE ON CATECHOLAMINERGIC TRANSMISSION IN AN INVERTEBRATE
Authors: SILINSKY E.M.
Published: July 2012

Secretory potentials produced by stimulation of the salivary duct nerves were recorded intracellularly from cockroach isolated salivary glands. The secretory potential normally consisted of a 40–80 mV hyperpolarization of the gland cell.

Bretylium (0.1–1 Mm) reduced the amplitude of the secretory potential without affecting the response of the gland to dopamine (0.25–1 μm). In addition, bretylium caused an increase in the frequency of miniature secretory potentials and the appearance of nerve terminal action potentials.

Guanethidine (1 Mm) reduced the response to nerve stimulation without depressing the sensitivity of the salivary gland to dopamine (0.25–0.5 μm) and without causing an increase in the occurrence of miniature potentials. Higher concentrations (4–5 Mm) completely eliminated secretory potentials but also reduced the sensitivity of the gland cell to dopamine.

These results indicate a presynaptic depression of the secretory potential by both bretylium and guanethidine. It is suggested that, in this system, bretylium acts by depolarizing the nerve terminal while guanethidine does not.
VARIATION IN NORADRENALINE OUTPUT WITH CHANGES IN STIMULUS FREQUENCY AND TRAIN LENGTH: ROLE OF DIFFERENT NORADRENALINE POOLS
Authors: HUGHES J. , ROTH R.H.
Published: July 2012

During adrenergic nerve stimulation the output/pulse of noradrenaline from the rabbit vas deferens and portal vein is not constant but increases as the stimulus frequency or train length is increased. Depending upon the stimulus frequency and train length the fractional release of noradrenaline may vary from less than 10−7 to greater than 10−4.

Endogenous tissue stores of noradrenaline were labelled by incubation with (–)‐[3H]‐noradrenaline and [14C]‐tyrosine. The output/pulse of newly synthesized [14C]‐noradrenaline remained constant as the train length was increased whilst the output/pulse of [3H]‐noradrenaline increased under the same conditions. This phenomenon was independent of the stimulus frequency. Newly synthesized noradrenaline also appeared in the superfusate following nerve stimulation more rapidly than exogenously loaded noradrenaline.

Both [3H]‐noradrenaline and [14C]‐tyrosine were found to label an easily releasable store of noradrenaline. Mobilization from this store was the same at low and high frequencies of nerve stimulation.

It is concluded that at least two functional stores of noradrenaline exist within the adrenergic nerve ending. Newly synthesized noradrenaline is probably only a minor constituent of transmitter output under normal conditions of adrenergic nerve activity.

At least two mechanisms control the amount of noradrenaline released per pulse during nerve stimulation. Facilitation of release with increasing train lengths appears to be due to the mobilization of transmitter from a secondary store. Facilitation of release with increasing stimulus frequency is not dependent on mobilization from any particular store and at present there is no satisfactory explanation for this phenomenon.
FORMATION OF A FACTOR INCREASING VASCULAR PERMEABILITY DURING ELECTRICAL STIMULATION OF THE SAPHENOUS NERVE IN RATS
Authors: LEME J. GARCIA , HAMAMURA L.
Published: July 2012

Increased vascular permeability following electric antidromic stimulation of the rat saphenous nerve was observed in the skin area supplied by the nerve, confirming previous results by other authors.

The phenomenon was not affected by pretreatment of the rats with diphenhydramine, burimamide or their combination; atropine, methysergide, methysergide plus diphenhydramine, carboxypeptidase B, acetylsalicylic acid, indomethacin or methiazinic acid. It was partially reduced by previous injection of cellulose‐sulphate, a kininogen‐depleting agent.

Perfusates from the subcutaneous tissue of the paw area supplied by the saphenous nerve contained permeability increasing activity as shown by intradermal tests in other rats. This activity was present in perfusates collected during nerve stimulation but not in those collected before stimulation. It was not destroyed by heating to 100°C, or by α‐chymotrypsin or trypsin.

Bradykinin‐like activity may appear later in the perfusates, depending on the intensity of the stimuli.

It is concluded that following electrical antidromic stimulation of the saphenous nerve a permeability increasing factor is released, possibly from nerves. It is dialysable and can be distinguished from acetylcholine, histamine, 5‐hydroxytryptamine, plasma kinins, substance P, prostaglandins and high molecular weight proteins. The increased vascular permeability induced by this factor leads to plasma exudation and activation of the kinin system.
TRYPTAMINE RECEPTORS IN RAT PULMONARY ARTERY
Authors: BAKHLE Y.S. , SMITH T.W.
Published: July 2012

Tryptamine and 5‐hydroxytryptamine (5‐HT) are equipotent in contracting spiral strips of rat isolated pulmonary artery, in doses between 5 and 20 μg. These 5‐HT receptors are blocked by low concentrations (c. 10−9 M) of both methysergide and morphine. In rat isolated lung perfused via the pulmonary circulation, 5‐HT caused increases in perfusion pressure which were also antagonized by methysergide and by morphine. These vascular 5‐HT receptors cannot therefore be classified as M or D receptors and, furthermore, are different from those 5‐HT receptors mediating release of spasmogens from rat isolated lungs.
THE ACTION OF INDORAMIN AND OTHER COMPOUNDS ON THE UPTAKE OF NEUROTRANSMITTERS INTO RAT CORTICAL SLICES
Authors: SUGDEN R.F.
Published: July 2012

Indoramin has been tested for its ability to inhibit the uptake of tritiated (–)‐noradrenaline and 5‐hydroxytryptamine into rat brain cortical slices. Other α‐blocking agents and tricyclic antidepressants were included for comparison. Activity against noradrenaline uptake is probably not important in the therapeutic action of indoramin. However, inhibition of 5‐hydroxytryptamine uptake may be responsible for the sedation in high dosage noted by some investigators
MYOCARDIAL FAILURE WITH ALTERED RESPONSE TO ADRENALINE IN ENDOTOXIN SHOCK
Authors: ARCHER L.T. , BLACK M.R. , HINSHAW L.B.
Published: July 2012

There is a growing concensus that myocardial performance in the early stages of experimental endotoxic and septic shock is relatively normal; however, recent reports have identified an intermediate phase of shock when myocardial dysfunction is clearly apparent.

The mechanism of dysfunction has become a subject of intense investigation. A current view is that altered myocardial responsiveness to circulating catecholamines may play an important role in the dysfunction observed after endotoxin administration. The present studies, in which an isolated working heart preparation of the dog was used, were designed to test this hypothesis. This particular experimental preparation was selected to provide an adequate interpretation of results; cardiac output, afterload, and concentrations of adrenaline reaching the coronary vascular bed were controlled in all experiments. Responses to infusions of adrenaline were recorded in the ‘steady‐state’ condition. Control (non‐shocked) heart responses to adrenaline were highly reproducible in terms of inotropic, chronotropic and coronary vascular behaviour.

Results from the study document myocardial dysfunction within 4–6 h following an LD70 endotoxin administration on the basis of increased left ventricular end diastolic pressure (LVEDP), decreased cardiac power and myocardial efficiency, and depressed negative and positive dP/dt parameters.

Findings suggest significantly altered responsiveness of the myocardium to infused adrenaline at rates of 1, 2, and 5 μg/min with concentrations between 10 and 1 ng/ml blood. LVEDP was elevated while calculated power and efficiency parameters remained significantly below control values during infusion of adrenaline in endotoxin‐treated hearts. Depressions of responsiveness were interpreted to occur on the basis of failure to restore positive and negative dP/dt to normal values and depressed coronary blood flow responses during adrenaline administration. Increases in coronary flow were regularly less in experimental hearts than the controls. Heart rate responses to adrenaline in both failing and non‐failing hearts were identical.

In conclusion, it is suggested that myocardial contractile and relaxation characteristics and coronary vascular responses to adrenaline infusion are depressed in endotoxin shock during the period of demonstrated myocardial dysfunction. No distinct causal relationships were observed between the altered myocardial responsiveness and pathogenesis of heart dysfunction since myocardial dysfunction and altered responsiveness to adrenaline were generally observed together. Myocardial oedema formation after endotoxin as previously reported by this laboratory may bear a relationship to the depressed negative dP/dt response to adrenaline.
ROLE OF CATECHOLAMINES IN THE CENTRAL MECHANISM OF EMETIC RESPONSE INDUCED BY PERUVOSIDE AND OUABAIN IN CATS
Authors: GAITONDÉ B.B. , JOGLEKAR S.N.
Published: July 2012

Peruvoside, (a glycoside obtained from the plant, Thevetia neriifolia Juss) and ouabain produce emesis in cats. Vomiting is not produced by these drugs in animals pretreated with catecholamine depleting drugs like reserpine, tetrabenazine or syrosingopine. Chloropromazine hydrochloride, mepyramine maleate, or BOL‐148 administered intravenously or intracerebroventricularly do not afford protection.

Phenoxybenzamine produces partial protection against peruvoside‐induced emesis.

Haloperidol (1 mg/kg i.v.) prevents vomiting induced by peruvoside or ouabain. Intracerebroventricularly administered haloperidol is ineffective.

Cats pretreated with SKF‐525‐A, are not protected by haloperidol. Animals pretreated with phenobarbitone in a dose of 25 mg/kg for a week were protected by haloperidol, 250 μg/kg i.e. one quarter of the effective antiemetic dose in normal cats.

It is postulated that catecholamines are involved in the mechanism of vomiting induced by cardiac gycosides. Further, a metabolite of haloperidol seems to be responsible for its effective antiemetic action.
HYPERGLYCAEMIA PRODUCED BY DRUGS WITH ANALGESIC PROPERTIES INTRODUCED INTO THE CEREBRAL VENTRICLES OF CATS
Authors: DEY P.K. , FELDBERG W.
Published: July 2012

The effects on blood glucose of four substances with analgesic properties (apomorphine, pethidine, codeine and etorphine) and of prostaglandin E1 were examined in unanaesthetized cats. They were applied by the intraventricular route being either injected into a lateral ventricle or infused into the fourth ventricle through implanted Collison cannulae.

Apomorphine gave rise to pronounced hyperglycaemia in a dose of 0.75 mg which produced scarcely any hyperglycaemia on intravenous injection. It was more effective on infusion into the fourth ventricle than on injection into a lateral ventricle and was approximately half as potent as morphine in provoking hyperglycaemia.

Codeine produced no hyperglycaemia in doses of 0.75 and 1.5 mg.

Pethidine had a weak hyperglycaemic action in doses of 0.75 and 1.5 mg, but the effect was not regularly obtained. Potency of the drug was at most only a third to a sixth that of morphine.

Etorphine produced strong hyperglycaemia on infusion into the fourth ventricle in a dose of 10 μg. Unlike apomorphine or morphine it was more potent on injection into a lateral ventricle when it produced a strong hyperglycaemic response in doses of 5 or 1 μg, which were subthreshold on infusion into the fourth ventricle. However, this response may have been brought about indirectly as a result of severe asphyxia and of convulsions associated with the injections. On infusion into the fourth ventricle, etorphine was about 75 times as potent as morphine in producing hyperglycaemia.

Prostaglandin E1 had no hyperglycaemic action when infused into the fourth ventricle in a dose of 400 ng.
ALTERNATIVE APPROACHES TO ANALGESIA: BACLOFEN AS A MODEL COMPOUND
Authors: CUTTING D.A. , JORDAN C.C.
Published: July 2012

It is suggested that analgesia could be produced by drug action at the spinal level through (a) interference with neurotransmission at primary afferent terminals; (b) enhancement of the ‘gate control’ of the sensory input to the spinal cord mediated through descending spinal tracts; or (c) increased presynaptic inhibition of primary afferents by a direct action.

Baclofen (9.4–70.3 μmol/kg, i.p.), which may mimic spinal presynaptic inhibition, produced a dose‐dependent increase in the response times of mice in a hot‐plate test, but high doses also impaired motor function.

Morphine hydrochloride (5.3–40 μmol/kg, i.p.) increased the response time of mice in the hot‐plate test and had little effect on motor function.

Combination of baclofen (9.4 or 23.4 μmol/kg) with morphine (13.3 μmol/kg) produced greater increases in response time than either drug administered alone but with little concurrent effect on motor function.

The possibility that baclofen may have some analgesic action and a potentiating effect on other analgesics is discussed.
CHARACTERIZATION OF AN INHIBITORY RECEPTOR IN RAT HIPPOCAMPUS: A MICROIONTOPHORETIC STUDY USING CON‐FORMATIONALLY RESTRICTED AMINO ACID ANALOGUES
Authors: SEGAL M. , SIMS K. , SMISSMAN E.
Published: July 2012

Pyramidal cells in rat hippocampus were used to study the molecular dimensions of a receptor for inhibitory amino acids in the central nervous system. The inhibitory potencies of γ‐aminobutyrate (GABA), β‐alanine and glycine were compared by standard microiontophoretic techniques. Subsequently, rigid cyclopentane and cyclohexane amino acid analogues were applied by iontophoresis and their relative efficacies were compared with those of the naturally occurring amino acids.

GABA was the most effective of the small aliphatic amino acids in producing inhibition of the firing of hippocampal pyramidal neurones. β‐Alanine was less effective and glycine was the least effective. GABA‐induced inhibition was antagonized by concurrent iontophoresis of picrotoxin or bicuculline, whereas strychnine did not antagonize GABA inhibition.

The ability of the series of substituted aminocyclopentane and aminocyclohexane carboxylic acids to produce inhibition of pyramidal cells was a direct function of the separation of amino and carboxylic acid groups. In both series of the cyclic amino acids the most potent inhibition was demonstrated when the spatial separation was similar to that of the extended GABA molecule (4.74 Å). Additionally, the inhibition of hippocampal pyramidal cells by (±)‐cis‐3‐amino‐cyclopentanecarboxylic acid, like that produced by GABA, could be blocked by simultaneous application of picrotoxin or bicuculline, but not by strychnine.

The present results suggest that the physiologically active conformation of GABA is the fully extended molecule, and additionally indicate that one dimension of the postsynaptic receptor site is within the range of 4.2 to 4.8 ångströms.
THE EFFECTS OF ADENOSINE TRIPHOSPHATE AND ADENOSINE DIPHOSPHATE ON TRANSMISSION AT THE RAT AND FROG NEUROMUSCULAR JUNCTIONS
Authors: RIBEIRO J.A. , WALKER J.
Published: July 2012

The effects of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) were investigated on evoked end‐plate potentials (e.p.ps) and on miniature end‐plate potentials (min. e.p.ps) recorded from muscle fibres of the rat diaphragm and the frog sartorius.

ATP and ADP decreased the quantum content of the e.p.ps and the frequency of the min. e.p.ps. The maximum effects produced by the two substances were similar.

The potency of ATP was found to be similar to that of adenosine. In the presence of adenosine, in a concentration producing its maximum effect, the addition of ATP had no further effect. This is compatible with the idea that ATP acts in the same way as adenosine.
ATYPICAL TRYPTAMINE RECEPTORS IN SHEEP PULMONARY VEIN
Authors: EYRE P.
Published: July 2012

Both the pulmonary artery and vein of the sheep contracted dose‐dependently to histamine, carbamoylcholine, prostaglandin F2α, noradrenaline and bradykinin and relaxed in the presence of isoprenaline or prostaglandin E1.

The effect of 5‐hydroxytryptamine (5‐HT) on the artery was consistently to produce dose‐dependent contractions without tachyphylaxis. The effect on the vein was biphasic. 5‐HT 5 × 10−10 to 5 × 10−8 M relaxed the partially constricted vein. 5‐HT 10−7 to 10−6 M caused brief venoconstriction followed by relaxation. 5‐HT > 10−6 M caused dose‐related contraction of the vein.

Methysergide effectively blocked the contractile response of the artery to 5‐HT, but only weakly inhibited the contractions of the vein (dose‐ratio <20).

Each of ten antagonists tested failed to inhibit the 5‐HT‐induced relaxation of the vein. Sheep pulmonary vein possesses tryptamine receptors which mediate relaxation and which are not of the classical M‐ or D‐type. These receptors appear not to be involved directly or indirectly with responses to acetylcholine, catecholamines, histamine or prostaglandins.