bluuebunny/crossref_metadata_2025 huggingface dataset:
β‐Adrenoceptor antagonist activity of 3‐methoxyisoprenaline
Authors: BASSETT J. R.
Published: July 2012

The β‐adrenoceptor antagonist activity of 3‐methoxyisoprenaline, the O‐methylated metabolite of isoprenaline, was studied on isolated driven atrial strip and tracheal chain preparations of the guinea‐pig and on the hind limb blood flow of the dog.

On both the atrial strip and tracheal chain preparations the blockade of responses to isoprenaline fulfilled the criteria for simple competitive inhibition.

3‐Methoxyisoprenaline decreased the vasodilator response to isoprenaline in the dog hind limb, but did not affect the response to noradrenaline.

3‐Methoxyisoprenaline had about 1/3,700 of the potency of propranolol as a β‐adrenoceptor antagonist on the tracheal chain preparation, 1/1,000 on the atrial strip preparation and less than 1/400 on the hind limb blood flow.

The antagonist activity of 3‐methoxyisoprenaline showed a slight specificity for cardiac β‐adrenoceptors, being 4.3 times more active on guinea‐pig atria than on trachea.

Although 3‐methoxyisoprenaline antagonized the actions of isoprenaline in the three preparations, its activity was extremely weak. It is unlikely that the formation of 3‐methoxyisoprenaline from isoprenaline, administered therapeutically, could lead to β‐adrenoceptor blockade.
Cardiovascular effects of toxins isolated from the cnidarian Chironex fleckeri Southcott
Authors: FREEMAN SHIRLEY E. , TURNER R. J.
Published: July 2012

Two unstable high molecular weight toxins have been isolated from tentacles of Chironex fleckeri by exclusion chromatography. Both are cardiotoxic; the lower molecular weight fraction is also a potent haemolysin.

Both toxins reduce the rate, amplitude of contraction and coronary flow in the isolated, perfused guinea‐pig heart. Relative to the mouse lethal dose the haemolytic fraction is less potent in this preparation than the purely cardiotoxic fraction.

Both toxins cause a rise in arterial pressure in anaesthetized rats and rabbits by a direct action on the vascular musculature. This is followed by hypotension, bradycardia and cardiac irregularity. An increase in respiratory rate is followed by apnoea of variable duration, which is associated with a rise in arterial pressure. Animals frequently show arterial pressure oscillations with periods of apnoea interspersed with hyperpnoea.

The carotid occlusion reflex is depressed during hypotensive periods after both toxins, although (–)‐noradrenaline can still elicit a marked pressor response. Bilateral cervical vagotomy has but little effect on the response to either toxin. save to prevent hyperpnoea, but radical denervation of sinoaortic afferents reduces the arterial pressure fall after the initial hypertensive response, suggesting that this fall is due to a combination of baroreceptor stimulation and a fall in cardiac output. Blood pressure oscillations are still seen, possibly due to central stimulation by hypercapnia.

Interference with the efferent arm of the vasomotor reflex arc with hexamethonium, bretylium or phenoxybenzamine either abolishes or markedly reduces the blood pressure oscillations without affecting the initial hypertensive response.

The cardiovascular effects of the two toxins are thought to be due to direct vasoconstriction, cardiotoxicity, baroreceptor stimulation and possibly depression of the vasomotor centre. The resultant disordering of the feed‐back system regulating vasomotor tone leads to the characteristic arterial pressure oscillations.
The inhibition by dexamethasone and disodium cromoglycate of anaphylactic bronchoconstriction in the rat
Authors: CHURCH M. K. , COLLIER H. O. J. , JAMES G. W. L.
Published: July 2012

. A method for the measurement of anaphylactic bronchoconstriction in the rat is described.

. Dexamethasone inhibited this response in a dose‐related manner.

. Disodium cromoglycate antagonized the response. A bell‐shaped dose‐response curve was obtained with peak activity at 1 mg/kg i.v.

. Meclofenamate was not active when given alone or in combination with dexamethasone.

. Methysergide significantly inhibited the response. Mepyramine, atropine, propranolol and adrenalectomy did not significantly modify the response.

. The relationships of anaphylactic bronchoconstriction in the rat to anaphylactic bronchoconstriction in the guinea‐pig and to human asthma are discussed.
The rat isolated colon as a specific assay organ for angiotensin
Authors: GAGNON D. J. , SIROIS P.
Published: July 2012

. The antagonism of the contractile effects of prostaglandins F2α and E2 by polyphloretin phosphate (PPP) was studied on the rat isolated colon.

. PPP (20 μg/ml) was found to reduce the myotropic action of angiotensin I (10 ng/ml) and II (0·3 ng/ml) whereas larger doses of both agents were not influenced.

. It is concluded that when a mixture of antagonists is used, including PPP, the rat isolated colon can be used to assay angiotensin with accuracy and specificity. The addition of 8‐L‐ala‐ATII affords a further test of specificity.
Release of monoamines from the striatum and hypothalamus: Effect of γ‐hydroxybutyrate
Authors: BUSTOS G. , ROTH R. H.
Published: July 2012

. A simple in vitro system was developed to study the effect of γ‐hydroxybutyrate on nerve cell depolarization‐induced release of labelled dopamine, noradrenaline and 5‐hydroxytryptamine from brain slices.

. The release of 3H‐dopamine formed in rat striatal slices incubated with 3H‐tyrosine was followed either by transferring the slices through successive media or by using a superfusion system. A one to three minute exposure to K+ (53 mm) caused up to a thirty fold increase in the release of newly synthesized 3H‐dopamine. This K+‐induced release was antagonized when γ‐hydroxybutyrate (1 × 10−3m) was present in the medium.

. Potassium (53 mm) increased (eighteen to thirty fold) the release of 3H‐dopamine from striatal slices initially loaded by preincubation with 3H‐dopamine. However, the K+‐induced release of this pool of dopamine was not antagonized by γ‐hydroxybutyrate.

. Potassium (53 mm) also increased the release from striatal slices of 3H‐5‐hydroxytryptamine newly synthesized from 3H‐tryptophan. This K+‐induced release of 5‐hydroxytryptamine was also not inhibited by γ‐hydroxybutyrate.

. The release of newly synthesized 3H‐noradrenaline from hypothalamic slices was also increased by K+. This K+‐induced release, however, unlike that of 5‐hydroxytryptamine, was antagonized when γ‐hydroxybutyrate was present in the superfusion medium.

. Removal of Ca++ had no effect on K+‐induced release of 3H‐dopamine when followed by transferring the slices through successive media. This K+‐induced release was abolished, however, when Mg++ (12 mm) was present in the medium.

. The removal of Ca++ from the superfusion medium abolished almost completely the K+‐induced release from striatal slices of either newly synthesized 3H‐dopamine or preloaded 3H‐dopamine. This is presumably due to a more effective washout of tissue Ca++ by the superfusion technique.

. The ability of γ‐hydroxybutyrate to antagonize the K+‐induced release of monoamines from brain slices does not appear to be unique to the release of newly synthesized dopamine from the striatum.
Monoamine mediation of the morphine‐induced activation of mice
Authors: CARROLL BERNARD J. , SHARP PETER T.
Published: July 2012

. The dose‐response relationship for hyperactivity in grouped mice following the injection of morphine sulphate has been established.

. The activation response can be modified by drugs which affect either catecholamines or indoleamines.

. The monoamine precursors l‐DOPA and 5‐hydroxytryptophan potentiate the response.

. The monoamine synthesis inhibitors α‐methyl‐p‐tyrosine and p‐chlorophenylalanine reduce the response.

. Inhibition of monoamine oxidase activity by pargyline caused a great increase in the response. The simultaneous administration of reserpine resulted in a further potentiation.

. Reserpine blocked the response whenever it was given alone, either before, with or after the injection of morphine.

. Blockade of α‐adrenoceptors with phentolamine or phenoxybenzamine reduced the response.

. Blockade of tryptaminergic receptors with methysergide or cinanserin also antagonized the response.

. The major tranquillizers haloperidol and chlorpromazine reduced the response. Haloperidol was especially effective in this regard.

. The tricyclic antidepressant drug imipramine potentiated the response.

. The morphine antagonist nalorphine completely prevented the response.

. The anticholinergic agent atropine and the antihistaminic drug mepyramine did not affect the response.

. We conclude that dopamine, noradrenaline and 5‐hydroxytryptamine are all involved in the normal activation response of grouped mice to morphine, with dopaminergic mechanisms being of primary importance.
Antagonism of noradrenaline and histamine by desipramine in the isolated artery of the rabbit ear
Authors: McCULLOCH M. W. , STORY D. F.
Published: July 2012

. The effects of desipramine (DMI) were examined on the vasoconstrictor responses of the isolated perfused artery of the rabbit ear to noradrenaline (NA) and to histamine. Innervated and sympathetically denervated arteries were used.

. In innervated arteries, DMI in concentrations of 1 × 10−8 to 1 × 10−7m enhanced the responses to NA; higher concentrations reduced the responses. In sympathetically denervated arteries, DMI caused only reduction of the responses to NA.

. Responses to histamine were reduced by DMI in both innervated and denervated arteries. DMI was considerably more potent as an antagonist of histamine than of noradrenaline.

. The reduction by DMI of the responses to NA and histamine in both innervated and denervated arteries was associated with a parallel shift to the right of the concentration‐response curves of the agonist and a depression of the maximal response. These effects of DMI were reversible.

. Analysis of the data by the method of Arunlakshana & Schild (1959) showed the following: the antagonism of the action of NA by DMI on denervated arteries fulfilled the requirements for competitive antagonism; antagonism of the action of NA on innervated arteries was not competitive; antagonism of the actions of histamine on innervated and denervated arteries was not competitive.

. It is suggested that DMI antagonizes the action of NA and histamine on the perfused artery of the rabbit ear in two ways: (i) reversible specific antagonism which is competitive for NA and not competitive for histamine; (ii) reversible non‐specific antagonism which is non‐competitive for both agonists.
Activation of arginine and tyrosine esterase in serum from patients with hereditary angio‐oedema
Authors: EISEN V. , LOVEDAY C.
Published: July 2012

. The role of clotting factor XII in the activation of the complement subunit C1s to C1 esterase was examined.

. In sera from patients with hereditary angio‐oedema who lack the α2‐glycoglobulin C1 inhibitor, silicates and other potent activators of clotting factor XII induced far less C1 esterase activity than did the weaker factor XII activators, carrageenin and cellulose sulphate. In contrast, the intensity of the induced plasma kallikrein activity corresponded more closely to the clot‐promoting effect of the factor XII activators.

. Spontaneous generation of C1 esterase activity was only slightly delayed in hereditary angio‐oedema sera previously depleted of factor XII. In normal sera, C1 esterase did not develop spontaneously and could not be induced.

. Experiments with inhibitors suggested that the spontaneous activation of Cls may consist of two phases: factor XII and other plasma proteases first activate small amounts of C1s; the resulting C1 esterase then activates the bulk of C1s. The observed spontaneous activation suggests that when fully activated, the C1s present in 1 ml of human serum will hydrolyse 1–2 μmol of ATEe/minute.
Time‐dose relationships for locomotor activity effects of morphine after acute or repeated treatment
Authors: BABBINI M. , DAVIS W. M.
Published: July 2012

. Effects of morphine sulphate (1·25, 2·5, 5, 10, 20 and 40 mg/kg i.p.) on locomotor activity of male rats were observed for 8 h after single doses in non‐tolerant rats. The lower three doses had only an excitatory effect, whereas the higher three doses caused initial depression followed by a delayed excitatory effect.

. The same doses of morphine were administered daily for 30 days. No tolerance developed within this time to the excitatory effect. The locomotor excitatory effect of the higher three doses of morphine became progressively more pronounced over treatment periods of 30 days (and 48 days for 20 mg/kg), while the latency to peak activity decreased.

. An explanation of these results is suggested on the basis of two different central drug‐receptor interactions affecting motility.
The effects of isoprenaline and noradrenaline on pentagastrin‐stimulated gastric acid secretion and mucosal blood flow in the dog
Authors: CURWAIN B. P. , HOLTON PAMELA
Published: July 2012

. Isoprenaline (0·02 to 2·0 μg kg−1 min−1) inhibited gastric secretion in response to pentagastrin in both conscious and anaesthetized dogs and in response to feeding in conscious dogs.

. The inhibition was unaffected during cardiac β‐adrenoceptor blockade by propranolol.

. The inhibition was not due to decreased mucosal blood flow.

. This effect of isoprenaline is different from its effect on histamine‐induced gastric secretion.

. Noradrenaline (0·05–2·0 μg kg−1 min−1) also decreased gastric secretion but it was less effective than isoprenaline.

. The mechanism of action of noradrenaline is probably a decrease in mucosal blood flow.
Factors affecting the extraneuronal inactivation of noradrenaline in cardiac and smooth muscle
Authors: BURNSTOCK G. , McCULLOCH M. W. , STORY D. F. , WRIGHT M. E.
Published: July 2012

. The relation between density of adrenergic innervation, noradrenaline (NA) accumulation (as seen with the fluorescence histochemical method) in tissues incubated in a high concentration of NA, and monoamine oxidase (MAO) and catechol‐O‐methyl transferase (COMT) activities, were examined in a wide range of tissues from different species.

. Evidence was obtained to support the proposal that accumulation of NA in the non‐innervated smooth muscle of the human umbilical artery and chick amnion is associated with very low activities of COMT within muscle cells.

. The wide variation in tissue accumulation of NA in adrenergically innervated muscles was confirmed. For example, in the rabbit atrium and rat vas deferens, there was high NA accumulation in vascular smooth muscle but not in other muscle cells. In the mouse vas deferens there appeared to be preferential NA accumulation in the outer longitudinal muscle in comparison with the circular muscle. In the ventricle of the rat and mouse individual muscle cells showed different degrees of accumulation of NA. Many unidentified fluorescent cells were revealed in the submucosa of the guinea‐pig ureter following loading with NA. The highest activities of COMT were found in the rat vas deferens and the lowest in the rabbit vascular tissues; the highest activity of MAO was found in the guinea‐pig ileum, and the lowest in the rat aorta.

. No simple relation between tissue activities of MAO and COMT and degree of NA accumulation was found. Possible directions for further investigation of the problem are discussed.
A comparison of the affinities of antagonists for acetylcholine receptors in the ileum, bronchial muscle and iris of the guinea‐pig
Authors: BARLOW R. B. , FRANKS FIONA M. , PEARSON J. D. M. , BUTT ALISON A.
Published: July 2012

. Isolated preparations of bronchial strip and of intact iris from the guinea‐pig have been adapted for the measurement of affinity constants of substances which block post‐ganglionic acetylcholine receptors.

. The affinity constants of 28 compounds on bronchial muscle and of 8 compounds on the iris have been compared with values measured on the guinea‐pig ileum.

. Although the compounds differed up to a million‐fold in affinity, most of the estimates of log affinity constant for the bronchial muscle and iris differed only slightly from those on the ileum.

. Some of the differences could be attributed to the actions of hexamethonium, used in the tests on the ileum but not, initially, in the tests with the bronchial strip and iris. Hexamethonium reduced most of the estimates of log K for the receptors in the bronchial strip by a variable but significant amount, which could be due, at least in part, to a weak post‐ganglionic blocking (atropine‐like) action. On average, hexamethonium had little effect on the estimates made with the ileum, appreciably decreasing estimates with some compounds and increasing those with others.

. The results indicate that, although there may be differences between the acetylcholine receptors in the three types of tissue, there is no conclusive evidence, because the differences in affinity which we have observed could have arisen from differences in the experimental conditions. This is illustrated by results obtained with the guinea‐pig ileum recorded with the same technique as was used for the bronchial strip, which are presented as an appendix.

. Such differences as may exist between these three types of acetylcholine receptor are likely to be limited to the replacement of one aminoacid in the receptor protein by a homologue.
Supersensitivity of salivation in response to pilocarpine after withdrawal of chronically administered hyoscine in the mouse
Authors: PARKES M. W. , PARKS JENNIFER C.
Published: July 2012

. The duration of the effect of a single large dose of hyoscine, in reducing the salivary response of mice to pilocarpine, was established as less than 66 hours.

. Supersensitivity was observed, after daily oral dosing with hyoscine, in the increased salivation of mice in response to pilocarpine injected at least 66 h after withdrawing hyoscine.

. The minimum duration of pretreatment with hyoscine that resulted in supersensitivity was 5 days. The daily dose was more effective if divided.

. The period after withdrawal for which supersensitivity could be detected was 6 days.

. The maximum salivary response to pilocarpine was increased by chronic hyoscine pretreatment.

. The antagonism of a single dose of hyoscine to pilocarpine salivation, as expressed by the dose‐ratio of pilocarpine, was not altered by chronic hyoscine pre‐treatment.
A myotoxin secreted by some piscivorous Conus species
Authors: FREEMAN SHIRLEY E. , TURNER R. J.
Published: July 2012

. Toxins isolated from the venom apparatus of Conus magus and Conus achatinus have the same pharmacological properties, but differ from the toxins of several other piscivorous species of cone shells.

. C. magus and C. achatinus toxins are heat labile at pH 8·5. A single lethal component with an approximate molecular weight of 10,000 was isolated from C. achatinus toxin by exclusion chromatography.

. Animals died from a characteristic spastic paralysis after intravenous injection of the toxin.

. Nerve transmission was unaffected by the toxin; skeletal muscle appeared to be the primary site of action. The toxin caused a persistent contracture of rat diaphragm muscle, and a dose‐dependent decline in twitch tension. The contracture was potentiated by caffeine.

. The decline in twitch tension was associated with depolarization of the cell membrane. Action potential height and the maximum rate of rise declined, and spike propagation failed when the resting potential had declined to approximately 60 mV. The muscle recovered very slowly on washout of the toxin. The depolarization could be reversed by exposure of the preparation to 5 mm Na+ solution or tetrodotoxin or saxitoxin.

. Miniature end‐plate potential frequency in the rat diaphragm decreased, as did the quantal content of the end‐plate potential. The acetylcholine‐induced contraction and depolarization of the chronically denervated rat diaphragm were increased by low doses of toxin and reduced by higher, depolarizing toxin doses. The K+‐induced contraction and depolarization of innervated diaphragm were similarly affected by the toxin.

. Cardiac and smooth muscle were relatively resistant to the toxin. The isotonic contraction of the isolated perfused guinea‐pig heart was increased by the toxins from both Conidae. The heart rate decreased. Guinea‐pig atrial cells showed a small decrease in action potential height and maximum rate of rise. Rabbit sino‐atrial cells showed increases in action potential height, maximum diastolic potential and maximum rate of rise of the spike at low toxin levels, and no change in any of these parameters at high levels. There was a decrease in the rate of the spontaneously beating atrium. Atrioventricular nodal potentials showed no change other than a slight increase in the maximum rate of rise of the action potential.

. It is postulated that the action of the toxin may be related to a change in the Ca++ permeability of the excitable membrane, which makes it unstable, leading to a secondary, depolarizing entry of Na+. The effects of the toxin are compared with those of batrachotoxin, which it somewhat resembles.
Effects of catecholamines and adenosine derivatives given into the brain of fowls
Authors: MARLEY E. , NISTICO G.
Published: July 2012

. Adult fowls (Gallus domesticus) with cannulae chronically implanted into the IIIrd cerebral ventricle and various other sites of the brain received micro‐infusions or injections of catecholamines, adenosine, 3′,5′‐cyclic AMP or its dibutyryl derivative. The effects of these substances on behaviour, electrocortical activity and body temperature were studied.

. Behavioural and electrocortical sleep with fall in body temperature were obtained with intraventricular noradrenaline, α‐methylnoradrenaline and isoprenaline; dopamine was ineffective. The doses required to elicit sleep were smaller than those affecting body temperature. Following mebanazine, the effects of noradrenaline were prolonged and doses of dopamine, previously ineffective, lowered body temperature and induced behavioural and electrocortical sleep.

. Noradrenaline, α‐methylnoradrenaline, isoprenaline and dopamine infused into the hypothalamus induced sleep and lowered body temperature. Effective doses of noradrenaline, α‐methylnoradrenaline and isoprenaline infused into the hypothalamus were one‐twentieth to one‐fifth those for intraventricular injection. Tachypnoea developed with isoprenaline and dopamine. Additionally with dopamine, there was deviation of the head to the contralateral side, together with repetitive jerking movements of the head. These effects were prolonged and intensified by mebanazine, whereas the involuntary movements with dopamine were greatly reduced by haloperidol.

. Involuntary movements, but without sleep, were induced by infusing dopamine into the paleostriatum augmentatum; noradrenaline infused into this site was ineffective.

. In three of five fowls pretreated with aminophylline, 3′,5′‐cyclic AMP infused into the hypothalamus induced behavioural and electrocortical sleep; without aminophylline pretreatment, 3′,5′‐cyclic AMP was ineffective. Adenosine infused into the hypothalamus, following pretreatment of fowls with aminophylline, consistently induced behavioural and electrocortical sleep. Dibutyryl cyclic AMP infused into the hypothalamus of intact fowls elicited behavioural arousal, followed by bursts of electrocortical spikes (6 Hz) over both cerebral hemispheres, spikes subsequently becoming regular at 1 Hz. Clonic limb and body movements occasionally accompanied the bursts of spike activity, infrequently developing into convulsions. In fowl encéphale isolé preparations, in which dibutyryl cyclic AMP was infused into the hypothalamus, spike activity was confined to the ipsilateral hemisphere.
Output of prostaglandins from the rabbit kidney, its increase on renal nerve stimulation and its inhibition by indomethacin
Authors: DAVIS HEATHER A. , HORTON E. W.
Published: July 2012

. In each of six experiments, prostaglandins were identified in the renal venous blood of the rabbit. The concentrations in renal venous blood were up to 45 times higher than in aortic blood, suggesting that most of the prostaglandins originate from the kidney.

. Prostaglandins E2, F2α and a prostaglandin of the A, C or B series were estimated by biological assay after solvent partition and column or thin‐layer chromatography.

. Prostaglandins E2 and F2α were identified conclusively by combined gas chromatography‐mass spectrometry.

. Electrical stimulation of the renal nerve increased the output of prostaglandins.

. Indomethacin (10 mg/kg) injected intravenously, reduced the output of prostaglandins into renal venous blood and prevented the increase in output on renal nerve stimulation.
Effects of brocresine (NSD‐1055) and cycloheximide on amino acid decarboxylase activities in gastric mucosa of normal and vagally denervated rats
Authors: HÅKANSON R. , LIEDBERG G.
Published: July 2012

. Histidine decarboxylase activity of rat stomach fluctuates depending upon the functional state of the stomach. This varying enzyme activity poses special problems in assessing the effectiveness of enzyme inhibitors. After vagal denervation gastric histidine decarboxylase is markedly activated and remains at a high, stable level, which is unaffected by the functional state of the stomach. Thus it appears that vagally denervated rats are well suited for studies on histidine decarboxylase inhibitors.

. In vivo, brocresine (NSD‐1055) was found to be a more effective inhibitor of gastric DOPA decarboxylase than of gastric histidine decarboxylase. With the fairly high dose given (200 mg/kg) the inhibition of histidine decarboxylase was at most 75–85% and quite short‐lasting. The DOPA decarboxylase activity, which was not affected by vagal denervation, was inhibited more than 95% by brocresine; this inhibition was longer‐lasting.

. Cycloheximide, which probably lowers gastric histidine decarboxylase activity by inhibiting enzyme synthesis, was maximally effective at a dose level as low as 1 mg/kg. Gastric DOPA decarboxylase was not inhibited by cycloheximide. Vagotomized rats and control rats responded similarly.

. Combined treatment of vagally denervated rats with brocresine and cycloheximide resulted in a rapid and persistent reduction of the histidine decarboxylase activity. It is concluded that the failure of brocresine alone to induce a lasting inhibition of histidine decarboxylase is due to continuous, rapid synthesis of new enzyme.

. The calculated half‐life of gastric histidine decarboxylase was 75 min in vagally denervated rats and 45 min in normal fasted rats. The results suggest that the increased enzyme activity after vagal denervation is caused by an increased rate of enzyme synthesis.
Effect of drugs on the synthesis of noradrenaline in guinea‐pig vas deferens
Authors: BOADLE‐BIBER MARGARET C. , ROTH R. H.
Published: July 2012

. Reserpine in vitro (10−5m) caused a profound inhibition (>85%) of the formation of both 14C‐catecholamine (14C‐CA) and 14C‐dihydroxyphenylalanine (14C‐DOPA) (in the presence of the amino acid decarboxylase inhibitor brocresine) from 14C‐tyrosine in guinea‐pig vas deferens. The magnitude of the inhibition was similar for both 14C‐CA and 14C‐DOPA suggesting that the inhibition occurred primarily at the tyrosine hydroxylase step.

. One hour after in vivo treatment with reserpine (1 mg/kg) when tissue stores of noradrenaline (NA) were depleted by 50%, there was a significant inhibition of the formation of 14C‐DOPA. Twenty‐four hours after such treatment, when endogenous NA could no longer be detected, synthesis of 14C‐DOPA was indistinguishable from untreated controls. However a 45% inhibition of 14C‐DOPA synthesis from 14C‐tyrosine could be produced in tissues which had been depleted of NA for 24 h or 48 h by the addition of reserpine, 10−5m, to the incubation medium.

. Addition of pteridine cofactor, 2‐amino‐6,7,‐dimethyl‐4‐hydroxy‐5,6,7,8‐tetrahydropteridine, to the incubation medium in a concentration of 5 × 10−3m enhanced the formation of both 14C‐CA and 14C‐DOPA from 14C‐tyrosine in guinea‐pig vas deferens. In 52 mm KCl Krebs‐Henseleit medium 14C‐CA formation increased from 2·58 ± 0·20 (nmol/g)/h to 6·35 ± 0·47 (nmol/g)/h whilst 14C‐DOPA formation increased from 5·04 ± 0·88 (nmol/g)/h to 11·29 ± 0·59 (nmol/g)/h.

. Pteridine cofactor (5 × 10−3m) did not reverse the inhibition of 14C‐DOPA formation seen with reserpine (10−5m) in previously untreated tissues or in vasa deferentia from animals pretreated with reserpine 1 mg/kg for 24 hours. However, the inhibition did disappear in the presence of pteridine cofactor when treatment with reserpine was prolonged to 48 h and included two doses of reserpine of 2 mg/kg.

. Tyramine (5·8 × 10−5m) and bretylium (10−5m) in vitro inhibited the formation of 14C‐CA and 14C‐DOPA from 14C‐tyrosine to the same extent in guinea‐pig vas deferens again indicating that their major site of action is on tyrosine hydroxylase. The inhibitory effects were reversed by pteridine cofactor.

. Synthesis of 14C‐NA from 14C‐tyrosine in calf splenic nerve was not increased by incubating the tissue in 52 mm KCl‐Krebs‐Henseleit solution.
The effect of phospholipids on anaphylactic histamine release
Authors: MONGAR J. L. , SVEC P.
Published: July 2012

. Histamine release by antigen from three sensitized rat tissues is potentiated by phosphatidyl serine (PS). The effect is greatest with isolated peritoneal cells. Phosphatidyl inositol, ethanolamine, choline and phosphatidic acid are inactive.

. PS greatly increases the rate of antigen‐induced histamine release and only slightly prolongs the duration of the release process.

. PS shows a concentration‐dependent effect over the range 1–10 μg/ml. At 10 μg/ml it is active over a wide range of antigen concentrations.

. Calcium ions are necessary for the potentiation by PS of antigen‐induced histamine release from rat peritoneal cells.
The pharmacology of the rat ureter in vivo
Authors: ANCILL R. J. , JACKSON D. M. , REDFERN P. H.
Published: July 2012

A method of recording the peristaltic frequency and the rate of transport of fluid (perfusion rate) in the rat ureter in vivo is described.

Acetylcholine and atropine did not alter ureteral activity. Histamine increased the rate of peristalsis by up to 15% and the rate of perfusion by up to 10%. Low doses of 5‐hydroxytryptamine increased peristaltic frequency whereas high doses decreased peristaltic frequency; all doses reduced the rate of perfusion.

Morphine reduced the rate of perfusion by 5–10% at all dose levels, but only the highest dose used reduced the frequency of ureteral peristalsis.

(—)‐Adrenaline, (—)‐noradrenaline and (±)‐isoprenaline reduced the frequency of peristalsis. The order of potency was isoprenaline>noradrenaline>adrenaline. The response was dose‐related and blocked by propranolol, which itself did not affect ureteral activity.
Effect of tetracyclines and 4‐epiderivatives on the ureter
Authors: ARRIGONI E. , BENZI G. , FERRARA A.
Published: July 2012

The effect of tetracyclines on the isolated dog ureter is dependent on: (a) the tetracyclines used—mepicycline and doxycycline antagonizing, and tetracycline and rolitetracycline increasing the contractor action of barium chloride; (b) the percentage of 4‐epiderivatives in the tetracyclines used—the higher the epiderivative concentration, the smaller the effect of mepicycline or doxycycline, and the greater the action of tetracycline or rolitetracycline.

In vivo the addition of the antibiotics into the renal pelvis shows no significant differences between the various tetracyclines or different 4‐epiderivative concentrations on the intra‐ureteral flow of the dog or guinea‐pig.

Intravenous injection of mepicycline or doxycycline does not induce a significant change in the intra‐ureteral flow, while intravenous administration of tetracycline or rolitetracycline produces a triphasic response: (a) a marked decrease of the intra‐ureteral flow for a few minutes; (b) a return to the control condition for 30–60 min; and (c) a lesser but persistent decrease in flow for 60–120 minutes. In the first phase the ureteral smooth muscle is directly affected by the antibiotics circulating in the blood, while in the third phase the tetracyclines act via the intra‐ureteral mucosa.

Neurogenic effects on the ureter‐bladder junction in vivo are not affected by the tetracyclines tested.
Sotalol for the protection of turkeys from the development of β‐aminopropionitrile‐induced aortic ruptures
Authors: SIMPSON CHARLES F.
Published: July 2012

The influence of feeding 2 levels of sotalol on the incidence of β‐aminopropionitrile (BAPN)‐induced aortic ruptures of immature turkeys was determined.

Four of 22 turkeys fed 0·12% sotalol and 0·07% BAPN died of aortic ruptures, but 6 of 21 turkeys fed only BAPN died of the syndrome.

Blood pressure, heart rate, aortic tensile strength, and aortic structure as seen by light‐ and electron‐microscope were similar in turkeys fed BAPN alone or both BAPN and 0·12% sotalol concurrently.

In a second experiment, 13 of 24 turkeys fed 0·7% BAPN alone died of aortic ruptures, but only 2 of 24 turkeys fed BAPN and 0·2% sotalol concurrently died of the disease.

Aortic tensile strength was lower, heart rate was faster, alterations of aortic elastic fibres as seen by light‐ and electron‐microscope were more severe, and aortic salt soluble collagen with a higher amino acid content was increased in turkeys fed only BAPN, as compared to turkeys fed both BAPN and 0·2% sotalol.
A neuronal basis for the alerting action of (+)‐amphetamine
Authors: BOAKES R. J. , BRADLEY P. B. , CANDY J. M.
Published: July 2012

(+)‐Amphetamine mimicked the excitatory and inhibitory actions of (—)‐noradrenaline on single neurones in the brain stem of acute halothane‐anaesthetized rats when these compounds were applied by iontophoresis. (+)‐Amphetamine had no actions on neurones unaffected by (—)‐noradrenaline.

These mimicking actions of (+)‐amphetamine could not be observed 20 h after treatment of the animals with reserpine 5 mg/kg.

The enzyme inhibitors α‐methyl‐p‐tyrosine and FLA 63 also greatly reduced the number of (—)‐noradrenaline‐mimicking responses to (+)‐amphetamine.

In animals pretreated with α‐methyl‐p‐tyrosine, but not in those pretreated with FLA 63, excitatory actions of (+)‐amphetamine on neurones excited by (—)‐noradrenaline could be elicited 45–90 min after systemic injection of l‐DOPA.

These results indicate that (+)‐amphetamine can release noradrenaline from presynaptic sites in the brain stem, which may be a basis for its alerting actions.
The rat anococcygeus muscle and its response to nerve stimulation and to some drugs
Authors: GILLESPIE J. S.
Published: July 2012

A new smooth muscle preparation, the rat anococcygeus muscle, is described. The muscle is paired, thin, consists of smooth muscle only and the muscle cells are organized in parallel bundles. It has a dense adrenergic innervation distributed throughout the muscle but apparently no cholinergic innervation. The muscles are easily isolated.

The muscle contracts to noradrenaline, acetylcholine, furmethide, 5‐hydroxytryptamine, but not to histamine. Isoprenaline produces contraction at high concentrations. The effects of noradrenaline and acetylcholine are blocked by phentolamine and atropine respectively. The response to isoprenaline is little affected by propranolol.

The muscle contracts in response to field stimulation or stimulation of extrinsic nerves. This response is completely blocked by phentolamine but unaffected by hexamethonium or atropine.

Guanethidine 10−6–5 × 10−6M blocks the motor response to nerve stimulation and potentiates that to noradrenaline. Higher concentrations of guanethidine raise tone. In the presence of raised tone, field stimulation produces an inhibitory response insensitive to hexamethonium but abolished by tetrodotoxin 2 × 10−7 g/ml. This inhibitory response to stimulation can also be shown after other drugs which raise tone.

The inhibitory response to nerve stimulation is not mimicked by acetylcholine, isoprenaline or ATP, nor blocked by atropine, phentolamine, phenoxybenzamine, propranolol, hexamethonium or lysergic acid diethylamide.
Fibrinolytic activity evoked in the plasma of the normal and adrenalectomized rat by cellulose sulphate
Authors: ROSA A. T. , ROTHSCHILD A. M. , ROTHSCHILD Z.
Published: July 2012

Cellulose sulphate, a kinin‐releasing agent, produced fibrinolytic activity in plasma when administered intravenously to the rat but not when added to fresh rat plasma in vitro. The in vivo effect was maximal within 1 min and disappeared within 10–20 minutes. It was retained in plasma taken 1 min after the injection and kept at room temperature for 30 minutes.

A decrease of anti‐fibrinolytic potency measured against urokinase‐activated bovine plasmin, was shown to occur in plasma of rats given cellulose sulphate.

Activated rat plasma lysed heat‐denatured fibrin: it probably contains free plasmin as well as plasminogen activator.

Adrenalectomized rats did not exhibit fibrinolytic activity nor statistically significant benzoyl‐arginine ethyl ester‐esterase activation in plasma after cellulose sulphate treatment.

Adrenalectomized rats had significantly increased levels of plasma kininogen, but were normally sensitive to the kininogen‐depleting action of cellulose sulphate.

The increased plasma kininogen of adrenalectomized rats seems to be a consequence of the impairment of the plasminogen activating mechanism.
The nature of the adrenoceptors in the post‐partum rat uterus
Authors: ABDEL‐AZIZ A. , BAKRY N.
Published: July 2012

Uteri were removed from rats 0·5 h to 8 days after parturition and were suspended in Locke solution at 37° C.

The agonists isoprenaline, adrenaline, noradrenaline and phenylephrine produced an inhibition of the post‐partum rat uterus.

In the presence of propranolol, the agonists noradrenaline, adrenaline, and phenylephrine had an excitatory effect on the post‐partum rat uterus. This excitatory effect was blocked by phenoxybenzamine indicating that it is mediated through α‐adrenoceptors.

These excitatory α‐adrenoceptors could be demonstrated for 5–6 days after parturition. By the 7th‐8th days their existence was no longer apparent.

Excitatory α‐adrenoceptors were also demonstrated in the late pregnant rat uterus.
The effect of Kö 1173, a new anticonvulsant agent on experimental cardiac arrhythmias
Authors: ALLEN J. D. , EKUE J. M. KOFI , SHANKS R. G. , ZAIDI S. A.
Published: July 2012

The effects of the intravenous injection of Kö 1173, a new anticonvulsant drug, phenytoin and procainamide were studied on three types of cardiac arrhythmia in dogs.

Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished by Kö 1173, 0·6 ± 0·1 mg/kg, phenytoin, 1·1 ± 0·3 mg/kg and procainamide, 4·1 ± 1·8 mg/kg.

Ventricular tachycardia was produced in anaesthetized dogs by the intravenous injection of ouabain and the three drugs infused intravenously at 0·2 (mg/kg)/min until sinus rhythm returned. Kö 1173 was effective in 8 out of 9 dogs after a mean dose of 1·3 ± 0·3 mg/kg; phenytoin in all 3 dogs after 2·7 ± 0·6 mg/kg and procainamide in the 3 dogs tested after 16·6 ± 1·3 mg/kg.

The intravenous injection of Kö 1173, 80 mg/kg, greatly reduced the number of ventricular ectopic beats occurring in conscious dogs 18–44 h after ligation of the anterior descending branch of the left coronary artery, with a resultant increase in the number of sinus beats. Phenytoin, 8·0 mg/kg, had a similar effect but procainamide was much less effective.

These results indicate that Kö 1173 is effective in abolishing experimental cardiac arrhythmias and suggest that its effects should be studied in patients.
Factors influencing the adrenergic neurone blocking action of propranolol
Authors: ELIASH SARAH , WEINSTOCK MARTA
Published: July 2012

The reversal by propranolol of its own adrenergic neurone blocking effect in the cat can be prevented by cutting the splanchnic nerves or by ligating the adrenal veins.

In the absence of secretion from the adrenal medulla the nerve blocking action of propranolol is more complete, but can still be reversed by repeated injections or a constant infusion of adrenaline.

Prior treatment with adrenaline or noradrenaline also prevents the development of the blocking action of propranolol in the cat and in the isolated guinea‐pig vas deferens.

It is suggested that in the cat, propranolol stimulates the release of catecholamines from the adrenal medulla which antagonize its nerve blocking effect.
The effect of anti‐inflammatory agents on the changes in local lymph after thermal injury
Authors: BUTLER K. , LEWIS G. P.
Published: July 2012

Lymph was collected directly from the hind limbs of rabbits anaesthetized with pentobarbitone and from unanaesthetized rabbits before and after one hind limb was injured by immersion in water at 60° C for 1 minute.

Rabbits were treated with anti‐inflammatory agents hydrocortisone or indomethacin which, in acute experiments, were infused close‐arterially into the limb either at the time of the injury or 90 min later. In chronic experiments hydrocortisone was given intravenously three times a day.

When given at the time of the injury both drugs reduced the subsequent mean increases in the lymph of the intracellular enzymes lactate dehydrogenase and glutamic pyruvate transaminase but not those of β‐glucuronidase and protein; whereas when given 90 min after the injury only the increase in lymph protein concentration was reduced.

The results indicate that these anti‐inflammatory agents probably inhibit the second phase of increase in vascular permeability which occurs after injury and in addition, reduce the leakage of intracellular protein by a non‐specific effect on membrane permeability.

The pronounced variability of the response of individual animals and the complexity of the experiments preclude the method as a suitable model for the estimation of anti‐inflammatory activity.
Effect of prostaglandins E1, E2 and A2 on vascular resistance and responses to noradrenaline, nerve stimulation and angiotensin in the dog hindlimb
Authors: KADOWITZ PHILIP J.
Published: July 2012

The relationship between the vasodilator and inhibitory effects of prostaglandin E1 (PGE1), E2 and A2 on responses to nerve stimulation, noradrenaline and angiotensin was evaluated in the dog hindlimb preparation.

PGE1 and PGE2 were equipotent as vasodilators in the hindlimb; however, PGE1 was much more potent as an inhibitor of vasoconstrictor responses to nerve stimulation, noradrenaline and angiotensin.

PGA2 and PGE2 were approximately equal as inhibitors of vasoconstrictor responses to noradrenaline, nerve stimulation and angiotensin; however, PGE2 was far more potent as a vasodilator.

Since there is no relationship between the vasodilator and inhibitory effects of PGE1, E2 and A2, and since the inhibitory effect of PGA2 was present at a time when hindlimb perfusion pressure had returned to control value, it is concluded that the inhibitory action is probably not the result of a physiological antagonism.

Since each prostaglandin inhibited responses to nerve stimulation and noradrenaline to approximately the same extent and responses to angiotensin were also inhibited, it is suggested that these agents antagonize vasoconstrictor responses by a nonspecific depressant effect on smooth muscle cells.
The effect of cold storage on the adrenergic mechanisms of intestinal smooth muscle
Authors: HATTORI K. , KURAHASHI K. , MORI J. , SHIBATA S.
Published: July 2012

In the guinea‐pig taenia caecum, fluorescent adrenergic fibres terminate in both muscle layers. The density of these fibres is greater in the taenia than in the underlying circular muscle layer. The myenteric plexus and individual ganglion cells are also densely innervated by intensely fluorescent adrenergic nerve fibres.

After three days of cold storage, the specific fluorescence disappeared from all tissue layers of the taenia caecum and smooth muscle fibres. In contrast, cholinesterase active substances were still demonstrable in all tissue layers even after seven days of cold storage but the density of these substances was decreased.

Cold storage (3–7 days) decreased the tissue noradrenaline content and did not modify the cholinesterase enzyme activity (4 days).

In cold stored strips, the inhibitory response to nicotine, 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) or electrical transmural stimulation was abolished and enhancement of the contractile response occurred. Cold storage also inhibited the inhibitory action of tyramine. Similar results were observed after reserpine treatment.

In fresh taenia, the relaxation produced by nicotine, DMPP and electrical transmural stimulation was inhibited by adrenoceptor blocking agents and bretylium. In cold storage preparations, contraction produced by these stimuli was blocked by parasympathetic blocking agents and potentiated by anticholinesterase. These results indicate that the inhibitory response to these stimulants is mediated by stimulation of the adrenergic nerve system more than by non‐adrenergic nerves; the excitatory effect is probably due to stimulation of cholinergic nerves.

These results suggest that the adrenergic mechanisms of the taenia caecum are more labile in cold storage than the cholinergic mechanisms. Thus, the inhibitory action of cold storage on the relaxation produced by nicotine, DMPP, and transmural stimulation is probably explained by selective physical degeneration of the adrenergic nerve terminal. Also, enhancement of the contractile response to these stimulants in cold stored preparations is explained by the lack of adrenergic inhibitory mechanisms.
The generation from arachidonic acid of rabbit aorta contracting substance (RCS) by a microsomal enzyme preparation which also generates prostaglandins
Authors: GRYGLEWSKI R. , VANE J. R.
Published: July 2012

Sodium arachidonate was incubated with a crude prostaglandin synthetase preparation made from dog spleen. The incubation was made in a dynamic system so that the products could be delivered to strips of rabbit aorta and rat stomach.

A rabbit aorta contracting substance (RCS) and a prostaglandin‐like substance were formed. The RCS had similar properties to that released in anaphylaxis. It was unstable and as the RCS activity declined, so the prostaglandin‐like activity increased. Its formation was prevented by prostaglandin synthetase inhibitors such as indomethacin.

A different rabbit aorta contracting substance was formed by incubation of arachidonate with lipoxygenase, which generates peroxides. This substance was stable and did not lead to prostaglandin production.

We conclude that RCS may be an intermediate in prostaglandin production, such as the postulated cyclic endoperoxide.
The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle
Authors: GODFRAIND T. , LESNE M.
Published: July 2012

The uptake of 3H‐digitoxin, 3H‐ouabain and 3H‐dihydro‐ouabain by isolated guinea‐pig atria has been studied and compared with the inhibition of the sodium pump and with the inotropic effect.

Analysis of the curve relating the uptake of digitoxin and ouabain at equilibrium to the bath concentration enabled a non‐saturable and a saturable binding site to be distinguished.

The uptake of inactive doses of dihydro‐ouabain was only by a non‐saturable mechanism.

The uptake of labelled digitoxin and ouabain was reduced in the presence of another glycoside. The amount of bound glycoside was nearly equivalent to the estimated non‐saturable uptake.

The uptake was reduced at 4° C to the clearance of the non‐saturable site.

ED50 of digitoxin and of ouabain for inhibition of the sodium pump were measured and compared to the ED50 for inotropic effect and to the concentrations producing a half‐saturation of the saturable binding site.

It is concluded that binding to the saturable site may be responsible for the cardiac actions of the glycosides.