bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucocerebrosidase Mutations alter the endoplasmic reticulum and lysosomes in Lewy body disease
Authors: Kurzawa‐Akanbi Marzena , Hanson Peter S , Blain Peter G , Lett Debra J , McKeith Ian G , Chinnery Patrick F , Morris Christopher M
Published: July 2012

J. Neurochem. (2012) 123, 298–309.

Lewy body disease (LBD) development is enhanced by mutations in the GBA gene coding for glucocerebrosidase (GCase). The mechanism of this association is thought to involve an abnormal lysosomal system and we therefore sought to evaluate if lysosomal changes contribute to the pathogenesis of idiopathic LBD. Analysis of post‐mortem frontal cortex tissue from 7 GBA mutation carriers with LBD, 5 GBA mutation carriers with no signs of neurological disease and human neural stem cells exposed to a GCase inhibitor was used to determine how GBA mutation contributes to LBD. GBA mutation carriers demonstrated a significantly reduced level of GCase protein and enzyme activity and retention of glucocerebrosidase isoforms within the endoplasmic reticulum (ER). This was associated with enhanced expression of the lysosomal markers LAMP1 and LAMP2, though the expression of ATP13A2 and Cathepsin D was reduced, along with the decreased activity of Cathepsin D. The ER unfolded protein response (UPR) regulator BiP/GRP78 was reduced by GBA mutation and this was a general phenomenon in LBD. Despite elevation of GRP94 in LBD, individuals with GBA mutations showed reduced GRP94 expression, suggesting an inadequate UPR. Finally, human neural stem cell cultures showed that inhibition of GCase causes acute reduction of BiP, indicating that the UPR is affected by reduced glucocerebrosidase activity. The results indicate that mutation in GBA leads to additional lysosomal abnormalities, enhanced by an impaired UPR, potentially causing α‐synuclein accumulation.
Reduced repression of cytokine signaling ameliorates age‐induced decline in hematopoietic stem cell function
Authors: Norddahl Gudmundur L. , Wahlestedt Martin , Gisler Santiago , Sigvardsson Mikael , Bryder David
Published: July 2012

Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self‐propagation of repopulating‐defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK−/− HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK−/− HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK−/− HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK−/− HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age‐related HSC decline.
Management of a cohesive tropical soil to enhance rootability and increase the efficiency of nitrogen and potassium use
Authors: MOURA E. G. , OLIVEIRA A. K. C. , COUTINHO G. , PINHEIRO K. M. , AGUIAR A. C. F.
Published: July 2012

The efficiency in the use of nitrogen (N) and potassium (K) may be severely limited in soils with high rates of nutrient loss and that also tend to harden and restrict root growth. The choice of legume residues should take into account the nutrient supply and the need for soil improvement. We assessed the capacity of alley cropping systems to enhance root development, increase nutrient uptake and improve the use of N and K in maize. The experiment included six treatments with residues of four perennial Fabaceae: Clitoria + Gliricidia (C + G); Acacia + Gliricidia (A + G); Leucaena +Gliricidia (L + G); Leucaena + Clitoria (L + C); Leucaena + Acacia (L + A) and a control without legumes. We determined chemical and physical indicators, root length density (RLD) and an efficiency index. The results demonstrate the effects of amending soils with N and K with root growth constrained by hard‐setting. The application of combined residues improved the physical properties of hard‐setting soils and increased basic cations in the topsoil. A combination of residues with N and K fertilizer increased the maize yield. The relative efficiency and RLD in the L + A treatments were highest as a result of increased application through the residues containing N and K. The choice of residues for hard‐setting soils should take into account the supply of nutrients as well as the improvement of soil properties.
Evidence for muscarinic receptors in the adrenal medulla of the dog
Authors: KAYAALP S. O. , TÜRKER R. K.
Published: July 2012

The release of catecholamines from the adrenal medulla by the cholinergic drugs was monitored by the perfusion pressure rise in autoperfused and sympathetically denervated hindlimbs of the dog.

Acetylcholine, dimethylphenylpiperazinium (DMPP) and methacholine, given in relatively small doses into the aorta proximal to the blood supply to the adrenal glands, caused a marked rise in perfusion pressure which was due to the release of catecholamines from the adrenal medulla.

Atropine (1 mg/kg intravenously) blocked the pressor response to methacholine only. The ganglion‐blocking agents (mecamylamine 4–5 mg/kg or hexamethonium 10 mg/kg) given subsequently blocked the pressor responses to the other two cholinergic drugs. The ganglion‐blocking agents, when given before atropine, blocked the pressor action only of DMPP. These agents partly depressed, rather than potentiated, the pressor response to methacholine.

The results suggest that muscarinic as well as nicotinic receptors are present in the adrenal medulla of the dog.

Neither atropine nor ganglion‐blocking drugs alone reduced the pressor response to acetylcholine. It is postulated that the blockade of one set of receptors makes more acetylcholine available for the other set of receptors and so inactivation of the former receptors are compensated by the increased release through the activation of the latter's.
Histamine release by sodium chloroplatinate
Authors: SAINDELLE A. , RUFF F.
Published: July 2012

The chloroplatinate ion can release histamine from the tissues in various species of animals.

This property is not shared by other complex ions with co‐ordination number 6, or other complex platinum ions.

The release of histamine may form the basis of the known disease platinosis which affects people who work in platinum refineries, and which is characterized by symptoms of an allergic nature.

The mechanism of the liberation of histamine by chloroplatinate resembles that which occurs during anaphylactic shock.
Chemotherapeutic reactions of Chandlerella hawkingi, the filarial parasite of the Indian jungle crow, Corvus macrorhynchos (Wagler)
Authors: CHATTERJEE R. K. , SEN A. B.
Published: July 2012

A high percentage of Indian jungle crows (Corvus macrorhynchos Wagler), found in and around Lucknow, harbour a natural filarial infection Chandlerella hawkingi. The microfilariae of this species are sheathed and show nocturnal periodicity.

Fourteen compounds active against other kinds of filariae, especially against Litomosoides carinii, were tested against Ch. hawkingi in jungle crows to find whether this infection would be suitable for routine filarial chemotherapy. This is apparently the first report of systematic screening of antifilarial compounds against an avian filariasis.

Tartar emetic (10 mg/kg intravenously, daily for 6 days) and arsenamide (5 mg/kg intraperitoneally, daily for 6 days) proved to be effective in killing adult worms. Trivalent tryparsamide, though effective, was toxic in the doses tried. Diethylcarbamazine and other compounds tested were ineffective.

The chemotherapeutic susceptibilities of Ch. hawkingi differ considerably from those of L. carinii and Wuchereria bancrofti.
Differences between the effects of saxitoxin (paralytic shellfish poison) and tetrodotoxin on the frog neuromuscular junction
Authors: EVANS M. H.
Published: July 2012

End‐plate potentials (e.p.p.) have been recorded from the neuromuscular junctions of frog sartorius and extensor longus dig. IV muscles, using intracellular micropipettes. Either curare or MgCl2 were present in the Ringer solution, to keep the e.p.p. amplitude below the threshold for a muscle action potential and contraction.

It has been shown that saxitoxin (paralytic shellfish poison) usually caused a progressive reduction in the amplitude of the e.p.p. Occasionally, when it was applied in the presence of MgCl2, the e.p.p. disappeared abruptly.

Tetrodotoxin usually caused the e.p.p. to disappear abruptly. Occasionally, when applied in the presence of curare, the e.p.p. declined progressively for a short time before disappearing abruptly.

It is concluded that at the frog neuromuscular junction the preferential site of action of saxitoxin is at the nerve terminals, but tetrodotoxin preferentially blocks nerve conduction at a site proximal to the junction.

It is suggested that this preparation would be a convenient and reliable test object for distinguishing saxitoxin from tetrodotoxin.
Hypothalamo‐pituitary‐adrenal function in the rat after prolonged treatment with Cortisol
Authors: HODGES J. R. , SADOW JANET
Published: July 2012

Cortisol, administered subcutaneously every day for long periods, caused growth retardation, adrenal atrophy and impaired hypothalamo‐pituitary‐adrenal (HPA) function in the rat.

The growth rate and the functional activity of the HPA system gradually returned to normal after steroid withdrawal.

Normal adrenal sensitivity to corticotrophin returned more rapidly than normal pituitary corticotrophic function, suggesting that the initial impairment of HPA function was due both to reduced responsiveness of the adrenal gland to corticotrophin and failure of the pituitary gland to secrete the hormone.
Modification of the vasoconstrictor action of sympathomimetic agents by bretylium tosylate and tranylcypromine in man
Authors: FREWIN D. B. , JELLETT L. B. , WHELAN R. F.
Published: July 2012

The vasoconstrictor actions of tyramine, methylamphetamine and ephedrine on the blood vessels of the human hand have been found to be potentiated by administration intra‐arterially of the adrenergic neurone blocking agent, bretylium tosylate.

One mechanism suggested for the enhancement of vasoconstriction is that bretylium possesses monoamine oxidase inhibitilng activity, which, in the case of tyramine, is protective both to the sympathomimetic agent and the intraneuronal transmitter which it releases. In the case of methylamphetamine and ephedrine, which are not substrates for the enzyme, protection of the intraneuronal transmitter alone might occur, accounting for the lesser degree of potentiation of the effect of these amines by bretylium.

Comparison of the influences of bretylium and the monoamine oxidase inhibitor, tranylcypromine, on the vasoconstrictor action of the sympathomimetic agents shows a similar pattern of enhancement in the presence of both these drugs.

Tranylcypromine caused enhancement of the response of the hand vessels to noradrenaline, and this action could contribute to its potentiation of the effect of the sympathomimetic amines.

For a monoamine oxidase inhibiting action of bretylium to be effective in potentiating the constrictor actions of the sympathomimetic agents on the hand blood vessels at a time when reflex sympathetic activity is blocked it is necessary to postulate that these drugs and reflex nerve activity act either on different compartments of the transmitter store or by different release mechanisms.
The effects of prostaglandins on the intraocular pressure of the rabbit
Authors: BEITCH BARBARA R. , EAKINS K. E.
Published: July 2012

. The effects of intracameral injections of prostaglandins E1, E2, F1α, F2α, and A1 were studied on the intraocular pressure (IOP) of rabbits anaesthetized with urethane.

. With the exception of prostaglandin F1α, all the prostaglandins studied were found to be capable of producing a large, sustained rise in IOP, accompanied in many cases by miosis.

. A marked decrease in response to repeated injections was found with all the prostaglandins studied; this effect was more pronounced following a large initial response to the prostaglandin.

. The descending order of potency in their ability to raise IOP was as follows: prostaglandin E1∼E2>F2α>A1>F1α.

. Intracameral injections of prostaglandins E1 and E2 resulted in an increase in the protein content of the aqueous humour, which was related to the magnitude of the sustained increase in IOP.

. Stabilization of the blood‐aqueous barrier with polyphloretin phosphate markedly reduced both the IOP response and the effect of prostaglandin E2 on the protein content of the aqueous humour.

. It is concluded that the production of local vasodilatation and increased permeability of the blood‐aqueous barrier play an important part in the effect of prostaglandins on the IOP. The involvement of prostaglandins in the response of the rabbit eye to irritation is discussed.
Structure and pharmacological actions of phyllocaerulein, a caerulein‐like nonapeptide: its occurrence in extracts of the skin of Phyllomedusa sauvagei and related Phyllomedusa species
Authors: ANASTASI A. , BERTACCINI G. , CEI J. M. , DE CARO G. , ERSPAMER V. , IMPICCIATORE M.
Published: July 2012

. The South American amphibian Phyllomedusa sauvagei contains in its skin large amounts of a polypeptide closely resembling caerulein in its pharmacological actions. This polypeptide, called phyllocaerulein, was obtained in a pure form, and upon acid hydrolysis, enzymic digestion and end‐group determination experiments it proved to be a nonapeptide of the following composition

Pyr‐Glu‐Tyr(SO3H)‐Thr‐Gly‐Trp‐Met‐Asp‐Phe‐NH2

It may be seen that caerulein and phyllocaerulein have in common the C‐terminal heptapeptide and the N‐terminal pyroglutamyl residue.

. Phyllocaerulein is indistinguishable from caerulein even in parallel bio‐assay. However, the former polypeptide seems to be somewhat more potent than the latter on all the preparations tested.

. In different batches of Phyllomedusa sauvagei skin the phyllocaerulein content ranged between 150 and 600 μg/g of fresh tissue.

Phyllocaerulein or similar polypeptides occur also in the skin of several other Phyllomedusa species, among which are Phyll. burmeisteri, Phyll. dachnicolor, Phyll, helenae, Phyll. annae, Phyll. callidryas and Phyll. bicolor.

. The qualitative identification and quantitative estimation of caerulein‐like polypeptides in crude skin extracts may be complicated by the concomitant occurrence of other active polypeptides. These, however, are poorly effective on some test preparations which seem to respond selectively to caerulein.

. Like that of caerulein, the biological significance of phyllocaerulein is completely obscure.
The effects of pronethalol and propranolol on the coronary circulation of the dog
Authors: DAVIS W. G. , MacDONALD D. C. , MASON D. F. J.
Published: July 2012

. The actions of pronethalol and propranolol have been studied to see if there was any relationship between the reduction in coronary flow and any other cardiovascular action they have.

. The experiments were carried out in anaesthetized open chest dogs. Measurements included central arterial, left and right venous or atrial pressures, heart rate, ventricular size and stroke volume, intra‐ventricular pressures, total left coronary flow, arterial and coronary sinus blood pO2. The pressure‐time index (PTI) and maximum rate of isovolumetric contraction (dp/dt) were obtained from these records.

. It was concluded that, in these experiments, the reduction in coronary flow produced by pronethalol and propranolol was not directly related to a decrease in perfusion pressure, a raised venous pressure, the increase in ventricular volume and hence wall tension, the decrease in heart rate, or to the increased duration of systole.

. The PTI and dp/dt were always reduced at the same time as the coronary flow. These findings are discussed.

. Studies of the effects of sympathetic stimulation, of phentolamine, of reduced arterial oxygen tension and electrical pacing of the heart, all after β‐blockade, did not support the suggestion that the reduction in coronary flow after β‐blockade was due to the unmasking of an active vasoconstriction.
Antagonism of some smooth muscle actions of prostaglandins by polyphloretin phosphate
Authors: EAKINS K. E. , KARIM S. M. M. , MILLER J. D.
Published: July 2012

The antagonism of the smooth muscle stimulating actions of PGF2α and PGE2 by polyphloretin phosphate (PPP) was studied on several isolated smooth muscle preparations and on the blood pressure of the anaesthetized rabbit.

PPP (2·5–20 μg/ml) reversibly inhibited contractions of the jird colon produced by PGE2 or PGF2α; PGF2α was more readily antagonized than PGE2.

PPP (2·5–30 μg/ml) reversibly antagonized contractions produced by PGE2 and PGF2α on the isolated rabbit jejunum and uterus. In these preparations PPP antagonized PGE2 as readily as PGF2α.

It is concluded that PPP is a selective antagonist to the prostaglandins on these tissues, for contractions produced by other agonists, such as acetylcholine, angiotensin, 5‐hydroxytryptamine and bradykinin were not reduced by concentrations of PPP which markedly antagonized responses to the prostaglandins.

Intravenous injections of PPP (25–200 mg/kg) resulted in a variable antagonism to the fall in blood pressure produced by intravenous injections of PGF2α in the anaesthetized rabbit; vasodepressor responses produced by PGE2 and acetylcholine were not antagonized.

The mechanism of this antagonism by PPP is not clear and must await further investigation.
Prostaglandin uptake and metabolism by the perfused rat liver
Authors: DAWSON W. , JESSUP SHEILA J. , McDONALD‐GIBSON WENDY , RAMWELL P. W. , SHAW JANE E.
Published: July 2012

The prostaglandins are C20 unsaturated fatty acids which exhibit diverse physiological effects of short duration. We have investigated the speed of removal of PGE1 and PGF1α from the circulating blood and their subsequent metabolism by the isolated perfused rat liver.

Following either a single injection of radiolabeled PGE1 or PGF1α into the hepatic artery or portal vein, or recirculation of prostaglandins through the liver for 2·5 h, the distribution of radioactivity within extracts of bile, blood and liver was determined. The nature of the radioactive products of metabolism was inferred by comparison of the distribution of radioactivity after injecting carbon and tritium labelled standards, and by thin‐layer chromatography, gas‐liquid chromatography, ultraviolet and bioassay analysis.

A single injection of 1–14C PGE1 indicated that the liver could efficiently remove 89–95% of circulating PGE1 on a single passage. Biliary excretion was excluded as a major route for elimination of unchanged PGE1, because only 0·3–0·8% of the injected radioactivity was detected in the bile. During recirculation of 1–14C PGE1, 11–19% of the injected radioactivity was detected as exchanged 14CO2. The radioactivity detected within liver was identified with further fragments resulting from decarboxylation of PGE1, which were incorporated into fatty acids and then phospholipids.

Studies with 5,6–3H PGE1, and comparison with the results obtained using 1–14C PGE1, revealed a 30‐fold increase in the percentage of radioactivity excreted into the bile, suggesting that biliary excretion may be a major route for elimination of compounds smaller than C20 prostaglandin. Evidence that the cyclopentane ring was intact was inferred by formation of a PGB compound on treatment with alkali; similar biliary excretion of 9–3H PGF1α also occurred. In addition, the increased radioactivity detected within the liver (37%) and blood (43%) after a single injection of 5,6–3H PGE1 had the solvent partition and thin‐layer chromatography properties of PGE1, but were associated with a less polar compound smaller than the C20 parent structure.

These results indicate rapid uptake of circulating prostaglandins by the rat liver. Decarboxylation of prostaglandins results in pharmacological inactivation. The products are excreted into the bile and venous effluent. These processes would curtail the duration of effects following prostaglandin injection.
Carbon tetrachloride metabolism in sheep and in Fasciola hepatica
Authors: FOWLER J. S. L.
Published: July 2012

The excretion of carbon tetrachloride and its metabolites in bile and urine were studied.

Liver flukes in vitro metabolized carbon tetrachloride and hexachloroethane by dechlorination.

Carbon tetrachloride, liver lipid from rabbits which received carbon tetrachloride and a carbon tetrachloride methyl oleate complex were toxic to liver flukes in vitro, in the presence of sheep bile.

A direct fasciocidal action of carbon tetrachloride may contribute to the therapeutic effect of the drug.
The effects of papaverine on the electrical and mechanical activity of the guinea‐pig taenia coli
Authors: TASHIRO N. , TOMITA T.
Published: July 2012

Effects of papaverine (5 × 10−6–5 × 10−5m) were studied on the spontaneous and evoked electrical and mechanical activity of the guinea‐pig taenia coli. In normal Locke solution, papaverine slowed and finally stopped the spontaneous spike discharge, usually with a small hyperpolarization of a few mV.

Papaverine did not change the membrane resistance in normal Locke solution. It abolished the repetitive firing of spikes during the depolarization in response to a current pulse, but a single spike of normal amplitude could always be evoked.

The mechanical response elicited by a single spike was reduced by papaverine in normal Locke solution. During the maintained depolarization produced by a long current pulse the tonic component of the contraction was more reduced than the phasic component related to the initial spike activity.

The effects of papaverine were essentially the same as in normal Locke solution when NaCl was replaced with LiCl, or in excess K (24 mm), except that the membrane resistance was increased by papaverine in the presence of excess K.

Excess Ca (6 mm) antagonized the effect of papaverine on the mechanical response, but not on the electrical response. When the muscle was depolarized in Ca‐free solution, papaverine caused repolarization of the membrane and electrical activity reappeared. This effect was similar to that of Mg (4 mm).

The mechanism by which papaverine suppresses the spontaneous spike activity is discussed and is compared with that of isoprenaline, from which it appears to differ. The observations indicate that papaverine, like Mg, may bind with a site at the membrane with which Ca normally binds, thereby modifying the electrical and mechanical activity controlled by Ca.
Stimulation by atropine of acetylcholine release and synthesis in cortical slices from rat brain
Authors: MOLENAAR P. C. , POLAK R. L.
Published: July 2012

. Cortical slices from rat brain were incubated in media containing the irreversible Cholinesterase inhibitor soman and a high KCl concentration, and the release and synthesis of acetylcholine (ACh) were determined.

. Atropine enhanced the release and synthesis of ACh.

. Tetrodotoxin, a substance which blocks nervous conduction, did not influence the release and synthesis of ACh, in the absence or in the presence of atropine. Therefore the nerve endings are probably the site at which atropine acts when stimulating the release and synthesis of ACh.

. Pretreatment of the slices with botulinum type A toxin partially blocked the release and synthesis of ACh and reduced the extra amounts of ACh released and synthesized under the influence of atropine.

. Lowering the calcium or raising the magnesium concentration in the incubation medium reduced the release and synthesis of ACh and their enhancement by atropine.

. Physostigmine decreased the total extractable ACh content of the slices during incubation in a 25 mm KCl containing medium. This decrease was nearly prevented when the release and synthesis of ACh were inhibited by omission of the calcium ions from the medium, but was enhanced by atropine.

. The observations made with pretreatment by botulinum type A toxin, with changes in the calcium and magnesium concentration as well as with physostigmine, all support the theory that it is primarily the release of ACh which is enhanced by atropine and that its stimulating action on the synthesis results from the increased release.
Inhibition of catecholamine Uptake2 by steroids in the isolated rat heart
Authors: Iversen L. L. , Salt P. J.
Published: July 2012

Various steroids (1 7‐fl‐oestradiol, cortico‐sterone, deoxycorticosterone, progesterone, testosterone and androsterone) produced a dose‐dependent inhibition of the uptake of 3H‐noradrenaline by the Uptake2 mechanism in the isolated perfused heart. It is suggested

that these results may explain the potentiating effects of such steroids on the responses of vascular smooth muscle to catecholamines.
Function of smooth muscle of the rat renal pelvis—response of the isolated pelvis muscle to angiotensin and some other substances
Authors: FINBERG J. P. M. , PEART W. S.
Published: July 2012

The circular component of the renal pelvis muscle of the rat appears as an intact band around the tip of the papilla.

The isolated pelvis muscle strip showed spontaneous rhythmic contractions in Locke solution at 38° C. The rate of contractions corresponded with the rate of pressure fluctuations recorded during free‐flow from a ureteral catheter inserted up to the renal hilum of anaesthetized rats.

Angiotensin and adrenaline (13 ng/ml) produced a rise in tone of the isolated pelvis muscle, and an increase in the rate of spontaneous contractions; noradrenaline produced mainly an increase in the amplitude and rate of spontaneous contractions. Angiotensin and noradrenaline injected intravenously also produced an increased rate of pressure fluctuations recorded from the ureteral catheter.

Acetylcholine, nicotine and 5‐hydroxytryptamine had no effect on the isolated tissue, but isoprenaline was capable of causing a decrease, and tyramine an increase, in the rate of spontaneous contractions in high dose (0.33 μg/ml).

An increase in the tone of the circular pelvis muscle could lead to a reversible obstruction of urine outflow from the kidney.
Specificity of some ganglion stimulants
Authors: BARLOW R. B. , FRANKS FIONA
Published: July 2012

The specificity of several ganglion stimulants has been tested on the isolated guinea‐pig ileum by measuring the dose ratios produced by concentrations of hexamethonium.

Most ganglion stimulants are also active at postganglionic receptors, some as blocking agents (for example, lobeline and dimethylphenylpiperazinium), others as agonists (for example, o‐aminophenethyltrimethylammonium and, to a lesser extent, nicotine). The most specific ganglion stimulant, with the least activity at postganglionic receptors, was p‐aminophenethyltrimethylammonium.

The affinity constants of lobeline and dimethylphenylpiperazinium for the muscarine sensitive receptors in the guinea‐pig ileum are 1·05 × 106 and 3·71 × 104, respectively.

The antagonism of p‐aminophenethyltrimethylammonium by hexamethonium gave results consistent with competition up to dose ratios of about 20. Such results could also be obtained if the antagonism were non‐competitive, however, provided large responses could be obtained with less than about 5% of the receptors in the ganglia activated. The affinity constant of hexamethonium is about 2·6 × 105.

It is suggested that the affinity of hexamethonium can largely be ascribed to hydrophobic bonding.
In vivo production of steroids with central depressant actions by the ovary of the rat
Authors: HOLZBAUER MARGARETHE
Published: July 2012

In addition to progesterone and 20‐dihydroprogesterone, the following unconjugated steroids were isolated from ovarian tissue and ovarian venous blood of mature, non‐pregnant rats: pregnenolone, 3βOH‐5α‐pregnan‐20‐one, 3αOH‐5α‐pregnan‐20‐one, 20αOH‐5α‐pregnan‐3‐one and 5α‐pregnane‐3α, 20α‐diol.

Their concentration in the ovarian tissue and their secretion rates into the ovarian venous blood was of the same order of magnitude as that of progesterone.

In the evening of the day of pro‐oestrus significant increases in the ovarian contents of the following steroids were observed: progesterone,+ 140%; 3αOH‐5α‐pregnan‐20‐one, +320%; 20αOH‐5α‐pregnan‐3‐one, +195%; sum of pregnenolone and 3βOH‐5α‐pregnan‐20‐one, +275%.

At the same time the ovarian progesterone secretion rate was increased by 365%, that of 3αOH‐5α‐pregnan‐20‐one by 190%.

A possible physiological role of the ovarian allopregnane derivatives as central depressant agents is discussed.
Actions of quazodine (MJ1988) on smooth muscle
Authors: PARRATT J. R. , WINSLOW EILEEN
Published: July 2012

Quazodine (MJ1988; 6,7‐dimethoxy‐4‐ethyl‐quinazoline) relaxed a variety of vascular and extravascular smooth muscle preparations and antagonized, non‐competitively, several substances which contract smooth muscle.

This activity was not due to β‐adrenoceptor stimulation or to α‐adrenoceptor blockade.

On the rabbit duodenum, the inhibitory effect was qualitatively similar to that of theophylline and was antagonized by the phosphodiesterase potentiator, imidazole.

The activity of quazodine was similar to, but up to 18 times greater than, that of theophylline and it is suggested that at least part of its activity on vascular and extravascular smooth muscle is due to inhibition of phosphodiesterase.
Effect of pretreatment with 6‐hydroxydopamine on the uptake and metabolism of catecholamines by the isolated perfused rat heart
Authors: HELLMANN G. , HERTTING G. , PESKAR B.
Published: July 2012

Isolated rat hearts from control and 6‐hydroxydopamine pretreated animals were perfused with 3H‐noradrenaline or 3H‐dopamine, either at a low perfusion concentration (1.50 × 10−10 mol/ml 3H‐dopamine; 1.18 × 10−10 mol/ml 3H‐noradrenaline) or a high perfusion concentration (296.69 × 10−10 mol/ml 3H‐noradrenaline, 327.45 × 10−10 mol/ml 3H‐dopamine) for 8 minutes.

At the low perfusion concentration, the total activity, the radioactivity in the alumina eluates (sum of 3H‐dopamine, 3H‐noradrenaline and deaminated catechol metabolites) and the concentration of 3H‐dopamine, 3H‐noradrenaline and the deaminated catechol metabolites were decreased in the hearts of the pretreated rats as compared with the controls. The O‐methylated amine metabolites were increased. The deaminated O‐methylated metabolites were increased in the experiments with 3H‐noradrenaline and decreased in the 3H‐dopamine experiments.

Uptake of 3H‐dopamine and 3H‐noradrenaline by the hearts of 6‐hydroxydopamine pretreated rats was decreased to a much smaller extent when perfused with the high concentration than with the low concentration.

At the high perfusion concentration there was a significant difference between control and pretreated animals with regard to the total radioactivity and the radioactivity in the alumina eluates only. The absolute and relative amounts of metabolites were not significantly changed by pretreatment with the exception of the deaminated catechol metabolites in the 3H‐dopamine experiments.

It is concluded that neuronal Uptake 1 is greatly impaired in the hearts from rats pretreated with 6‐hydroxydopamine, but extraneuronal Uptake 2 remains intact.
Stimulating action of catecholamines on isolated preparations of the rat colon and human and rabbit taeniae coli
Authors: BELISLE S. , GAGNON D. J.
Published: July 2012

Adrenaline and noradrenaline induced dose related relaxations of the superfused rat colon. The relaxations were progressively transformed into contractions when β‐adrenoceptors were blocked with increasing doses of oxprenolol.

Since phentolamine or phenoxybenzamine inhibited the contractions induced by adrenaline or noradrenaline in the presence of oxprenolol, it is assumed that the contractions are caused by stimulation of excitatory α‐adrenoceptors.

Human and rabbit taeniae coli showed responses that were qualitatively similar to those observed with the rat colon.
Myocardial and haemodynamic effects of phentolamine
Authors: DAS P. K. , PARRATT J. R.
Published: July 2012

In cats anaesthetized with pentobarbitone, intravenous infusions of phentolamine ((10–50 μg/kg)/min for 5 min) increased heart rate, left ventricular dp/dt max (without increasing end‐diastolic pressure), aortic dp/dt, cardiac output, myocardial blood flow and metabolic heat production.

Phentolamine‐induced increases in myocardial contractility occurred irrespective of the direction or magnitude of the blood pressure change and were maintained well beyond the actual infusion period.

In cats treated with alprenolol, bretylium or reserpine there was no evidence of increased cardiac contractility following phentolamine administration.

It is concluded that phentolamine, in doses less than those required to produce significant α‐adrenoceptor blockade, increased myocardial contractility through an effect on the sympathetic nervous system.
Spasmolytic effects of cadmium and zinc ions upon the guinea‐pig isolated ileum preparation
Authors: SCHNIEDEN H. , SMALL R. C.
Published: July 2012

An investigation has been made of the effects of cadmium and zinc ions upon the contractile response of the guinea‐pig isolated ileum to methacholine, histamine, potassium ion and a.c. field stimulation. The metal ions depress the response to all of these agents.

Radioisotope studies showed that cadmium and zinc ions have very much larger apparent volumes of distribution than sorbitol, both within whole ileum and within strips of the longitudinal smooth muscle layer. The results of these studies were indicative of surface binding and/or intracellular accumulation of these ions.

It is suggested that cadmium and zinc ions directly depress smooth muscle contractility in a non‐specific manner. This action may result from their binding to or accumulation within the muscle cells.
Estimation of urinary 5‐hydroxytryptamine‐O‐glucuronide, a metabolite of endogenous 5‐hydroxytryptamine in sheep
Authors: BARTLET A. L. , GILBERT FRANCES M.
Published: July 2012

5‐Hydroxytryptamine‐O‐glucuronide has been extracted from sheep urine and characterized by its chemical reactions and RF values on paper chromatograms.

5‐Hydroxytryptamine‐O‐glucuronide in urine was separated from an inhibitor of β‐glucuronidase using an anion exchange resin, and then estimated by measurement of the 5‐hydroxytryptamine (5‐HT) liberated on incubation with β‐glucuronidase.

About 20% of the 5‐hydroxyindoles found in sheep urine was 5‐HT conjugated with glucuronic acid (1.18 ± 0.08 mg 5‐HT/24 h, thirty experiments).

Sheep urine also contained free 5‐HT (0.35 ± 0.04 mg/24 h, thirty experiments) and 5‐hydroxyindolylacetic acid (4.43 ± 0.33 mg/24 h, thirty experiments).

5‐Hydroxytryptamine‐O‐sulphate was not found in sheep urine.
Effects of the diuretics, triamterene and mersalyl on active sodium transport mechanisms in isolated frog skin
Authors: SALAKO L. A. , SMITH A. J.
Published: July 2012

Triamterene reduces the rate coefficients for sodium movement into the transporting system of the isolated frog skin. The isotopically measured ‘active sodium transport pool’ is also reduced.

Mersalyl reduces the rate coefficient for sodium and the calculated sodium flux from the transporting system to the inner bathing solution. The ‘active sodium transport pool’ is increased by this diuretic.

The action of triamterene closely resembles that of amiloride and both reduce the entry of sodium into the system. In contrast, mersalyl limits the exit of sodium ions from the skin.
Effect of morphine on the cerebral contents of metabolites of dopamine in normal and tolerant mice: its possible relation to analgesic action
Authors: FUKUI K. , TAKAGI H.
Published: July 2012

The administration of an analgesic dose (10 mg/kg, s.c.) of morphine increased the concentrations of the dopamine metabolites, 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brains of normal mice, and the time course of the change in the DOPAC concentration corresponded approximately to that of morphine analgesia. The increase in the concentration of the DOPAC induced by morphine (20 mg/kg, s.c.) was completely suppressed by nalorphine (2 mg/kg, s.c.) given 5 min after the morphine administration.

In morphine‐tolerant mice the concentrations of DOPAC and HVA in the brain did not differ from those observed in normal mice, and the increase in the concentrations of DOPAC and HVA in brain after the acute administration of morphine no longer occurred.

Nalorphine (2 mg/kg) given alone did not cause any change in brain DOPAC and HVA concentrations in normal mice.

The morphine‐induced increase in DOPAC and HVA concentrations in the brain are discussed in the light of the hypothesis that dopamine might participate not only in the extrapyramidal motor system but also in the sensory mechanisms of the brain.
Anterograde amnesic effects of pethidine, hyoscine and diazepam in adults
Authors: DUNDEE J. W. , PANDIT S. K.
Published: July 2012

The intravenous administration of 5 and 10 mg of diazepam caused anterograde amnesia in 50 and 90% of adults, the peak effect occurring in 2–3 min and action persisting for 20–30 minutes.

Hyoscine (0·4 and 0·6 mg) caused amnesia in 35 and 50% of patients with peak effect not occurring until 50–80 min after injection and action persisting for at least 120 minutes.

With neither drug was there any relationship between the incidence of amnesia and the degree of drowsiness.

Amnesia was not observed after saline or after 50 mg pethidine.

On questioning 6 h after a short operation many patients had no memory of an object which they clearly recognized and described 1 h after surgery.
Berberine in toxin‐induced experimental cholera
Authors: DUTTA N. K. , MARKER P. H. , RAO N. R.
Published: July 2012

Appendix on berberine in toxin‐induced experimental cholera

Oral administration of berberine to infant rabbits 18–24 h before the intraintestinal administration of choleragenic toxins, arrests diarrhoea or significantly prolongs the survival time.

The use of berberine in the treatment of clinical cholera is further justified.

Berberine is an antidiarrhoeal drug and the host tissues play a major part in the control of diarrhoeal symptoms.
Distribution of Δ9‐tetrahydrocannabinol in the mouse
Authors: FREUDENTHAL R. I. , MARTIN J. , WALL M. E.
Published: July 2012

The distribution of Δ9‐tetrahydrocannabinol‐14C in the pregnant and nonpregnant mouse is very similar. High concentrations of radiolabel can be seen in the maternal liver, spleen, lungs, brown fat, adrenal glands, mammary glands, yolk sac placenta and corpora lutea. In the pregnant mouse Δ9‐THC crosses the placenta and enters the foetuses in very low concentrations, with no apparent selective intrafoetal radiolabel accumulation sites. Autoradiograms showing the distribution of 14C‐cannabinoid 2 h after dosing are presented.

A small amount of maternal liver and foetal tissue was removed from the mice, used for autoradiography and extracted with ethyl acetate. Most of the radiolabel in these tissues was solvent extractable and was separated by thin layer chromatography into two fractions, THC and metabolites.

It appears that most of the cannabinoid is present in a free rather than conjugated form.
Uptake of desipramine by the rat vas deferens
Authors: BININI R. , BONACCORSI A. , GARATTINI S. , MORSELLI P. L. , MUSCETTOLA G.
Published: July 2012

Determinations of desipramine in the isolated rat vas deferens were carried out in order to study the uptake of the drug and to evaluate how this may correlate with the effect on noradrenaline (NA)‐induced contraction.

Vasa deferentia, in contact with concentrations of desipramine of 1 ng—25 μg/ml for 10 min accumulated the drug about 6‐fold in respect to the medium. When the time of contact was prolonged to 4 h, desipramine (200 ng/ml) was concentrated about 100‐fold. The uptake was not saturable and it was not affected by the presence of imipramine, cocaine, ouabain, dinitrophenol and iodoacetate.

No metabolic process is involved although the accumulation of desipramine is temperature dependent. The release of desipramine from the vas deferens is exponential and it is not affected by the presence of plasma in the medium.

No clear correlation was found between tissue concentration of the drug and the potentiation of noradrenaline responses, probably because of the high non‐specific binding of the drug to tissue components which may mask specific binding sites for NA resulting in potentiation. However, the concentration of desipramine seems to correlate with the inhibition of NA effect which occurs at high doses of desipramine.
Atropine resistant excitation of the urinary bladder: the possibility of transmission via nerves releasing a purine nucleotide
Authors: BURNSTOCK G. , DUMSDAY B. , SMYTHE A.
Published: July 2012

The possibility that a purine nucleotide is involved in excitatory transmission to the urinary bladder has been tested. All the purine compounds tested which contained a pyrophosphate bond produced contraction, adenosine triphosphate (ATP) being the most potent. Adenosine and adenosine monophosphate caused relaxation.

The response to ATP closely mimicked the nerve‐mediated contraction, both being characterized by a rapid contraction which was not maintained. A lack of sensitivity to ATP was noted in some preparations of the rat urinary bladder.

Both nerve‐mediated contractions and contractions caused by ATP were blocked by quinidine, while the response to acetylcholine persisted.

Nerve‐mediated responses were depressed during tachyphylaxis produced by high concentrations of ATP. Tachyphylaxis did not occur when low concentrations were used. Possible explanations for these results are discussed.

The results are consistent with the hypothesis that non‐cholinergic excitatory nerves to the guinea‐pig bladder release a purine nucleotide, but do not provide critical evidence for it.
Alterations of histamine metabolism after injections of sex hormones in mice
Authors: HENNINGSSON S. S. G. , ROSENGREN ELSA
Published: July 2012

Urinary excretion of histamine in female mice was determined after the injection of oestradiol, progesterone or testosterone. Histamine excretion was increased by oestradiol but was not affected by progesterone. Testosterone administration, by contrast, effected a striking reduction of histamine excretion.

After injection of oestradiol, the kidney histamine forming capacity was greatly elevated, but in the other tissues investigated no significant change occurred.

Testosterone administered in vivo but not in vitro reduced the histidine decarboxylase activity of female mouse kidney to a small fraction of normal.

On thin‐layer chromatography, after extraction and coupling of the amines to 2,4‐dinitrofluorobenzene, the amount of histamine and to a lesser extent, methyl histamine in urine was reduced after testosterone administration. On the chromatogram of urine from untreated mice, an unidentified yellow spot appeared and the quantity of this spot was increased during testosterone treatment.
Excretion of 14C‐edrophonium and its metabolites in bile: role of the liver cell and the peribiliary vascular plexus
Authors: BACK D. J. , CALVEY T. N.
Published: July 2012

The metabolism and biliary excretion of 14C‐edrophonium chloride was studied in Wistar rats.

Approximately 5% of the dose was recovered from bile in 6 hours. Most of the radioactivity was eliminated as 14C‐edrophonium glucuronide. Small amounts of the unchanged drug were also detected in bile, particularly during the first hour after administration of the drug.

The concentration of 14C‐edrophonium glucuronide in bile was approximately 15–20 times its concentration in plasma.

In contrast, the concentration of unchanged 14C‐edrophonium was similar in bile and plasma.

Evidence is presented that unchanged 14C‐edrophonium is transferred from plasma to bile via the peribiliary vascular plexus.
Effect of cigarette smoking on human precapillary sphincters
Authors: MATSUBARA ICHIRO , SANO TOYOMI
Published: July 2012

. Capillary filtration coefficient of human calf was measured by pressure plethysmography before and after cigarette smoking, which is known to release noradrenaline from nerve terminals of sympathetic vasoconstrictors. Calf blood flow and venous pressure‐volume curves of the calf were also obtained before and after smoking.

. Capillary filtration coefficient decreased by 19% when cigarette smoke was inhaled deeply at 30 s intervals for 12–15 min, indicating the closure of precapillary sphincters.

. Calf blood flow decreased by 31% after smoking, indicating that arterioles were constricted. The degree of arteriolar constriction, however, was not strong enough to lessen the capillary hydrostatic pressure, since the absorption of tissue fluid into capillary blood vessels did not occur.

. The venous system seemed little affected by cigarette smoking, since venous pressure‐volume curves were unaltered.
The presence of β‐adrenoceptors in the guinea‐pig seminal vesicle
Authors: SPEDDING M. , WEETMAN D. F.
Published: July 2012

. The preparation of longitudinal smooth muscle strips from guinea‐pig seminal vesicles is described.

. Isoprenaline and salbutamol inhibited contractions produced by parasympathomimetic agents.

. The inhibitory action of isoprenaline was blocked by low concentrations of propranolol and butoxamine. It was concluded that β2‐adrenoceptors were present in the tissue.

. The inhibitory action of isoprenaline was not apparent when adrenaline, noradrenaline, hypogastric nerve or transmural stimulation were used to contract the tissue.
Nicotine washout rates from isolated rat ganglia in relation to recovery from nicotine depolarization
Authors: BROWN D. A. , SCHOLFIELD C. N.
Published: July 2012

. Isolated rat superior cervical ganglia recovered more slowly from the depolarizing action of nicotine than from that of carbachol or acetylcholine. This was due to sustained high nicotine concentrations in the vicinity of the receptors, since recovery was hastened by adding hexamethonium to the washout fluid.

. Ganglia incubated for 4 min in 80 μm 3H‐nicotine accumulated nicotine to a level exceeding the extracellular space, as judged from the uptake of 3H‐mannitol.

. The subsequent efflux of 3H‐nicotine into non‐radioactive solution could. be largely resolved into two exponential components, with rate constants of 0·55 ± 0·04 and 0094 ± 0007 min−1. The former was similar to that for total mannitol efflux, and so might be largely ascribed to clearance of extracellular nicotine. The slower efflux might be due to clearance from intracellular compartments. Nicotine efflux rates were not affected by hexamethonium indicating that receptor‐activation did not modify the slow efflux.

. Efflux of choline compounds (3H‐acetylcholine, 3H‐choline and 3H‐carbachol) showed an additional, very slow component (rate constant 0·001 to 0·002 min−1).

. It was suggested that slow efflux of intracellular nicotine might sustain depolarization on washing by maintaining high perineuronal concentrations of nicotine. With choline compounds the efflux rate from such sources may be too slow to affect perineuronal concentrations.
Histochemical localization of adrenergic nerves in the guinea‐pig trachea
Authors: O'DONNELL STELLA R. , SAAR NILI
Published: July 2012

Specific catecholamine fluorescence was demonstrated in guinea‐pig trachea in fine, varicose, nerve fibres running parallel to the tracheal smooth muscle fibres.

The density of nerves in tracheal smooth muscle was greater at the laryngeal end than at the bronchial end of the trachea.

The findings confirm pharmacological evidence for an adrenergic innervation of the guinea‐pig isolated tracheal chain preparation.