bluuebunny/crossref_metadata_2025 huggingface dataset:
EEFECTS OF REPEATED LITHIUM ADMINISTRATION ON THE SUBCELLULAR DISTRIBUTION OF 5‐HYDROXYTRYPTAMINE IN RAT BRAIN
Authors: ATTERWILL C. K. , TORDOFF ANN F.C.
Published: July 2012

The content and distribution of 5 ‐hydroxytryptamine (5‐HT) between subcellular fractions from rat whole brain (excluding cerebellum) were examined following repeated lithium administration.

Lithium chloride (3 mEq/kg body wt. s.c.) administered twice daily for 3 days produced no change in the 5‐HT content of primary subcellular fractions (P1—nuclear; P2—crude synaptosomal; SNT—soluble) measured on the 4th day.

Similarly, repeated lithium treatment alone did not appear to produce increases in the 5‐HT content of either cytoplasmic (S) or vesicular (M2) fractions derived from hypo‐osmotically disrupted synaptosomes (P2) when compared to control rats receiving NaCl only.

One hour after monoamine oxidase inhibition with tranylcypromine, there was a further selective 25% increase in 5‐HT accumulation in the lithium‐treated rats over control values in the soluble cytoplasmic fraction (S) and in fractions containing occluded cytoplasm only. This increase did not occur in the synaptic vesicle fraction (M2). This corresponds to an increase in 5‐HT turnover rate due to the lithium treatment of approx. 50%.

These findings lend additional support to the hypothesis that lithium treatment alters the intraneuronal storage or compartmentation of 5‐HT between vesicles and cytoplasm.
EFFECTS OF β‐ADRENOCEPTOR DRUG STIMULATION ON VARIOUS MODELS OF GASTRIC ULCER IN RATS
Authors: ESPLUGUES JUAN , LLORIS JOSÉ M. , MARTÍ‐BONMATÍ EZEQUIEL , MORCILLO ESTEBAN J.
Published: July 2012

Experiments were designed to evaluate the effect of the pharmacological activation of β‐adrenoceptors on various models of gastric ulcer in the rat.

Pretreatment with the β‐adrenoceptor stimulant drugs, isoprenaline or salbutamol, significantly inhibited stress‐induced gastric ulcers. This anti‐ulcer effect was abolished by propranolol but not by atenolol, suggesting that β2‐adrenoceptors mediate this response.

In the pylorus‐ligation model, salbutamol inhibited lesion formation and reduced the intragastric content of hydrogen ions, histamine and pepsin although the latter was only affected with the higher dose of salbutamol.

Salbutamol also prevented the ulcerogenic action on the gastric mucosa of an exogenously perfused artificial gastric juice, showing that the anti‐ulcer effect is not necessarily dependent on acid inhibition.

Salbutamol also reduced the formation of acute ulcers induced by various iatrogenic means (histamine, polymyxin B, reserpine and indomethacin).

Long‐term treatment with salbutamol accelerated the healing of experimental chronic gastric ulcer.

In anaesthetized rats, salbutamol produced a dose‐related increase in mucosal blood flow which may contribute to its mode of action.

It is concluded that β‐adrenoceptor agonists exert preventive and curative effects on gastric damage induced in the rat. This effect seems specific and mediated through β‐adrenoceptor activation.
INHIBITION OF RAT LIVER TRYPTOPHAN PYRROLASE ACTIVITY AND ELEVATION OF BRAIN TRYPTOPHAN CONCENTRATION BY ACUTE ADMINISTRATION OF SMALL DOSES OF ANTIDEPRESSANTS
Authors: BADAWY A. A.‐B. , EVANS M.
Published: July 2012

Administration to rats of a 0.5 mg/kg dose of any of 19 antidepressants, but not that of many other drugs, causes a significant inhibition of the total enzyme and apoenzyme activities of liver tryptophan pyrrolase (of 24–48% and 37–65% respectively) and elevates brain tryptophan concentration by 13–66%.

When liver tryptophan pyrrolase activity is enhanced by pretreatment with cortisol or haematin, subsequent administration of a 0.5 mg/kg dose of some, but not other, antidepressants causes inhibition, which is weak (up to 38%).

This weak inhibition of the enhanced pyrrolase activity together with other pharmacological and physiological factors could explain the time lag between the start of antidepressant medication and the occurrence of a therapeutic response.

The cortisol‐induced and haematin‐activated pyrrolases respond differentially to inhibition by imipramine and amitriptyline, and this may explain the differential response to these two drugs of depressed patients in relation to urinary excretion of the noradrenaline metabolite 3‐methoxy‐4‐hydroxyphenylglycol.

The results are discussed in relation to the mechanism of action of antidepressants and the possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.
PERIPHERAL TOXICITY OF HEMICHOLINIUM‐3 IN MICE
Authors: FREEMAN J.J. , KOSH J.W. , PARRISH J.S.
Published: July 2012

The site (i.e. peripheral or central) of the toxicity produced by hemicholinium‐3 in mice was investigated.

Hemicholinium‐3 was measured fluorometrically and acetylcholine was determined by gas chromatography after intraventricular or intraperitoneal administration of hemicholinium‐3.

Hemicholinium‐3 was not detected in the brain nor were acetylcholine levels decreased in the brain after systemic administration.

The dose‐response curve following intraventricular administration demonstrated that hemicholinium‐3 was not as lethal after central administration as it was after peripheral administration.

Approximately 24% of a 75 μg intraventricular dose of hemicholinium‐3 was found in the periphery at death.

These results suggest that hemicholinium‐3 manifests its toxicity primarily in the periphery.
PULMONARY INACTIVATION OF 5‐HYDROXYTRYPTAMINE IS DECREASED DURING CIGARETTE SMOKE VENTILATION OF RAT ISOLATED LUNGS
Authors: KARHI TAINA , RANTALA ARTO , TOIVONEN HANNU
Published: July 2012

The effect of cigarette smoke ventilation on the inactivation of [14C]‐5‐hydroxytryptamine (5‐HT) was studied in isolated perfused lungs of the rat.

[14C]‐5‐HT 9.6 nmol was infused into the pulmonary circulation of rat lungs in 3 min. The nonrecirculating perfusion effluent was collected during the 5‐HT infusion in three consecutive 1 min fractions. The amount of metabolites of 5‐HT was determined from the perfusion effluent and from the perfused lungs.

The amount of metabolites of 5‐HT in the perfusion effluent was decreased during cigarette smoke ventilation.

The amount of metabolites of 5‐HT in the perfused lungs was also decreased by cigarette smoke ventilation, although the total amount of radioactivity in the lung tissue was not significantly changed.

The decreased pulmonary inactivation of 5‐HT may cause increased circulating levels of 5‐HT, which would explain some cardiovascular changes during smoking.
ELECTROPHYSIOLOGICAL EFFECTS OF THE SALICYLATES ON ISOLATED ATRIAL MUSCLE OF THE RABBIT
Authors: NETO FRANCISCO RICCIOPPO
Published: July 2012

Intracellular recordings were made from cells of the sinoatrial (S‐A) node region and from atrial muscle fibres of rabbit hearts. The effects of sodium salicylate and 5‐bromo salicylate on various parameters of the membrane action potential were studied.

5‐Bromo salicylate (30–100 μm) and sodium salicylate (300–500 μm) caused a dose‐dependent decrease in the frequency of discharge of the SA node cells. Applications of atropine (2.6 μm) with propranolol (3.3 μm) did not affect the negative chronotropic effect, whereas adrenaline (5 μm) reversed it.

Depolarization and shortening of the action potential duration were found in atrial muscle fibres after the application of 5‐bromo salicylate (60–100 μm). The reduction of the action potential duration (APD) was not affected by atropine (2.6 μm).

Higher concentrations of 5‐bromo salicylate (> 100 μm) also caused a dose‐dependent reduction in the action potential amplitude (APA), in the overshoot (OS) of the action potential and in the maximum rate of rise of the action potential (Vmax). All these effects were completely reversed on washing.

Substitution of the NaCl of the bathing Tyrode solution by an equimolar concentration of Na isethionate did not affect the plateau depression induced by the salicylates in atrial muscle fibres.

After increasing the K concentration to 27 mm in the presence of isoprenaline (1 μm), ‘slow responses’ were obtained upon stimulation. 5‐Bromo salicylate (20–60 μm) and sodium salicylate (100 μm) decreased reversibly the amplitude and the rate of rise of the ‘slow response’.

A four fold increase in Ca concentration of the standard Tyrode solution did not antagonize the plateau depression of atrial muscle fibres or the negative chronotropism induced by salicylates.

Addition of CsCl (10 mm) to the Tyrode solution did not affect the shortening of the APD induced by the salicylates in atrial muscle fibres.

When the K concentration in the Tyrode solution was increased from 2.7 mm to 5.4 mm, the effects of 5‐bromo salicylate on the APA, OS and Vmax were potentiated. However, a significant reduction in the shortening of the APD produced by the salicylate was observed.

It is suggested that the salicylates possibly depress the slow inward current in both S‐A node cells and atrial muscle fibres of the rabbit heart. In atrial muscle fibres, a concomitant increase in the outward potassium current is probably involved.
DOPAMINE ACTS AT THE SAME RECEPTORS AS NORADRENALINE IN THE RAT ISOLATED VAS DEFERENS
Authors: LEEDHAM JUDITH A. , PENNEFATHER JOCELYN N.
Published: July 2012

The proposal that dopamine activates a different population of receptors from those activated by noradrenaline and phenylephrine to cause contraction of the rat vas deferens has been investigated using a preparation of the epididymal half of this tissue.

In preparations preincubated in cocaine, oestradiol and propranolol, to block sites of amine loss and β‐adrenoceptors, noradrenaline was the most, and dopamine the least, potent of the three agonists. Phentolamine competitively inhibited each of the agonists to a similar extent. Prazosin also inhibited the actions of the three agonists to a similar extent. These results indicate that the three agonists activate a single population of α1‐adrenoceptors to cause contraction in this preparation.

In experiments using the prostatic half of the rat vas deferens, in the presence of cocaine, oestradiol, propranolol and prazosin, noradrenaline was approximately 40 times more potent than dopamine in causing inhibition of twitches induced by electrical field stimulation. Yohimbine competitively antagonized the effects of the two agonists to a similar extent indicating that both act at the same population of α2‐adrenoceptors.

Taken together, these findings do not lend support to proposals that there are populations of specific dopamine receptors located pre‐ and postjunctionally in the rat vas deferens.
COMPETITIVE INHIBITION BY ADENOSINE 5′‐TRIPHOSPHATE OF THE ACTIONS ON HUMAN PLATELETS OF 2‐CHLOROADENOSINE 5′‐DIPHOSPHATE, 2‐AZIDOADENOSINE 5′‐DIPHOSPHATE AND 2‐METHYLTHIOADENOSINE 5′‐DIPHOSPHATE
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

Adenosine 5′‐diphosphate (ADP) induces human platelet aggregation and noncompetitively inhibits stimulated human platelet adenylate cyclase; these two effects are mediated by the same ADP receptor, at which adenosine 5′‐triphosphate (ATP) is a competitive antagonist.

Two ADP analogues, 2‐azidoadenosine 5′‐diphosphate (2‐azido‐ADP) and 2‐methylthioadenosine 5′‐diphosphate (2‐methylthio‐ADP) have been reported to be more potent as inhibitors of adenylate cyclase than they are as aggregating agents, but no evidence has been presented that these actions are mediated solely by the ADP receptor.

We therefore tested the ability of ATP to inhibit the actions of these compounds and of another ADP analogue, 2‐chloroadenosine 5′‐diphosphate (2‐chloro‐ADP).

2‐Chloro‐ADP, 2‐azido‐ADP and 2‐methylthio‐ADP each induced aggregation and inhibited stimulated adenylate cyclase. Both of these actions were competitively inhibited by ATP (50 μm) with pA2 values similar to those previously found for inhibition by ATP of these effects of ADP.

The reported greater potency of 2‐azido‐ADP and of 2‐methylthio‐ADP as inhibitors of adenylate cyclase than as aggregating agents is therefore due only to their greater efficacy for this effect, not to some extra actions elsewhere.
HISTAMINE H1‐AGONIST POTENTIATION OF ADENOSINE‐STIMULATED CYCLIC AMP ACCUMULATION IN SLICES OF GUINEA‐PIG CEREBRAL CORTEX: COMPARISON OF RESPONSE AND BINDING PARAMETERS
Authors: DAUM P.R. , HILL S.J. , YOUNG J.M.
Published: July 2012

A range of histamine analogues have been examined as potentiators of the adenosine‐stimulated accumulation of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) in slices of guinea‐pig cerebral cortex. Dose‐response curves were constructed for the 6 most active compounds and characterized in terms of the IC50, the slope and the maximum response attainable relative to that of histamine.

Histamine, 2‐thiazolylethylamine and Nα‐methylhistamine produced a maximal or near maximal response. Nα,Nα‐dlmethylhistamine and 2‐methylhistamine appear to be partial agonists.

The response to all the agonists was practically abolished by mepyramine 1 μm, indicating that the response is mediated largely or wholly via histamine H1‐receptors.

The relative potencies of the agonists on cyclic AMP accumulation were in general similar to relative potencies in causing contraction of intestinal smooth muscle. The biggest difference was observed with Nα‐methylhistamine.

The histamine analogues were also examined as inhibitors of [3H]‐mepyramine binding in homogenates of guinea‐pig cerebral cortex. The inhibition curves were characterized in terms of IC50, the slope and the maximum percentage inhibition. This last value was compared with the inhibition produced by promethazine 2 μm.

For the 6 most potent agonists, the EC50 for cyclic AMP accumulation was compared with the IC50 against [3H]‐mepyramine binding, corrected for inhibition of non‐receptor binding and for competition with [3H]‐mepyramine. With the possible exception of 2‐pyridyletfiylamine, the values did not differ by more than a factor of 3.
Effect of disopyramide on isolated aortic ring of the rat
Authors: DE Moura R. Soares , Lima J. Socrates
Published: July 2012

Disopyramide produces a contraction of the isolated aortic ring of the rat which is graded, develops slowly, and has a time course similar to the tonic phase of the noradrenaline response. This effect is not modified by α‐adrenoceptor blockade (yohimbine) but is completely abolished by a Ca2+ antagonist (verapamil) or by removal of Ca2+ from the bathing solution. These results indicate that, in the rat aorta, disopyramide has a vasoconstrictor effect dependent on Ca2+ influx across the vascular smooth muscle membrane.
Effects of the venom of the Brazilian scorpion (Tityus serrulatus) on the compound action potential of the rabbit vagus nerve fibres
Authors: Neto Francisco Riccioppo
Published: July 2012

The effects of the venom of the scorpion (Tityus serrulatus) on nerve fibres of the rabbit cervical vagus were studied by the single sucrose‐gap technique. Scorpion venom (1 μg/ml) increased irreversibly the duration of the B component of the compound action potential of the vagus nerves, leaving the C component with its normal configuration. Tetrodotoxin (200 n m) supressed the prolongation of the action potential duration in venom‐treated B fibres.

At the same concentration (1 μg/ml), scorpion venom reduced the amplitude and the rate constant of decay of the hyperpolarization produced by tetanic stimulation of non‐myelinated nerve fibres.

A lower concentration (0.2 μg/ml) blocked completely the hyperpolarization of the potassium‐activated response. After washing, the potassium‐activated response partially recovered its amplitude but there was a significant increase in the time constant of the decay of hyperpolarization.

It is suggested that scorpion venom may modify the sodium pumping mechanism within fibres as well as affecting the passive and active sodium permeability systems.
Storage of biogenic amines in guinea‐pig brain synaptosomes: influence of proton gradient and membrane potential
Authors: Affolter H. , Peyer M. , Pletscher A.
Published: July 2012

The effects of K+, NaCN and the ionophores monensin, nonactin and carbonyl‐cyanide‐p‐trifluoro‐methoxyphenylhydrazone (FCCP) on the contents of [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT), [3H]‐dopamine and [3H]‐noradrenaline ([3H]‐NA) in guinea‐pig synaptosomes preloaded with these amines were measured.

In the presence of Ca2+, K+ markedly reduced the amine content of the synaptosomes, indicating an acceleration of spontaneous amine release. In the absence of Ca2+, K+ had much less effect.

Monensin, nonactin and FCCP caused a release of all the three labelled amines. This release was considerably faster and more marked than that induced by K+ and showed no dependence on Ca2+. The ionophores did not release lactate‐dehydrogenase from synaptosomes.

NaCN, a blocker of oxidative energy production, did not enhance the spontaneous release of [3H]‐5‐HT nor did it influence the monensin‐induced release of [3H]‐5‐HT.

It is concluded that (a) the intragranular storage of 5‐HT, dopamine and NA is dependent on the maintenance of a pH‐gradient across the granular membrane as well as on the granular membrane potential; (b) the ionophores cause a non‐exocytotic release of granular amines, and (c) blood platelets are partial models for aminergic brain neurones as far as intragranular amine storage is concerned.
In vivo characterization of histamine H1‐ and H2‐receptors in the rat stomach microcirculation
Authors: Koo A.
Published: July 2012

Using a video microscope system, an in vivo microcirculation preparation was designed to characterize histamine receptors in the rat stomach submucosal arterioles (diameter 50 μm).

Each in vivo stomach microcirculation preparation received topically applied multiple concentrations of either the selective histamine H1‐ or H2‐ receptor agonist and antagonist and the respective responses (changes of the arteriolar diameter) were used to construct the concentration‐response curves.

Results showed that both 2‐thiazolylethylamine and impromidine, the respective selective H1‐and H2‐receptor agonists, produced concentration‐dependent vasodilator responses in the in vivo stomach submucosal arterioles. These vasodilator responses were competitively and selectively blocked by the respective H1‐receptor antagonist mepyramine and the H2‐receptor antagonist cimetidine.

Data from each in vivo preparation were examined separately to yield a Schild plot and a Hill plot, from which the in vivo estimates of the pA2 value, the slope of the Schild plot, and the Hill coefficient were obtained.

The estimated pA2 values for mepyramine (9.60 ± 0.033, mean ± s.e. mean) and cimetidine (5.98 ± 0.037) conformed to similar values found in other tissues, showing that the rat stomach microvascular H1‐ and H2‐receptors are of the same nature as similar receptors elsewhere.

Both the Hill and the Schild plots yielded regressions with unity slopes, indicating that the agonist‐receptor and the antagonist‐receptor reactions followed a simple one‐to‐one stoichiometry.

The findings in the present study are discussed and compared with those from other in vitro tissue preparations; it appears that the present in vivo technique is a satisfactory system for characterizing receptors in the vascular smooth muscle of the microcirculation.
The effects of yohimbine on presynaptic and postsynaptic events during sympathetic nerve activation in cattle iris: a critique of presynaptic receptor theory
Authors: Kalsner Stanley
Published: July 2012

The effects of presynaptic α‐adrenoceptor blockade on both the efflux of 3H‐transmitter and on the magnitude of the effector response were measured simultaneously in a smooth muscle preparation which responds to field stimulation with noradrenergic β‐receptor‐mediated relaxation.

In the presence of atropine, the circular muscle of cattle iris relaxes in response to noradrenaline and to field stimulation at 2 Hz with 10, 20, 50 and 100 pulses:

Yohimbine (3 × 10−6M), a potent presynaptic α‐adrenoceptor antagonist, increased the stimulation‐induced efflux of tritium to about 2.0 times control values and, contrary to theory, did so to a similar extent regardless of pulse number and with apparent indifference to the synaptic concentration of transmitter, as confirmed by the varying size of the postsynaptic response.

In most cases, yohimbine had no significant effect on the magnitude of the relaxations to nerve stimulation.

It is concluded that negative feedback regulation of transmitter release, if it functions at all, and this itself seems doubtful, would not have a substantial impact on the size of the effector response.
Vitamin C increases the formation of prostacyclin by aortic rings from various species and neutralizes the inhibitory effect of 15‐hydroperoxy‐arachidonic acid
Authors: Beetens Johan R. , Herman Arnold G.
Published: July 2012

Aortic rings from rats, rabbits and guinea‐pigs produce different amounts of 6‐oxo***‐prostaglandin F1α (6‐oxo‐PGF1α), the stable breakdown product of prostacyclin, i.e. 2760 ± 195, 160 ± 10 and 87 ± 17 pg 6‐oxo‐PGF1α per mg wet weight in 30 min.

Vitamin C enhances the production of 6‐oxo‐PGF1α by the aortic tissue of these three species, independent of their basal release. This increase was only significant if vitamin C was present in the preincubation as well as in the incubation fluid.

15‐Hydroperoxy‐arachidonic acid inhibits the production of 6‐oxo‐PGF1α (IC50:6 μm) and this inhibitory effect was completely neutralized by vitamin C.

The increased production of 6‐oxo‐PGF1α is not due to an increased release of the substrate arachidonic acid. It is suggested that vitamin C enhances the formation of 6‐oxo‐PGF1α by protecting the cyclo‐oxygenase and PGI‐synthase.
Indomethacin enhances the effect of histamine on airways resistance in the anaesthetized guinea‐pig
Authors: Mitchell H.W.
Published: July 2012

In anaesthetized guinea‐pigs intravenous histamine caused an increase in airways resistance (RA) and a fall in dynamic compliance (CDyn).

Indomethacin (1 mg kg−1, i.v.) significantly enhanced the effect of histamine on RA. Indomethacin also increased the basal RA and the RA response to a histamine infusion. The effect of indomethacin on CDyn was less consistent but here also there was a trend for an increased response to histamine. Sodium carbonate (the vehicle for indomethacin, 0.05 ml 100 mm solution) had no effect on RA or CDyn in control experiments.

Propranolol (0.1 mg kg−1, i.v.) enhanced the effect of histamine on RA in animals pretreated with either indomethacin or Na2CO3 vehicle, but the effect was more consistent in indomethacin pretreated animals.

Indomethacin also tended to enhance the effect of histamine on RA in animals pretreated with reserpine or BW755c but it had little effect on the CDyn response to histamine.

The results show that indomethacin augments the responsiveness of the airways to histamine in the anaesthetized guinea‐pig. The results with propranolol and reserpine suggest that an operational β‐adrenergic system is not required for the effect of indomethacin on RA. No confirmation for lipoxygenase involvement was obtained with the lipoxygenase inhibitor, BW755.
Characterization of the opiate receptor population mediating inhibition of VIP‐induced secretion from the small intestine of the rat
Authors: Coupar Ian M.
Published: July 2012

Net water transport was measured from the jejunum of anaesthetized rats by a re‐circulation technique.

Several narcotic analgesics were administered intravenously and assessed for activity in reversing net fluid secretion induced by intra‐arterial infusion of vasoactive intestinal peptide (VIP).

The μ‐opiate agonists, morphine, RX 783006 and FK 33–824 produced full reversal of the secretory phase of the VIP response, but failed to restore totally fluid transport to the control level of net absorption.

The κ‐agonist, ethylketocyclazocine, caused only partial reversal of VIP‐induced secretion while the more selective κ‐agonist, MR 2034, produced a small though non‐significant antisecretory effect at high doses. The δ‐agonist, d‐Ala2‐d‐Leu5‐enkephalin also had negligible antisecretory activity.

Naloxone caused a parallel displacement to the right of the antisecretory dose‐response line to morphine. The ‘in vivo PA2’ value of naloxone was 7.14.

The results are compared with previously published antinociceptive activities of the opiate agonists and in vivo pA2 values of naloxone. It is concluded that stimulation of μ‐opiate receptors mediates inhibition of VIP‐induced fluid secretion from the rat jejunal mucosa.
Age related changes in the antilipolytic effects of nicotinic acid in rat adipose tissue
Authors: Caparrotta L. , Fassina G. , Gaion R.M. , Tessari F.
Published: July 2012

The effect of nicotinic acid on lipolysis was tested in vitro in adipose tissue from three groups of rats, selected according to age: 6–7 weeks, 10–12 weeks and 16–20 weeks old.

Although the changes were not statistically significant, the basal release of free fatty acid (FFA) was increased and glycerol was decreased by nicotinic acid (0.01–1 mm); the drug caused a statistically significant increase in basal FFA: glycerol ratio in a concentration‐dependent manner. This ratio also increased with age in the absence of drug.

(−)‐Noradrenaline (10 μm) and theophylline (3 mm) each stimulated lipolysis. When glycerol release was calculated as a percentage increase, the effects of these drugs became more marked with age. By contrast, the highest absolute rate of induced release occurred in adipose tissue from the youngest rats.

The lipolytic effect of 10 μm (−)‐noradrenaline was generally unaffected by nicotinic acid except in adipose tissue from the oldest rats when the glycerol release was reduced by 1 mm nicotinic acid, although it did not alter FFA: glycerol ratio.

The stimulation of glycerol release induced by 3 mm theophylline was not affected by the presence of nicotinic acid in the youngest rats, but the drug elicited a concentration‐dependent antilipolytic effect in adipose tissue from 10–12 weeks old rats, which was even more pronounced in the oldest animals. Lower theophylline concentrations (0.6–1 mm) were also sensitive to nicotinic acid inhibition in the 6–7 weeks old rats. In the presence of theophylline, nicotinic acid had no effect on FFA: glycerol ratio.

These data show a direct influence of age on the antilipolytic action of nicotinic acid.
Comparison of two calcium antagonists, verapamil and fendiline, in an experimental model of myocardial ischaemia mimicking classical angina on effort
Authors: Csik Vera , Szekeres L. , Udvary Eva
Published: July 2012

The effects of verapamil (0.15/kg) and fendiline (3 mg/kg) were studied in anaesthetized, thoracotomised dogs with a critical constriction of the left anterior descending coronary artery, paced in excess of the initial rate by 60–70 beats/min. Epicardial ST‐segment elevation and changes in lactate uptake were used to assess the severity of myocardial ischaemia.

Both drugs prevented the ST‐segment elevation and the reduced lactate uptake that resulted from atrial pacing.

The anti‐ischaemic effect of fendiline is mainly due to its negative chronotropic action, whereas that of verapamil is due in part to bradycardia and in part to the reduced preload and afterload. In addition, both agents increase coronary flow to the ischaemic area and thus improve the myocardial oxygen supply/oxygen requirement ratio.
Effect of 6‐hydroxydopamine on bovine adrenal chromaffin cells in culture
Authors: Kirpekar S.M. , Nobiletti J. , Trifaró J.M.
Published: July 2012

The effect of 6‐hydroxydopamine on the catecholamine content and cell morphology of bovine adrenal chromaffin cells in culture was investigated.

6‐Hydroxydopamine markedly reduced the catecholamine content of the cultured chromaffin cells after 6 and 24 h exposure. The effect was dose‐related, with half‐maximal depletion occurring at 2.4 × 10−5 M

Cells exposed to 6‐hydroxydopamine for 3 h and then to normal medium without the drug for 3 h more showed the same degree of toxicity as cells exposed to the drug for the entire 6 h.

Ascorbate at high concentrations also exhibited toxicity toward chromaffin cells between 6 and 24 h of exposure.

6‐Hydroxydopamine produced marked changes in cell morphology. At 1 h the cells appeared normal, at 3 h the processes were markedly shortened, and at 6 h they were completely retracted. On exposure for 24 h there were gross morphological changes and most cells were detached and free‐floating in the medium.

The toxicity of 6‐hydroxydopamine in bovine adrenal chromaffin cells is discussed.
Propranolol‐induced airway hyperreactivity in guinea‐pigs
Authors: Ney U.M.
Published: July 2012

In anaesthetized, spontaneously breathing guinea‐pigs, enhanced bronchoconstrictor responses (↑ RL) to histamine were measured following intravenous injection of practolol, (±)‐propranolol, (+)‐ and (−)‐propranolol.

Propranolol enhanced not only histamine‐ but 5‐hydroxytryptamine (5‐HT)‐induced bronchoconstrictions and its effects lasted up to 2 h.

This increased airway sensitivity was not due to β‐adrenoceptor blockade because: (a) similar effects were produced by racemic propranolol and its two isomers (+)‐ and (−)‐propranolol and (b) whilst equal doses of (±)‐ and (+)‐propranolol produced the same potentiation of histamine bronchoconstriction, only (±)‐propranolol also caused a measurable β‐adrenoceptor blockade in the airways.

The enhanced histamine‐ and 5‐HT‐induced bronchoconstrictions were antagonized by the leukotriene antagonist FPL 55712 and by the lipoxygenase/cyclo‐oxygenase inhibitor BW755c.

The results demonstrate that endogenously released leukotrienes can produce not only a direct bronchospasm but may enhance the effects of other bronchoconstrictor agents.

The relevance of this leukotriene‐mediated hyperreactivity to the non‐specific airway hyperreactivity seen in asthmatics is discussed.
The effects of chlormethiazole on single unit activity in rat brain; interactions with inhibitory and excitatory neurotransmitters
Authors: Gent J.P , Wacey T.A.
Published: July 2012

Extracellular recordings were made of single unit activity in the brainstem of urethane anaesthetized rats. Drugs were applied by microiontophoresis from multibarrelled micropipettes or administered intraperitoneally.

Chlormethiazole (CMZ) caused a decrease in spontaneous firing rate when applied with high currents (>40 nA).

When applied with lower currents CMZ did not cause changes in firing rate, but enhanced the inhibitory effects of γ‐aminobutyric acid (GABA), muscimol and glycine in a dose‐dependent manner. The inhibitory actions of acetylcholine were not affected.

Excitatory responses to glutamate and acetylcholine were unaffected by applications of CMZ which caused potentiation of GABA, muscimol and glycine. When applied at higher currents CMZ caused a decrease in the response to glutamate.

Intraperitoneal administration of CMZ (50–600 μmol kg−1) also enhanced responses to microiontophoretically applied GABA, muscimol and glycine.

These results are compared with those reported for other anticonvulsant drugs and possible mechanisms of action of CMZ are discussed.
Effects of sodium and calcium concentrations on the potentiation by indomethacin of the responses of rabbit mesenteric and coeliac arteries to vasoconstrictor agonists
Authors: Novelli Ethel L.B. , Oshiro Maria E.M. , Paiva Antonio C.M. , Paiva Therezinha B.
Published: July 2012

The contractile responses of the rabbit isolated coeliac and mesenteric arteries to five agonists (angiotensin, adrenaline, histamine, acetylcholine and 5‐hydroxytryptamine), but not to K+, were potentiated by indomethacin (8.4 μm)

The potentiation was similar whether indomethacin was added 1 h before or during the response to the agonist.

The agonists that were more potentiated by indomethacin were also more dependent on the Ca2+ concentration in the medium, for their contractile action.

Prostaglandin E2 in low concentrations (micromolar) did not affect the resting tone but relaxed the agonist‐contracted arteries both in normal and in Ca2+‐free medium.

No prostaglandin E (PGE)‐like substances were detected in the perfusate of arteries contracted by angiotensin.

Reduction of the external Na+ concentration to 80 mm resulted in potentiation of the responses to agonists (angiotensin and adrenaline), but not to K+, and in this Na+‐deficient medium potentiation by indomethacin was greatly reduced.

These results suggest that potentiation by indomethacin of the arteries' responses to vasoactive substances may result from that drug's inhibitory action on sodium influx and consequent increase in calcium entry through receptor‐operated channels.
The contractile response to and the release of noradrenaline by transmural nerve stimulation in the guinea‐pig vas deferens and a comparison with the response to noradrenaline
Authors: Gillespie J.S. , Macrae I.M.
Published: July 2012

The release of noradrenaline from the guinea‐pig vas deferens by transmural stimulation was measured electrochemically after separation by h.p.l.c. Variations in release with different durations of stimulation were then compared with the mechanical response during stimulation.

During long periods of 270 s of stimulation at 10 Hz the average release of noradrenaline in the final 250 s remained at about 50% of that released during the first 20 s yet the mechanical response throughout the later time declined to near zero.

Superfusion with constant concentrations of noradrenaline produced mechanical responses similar to those from transmural nerve stimulation, an initial rapid contraction declining to a low level of maintained activity. During the later period, when the response to infused noradrenaline was low, the twitch response to transmural stimulation was potentiated.

Phentolamine 10−6 m reduced the potentiation of the twitch response to transmural stimulation by noradrenaline and propranolol 10−6 m enhanced the potentiation.

These results suggest that the decline in the adrenergic component of the response to prolonged transmural nerve stimulation is not the result of a decline in noradrenaline release but mainly due to desensitization to the contractile effect of noradrenaline. Since the similar desensitization produced by infused noradrenaline does not reduce the twitch response to transmural nerve stimulation it is unlikely that the transmitter responsible for that component is noradrenaline.
Sensitivity to indomethacin of tetrodotoxin‐resistant contractions of smooth muscle from the base of rabbit bladder
Authors: Downie J.W. , Slack B.E.
Published: July 2012

Tetrodotoxin (TTX) reduced the contractions to field stimulation of strips of rabbit bladder base by 58% of control (at 40 Hz), and increased the spontaneous activity occurring between the evoked responses. The TTX‐resistant contractions resembled the spontaneous activity in that they were of comparable size and poorly sustained; in the presence of indomethacin, TTX produced a significantly greater reduction (to 13% of control at 40 Hz), of the evoked contractions. Indomethacin abolished spontaneous activity in the presence and absence of TTX, but did not affect evoked responses in strips that were not exposed to TTX. The results imply that a prostaglandin‐like substance may potentiate residual evoked responses in TTX‐treated strips, but does not contribute to field stimulation‐induced contractions in untreated bladder base smooth muscle.
The pharmacological modulation of [3H]‐disaturated phosphatidylcholine overflow from perifused lung slices of adult rats: a new method for the study of lung surfactant secretion
Authors: Gilfillan A.M. , Hollingsworth M. , Jones A.W.
Published: July 2012

Lung slices from adult rats incubated in [methyl‐3H]‐choline chloride formed [3H]‐disaturated phosphatidylcholine ([3H]‐DSPC) which was used as an index of lung surfactant.

The slices were perifused after 3 h incubation in [methyl‐3H]‐choline chloride and the overflow of [3H]‐DSPC, as a rate coefficient, was used as a measure of surfactant secretion. The basal overflow of [3H]‐DSPC rapidly declined over the first 30 min of perifusion and then declined slowly.

Salbutamol induced a prolonged, and sometimes delayed, increase in [3H]‐DSPC overflow, which was reduced by (±)‐propranolol. Potassium chloride produced an immediate, and usually transient, increase in [3H]‐DSPC overflow which was not modified by atropine or (±)‐propranolol. Adenosine 5′‐triphosphate, but not phenylephrine, also increased [3H]‐DSPC overflow.

This method can measure the magnitude and time‐course of lung surfactant secretion induced by drugs.
Differential anatomical location of [3H]‐N,n‐propylnorapomorphine and [3 H]‐spiperone binding sites in the striatum and substantia nigra of the rat
Authors: Hall M.D. , Jenner P. , Kelly E. , Marsden C.D.
Published: July 2012

Specific [3H]‐spiperone and [3H]‐N,n‐propylnorapomorphine (NPA) binding was measured in striatum and substantia nigra of the rat following unilateral 6‐hydroxydopamine (6‐OHDA) lesions of the medial forebrain bundle, kainic acid lesions of the substantia nigra or striatum, and following decortication.

Binding sites labelled by [3H]‐spiperone in striatum were found to lie on striatal cell bodies and on the terminals of cortico‐striate glutamate fibres, but not on presynaptic dopamine terminals. In contrast, binding sites labelled by [3H]‐NPA were demonstrated on striatal cell bodies and on the terminals of nigro‐striatal dopamine fibres, but not on cortical afferents.

In substantia nigra, specific [3H]‐spiperone binding sites were found only on non‐dopamine cell bodies. No clear evidence was found for their existence on dopamine cell bodies, the terminals of strio‐nigral fibres or the terminals of cortico‐nigral fibres. In contrast, specific binding sites for [3H]‐NPA were found on dopamine cell bodies and the terminals of strio‐nigral fibres. Localization on non‐dopamine cell bodies or on cortico‐nigral fibres was not demonstrated.

These studies support the concept of differential localization of agonist and antagonist binding sites.
Glycine‐induced changes in acetylcholine release from guinea‐pig brain slices
Authors: Beani Lorenzo , Bianchi Clementina , Siniscalchi Anna , Tanganelli Sergio
Published: July 2012

The effect of glycine (Gly) on acetylcholine (ACh) release from superfused, resting or electrically‐stimulated slices of guinea‐pig caudate nucleus (CN), brain stem (BS) and cerebral cortex (CC) was studied.

The amino acid 1 × 10−4‐6 × 10−3mol l−1 reduced the electrically‐induced release and increased the spontaneous and KCl‐evoked transmitter outflow, mostly in CN but also in BS, whereas it was ineffective in CC. Taurine, chosen as a structurally related compound, moderately affected only the spontaneous release in CN.

Strychnine 2 × 10−7 mol l−1 was per se ineffective, but prevented most Gly effects. The Gly‐induced increase of ACh outflow in resting CN slices, however, could be completely antagonized only by administering strychnine and picrotoxin together.

These findings suggest that: (i) the overall pattern of Gly influence on cholinergic function is similar to that previously described for γ‐aminobutyric acid (GAB A); (ii) specific receptors seem to be present in BS and, above all, in CN; (iii) a positive cooperation between endogenous GAB A and Gly is evident in resting CN slices; (iv) the absence of any apparent endogenous glycinergic control on the cholinergic neurones casts doubt on but does not exclude the existence of glycinergic neurones in CN.
Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle
Authors: Campbell Terence J.
Published: July 2012

The effects of Class I antiarrhythmic drugs on the maximum rate of depolarization of guinea‐pig ventricular action potentials were studied by standard microelectrode techniques.

The ability of seven different drugs to depress in unstimulated tissue (‘resting block’) was found to correlate poorly with the lipophilicity (log P) of the compounds and only a little better with their molecular weights.

Depression of in stimulated tissue was studied for 11 drugs and found, in all cases, to increase with stimulation frequency (‘rate‐dependent block’).

The rapidity of onset of rate‐dependent block (at approximately equipotent concentrations) varied markedly between drugs. It correlated well with molecular weight (r = 0.83; P < 0.01).

The time constant of recovery from rate‐dependent block (ire) also correlated very well with molecular weight (r = 0.94; P < 0.001) for the seven drugs thus studied.

A simplified model for the interaction of Class I drugs with the fast sodium channel is proposed in which the drugs all act as ‘inactivation enhancers’; (as suggested by other workers) but in which their molecular weight plays a central role in determining the kinetics of this interaction.
Sgd 101/75: cardiovascular effects in various animal preparations; interactions with vascular postjunctional α1‐ and α2‐adrenoceptors
Authors: Mathy M.J. , Thoolen M.J.M.C. , Timmermans P.B.M.W.M. , van Zwieten P.A.
Published: July 2012

The effect of the imidazolidine Sgd 101/75 (2‐[2‐methylindazol‐4‐imino]‐imidazolidine HCl) on blood pressure, as well as its α‐adrenoceptor agonist activity and affinity for these receptors, were examined in various animal preparations.

After both intravenous administration to conscious spontaneously hypertensive rats and intravenous injection or infusion via the vertebral artery in chloralose‐anaesthetized cats, Sgd 101/75 (1–10 mg kg−1) elicited pressor responses. Intracisternal application of Sgd 101/75 (1 mg kg−1) to chloralose‐anaesthetized cats did not affect blood pressure.

In the pithed rat and pithed cat the vasopressor responses to i.v. Sgd 101/75 were effectively antagonized by prazosin (0.1–1.0 mg kg−1, i.v.) but much less by yohimbine (1 mg kg−1, i.v.).

Sgd 101/75 proved a less potent and less selective displacing agent of [3H]‐clonidine‐ and [3H]‐prazosin‐binding in rat brain membranes than clonidine.

The results suggest that Sgd 101/75 is a selective α1‐adrenoceptor agonist, devoid of any centrally or peripherally mediated hypotensive activity; this is probably caused by the low capacity of Sgd 101/75 for stimulating α2‐adrenoceptors.
Neonatal capsaicin treatment impairs vasopressin‐mediated blood pressure recovery following acute hypotension
Authors: Bennett T. , Gardiner S.M.
Published: July 2012

Rats were treated with a single injection of either capsaicin (50 mg kg−1 s.c.) or vehicle on day 2 after birth. When the animals were adult, they were challenged with osmotic (water deprivation) and haemodynamic (acute hypotension) stimuli that normally evoke vasopressin release.

Capsaicin‐treated and vehicle‐injected rats showed similar body weight losses and plasma osmolalities following 48 h of water deprivation. Thus it appears that neonatal treatment with capsaicin does not impair the antidiuretic response to plasma hyperosmolality.

Following acute ganglion blockade in the presence of angiotensin converting enzyme inhibition, there was some recovery of blood pressure in the vehicle‐injected rats, but recovery was significantly (P < 0.001) less in the capsaicin‐treated animals. The recovery may be attributed to vasopressin since it was abolished by an antagonist selective for the pressor action of the peptide (d(CH2)5DAVP).

These results suggest that neonatal treatment with capsaicin impairs vasopressin‐mediated recovery of blood pressure following acute hypotension. The possible involvement of baro‐ or chemoreceptor afferents is discussed.
Biphasic effect of methylxanthines on acetylcholine release from electrically‐stimulated brain slices
Authors: Pedata Felicita , Pepeu G. , Spignoli G.
Published: July 2012

The effect of caffeine and aminophylline on the release of acetylcholine (ACh) was investigated in slices of rat cortex perfused with Krebs solution at rest and during electrical stimulation at frequencies of 0.2, 1 and 5 Hz.

Both methylxanthines added to the supervising Krebs solution at a concentration of 50 μm enhanced ACh release. Conversely, at a concentration of 0.5 mm both caffeine and aminophylline decreased ACh release.

Neither caffeine nor aminophylline affected the unstimulated ACh release.

Dipyridamole 10 μm potentiated the inhibitory effect of adenosine 30 μm on ACh release and antagonized both the stimulatory and inhibitory effects of caffeine on ACh release.

The inhibitory effect of caffeine was antagonized by cyclohexyladenosine (CHA) 0.5 μM and N‐ethylcarboxamideadenosine (NECA) 5 μm.

The results indicate that methylxanthines exert both stimulatory and inhibitory effects on ACh release by acting on adenosine receptors. Methylxanthines may enhance the electrically‐evoked ACh release by antagonizing the effect of endogenous adenosine on inhibitory adenosine receptors. On the other hand the mechanism through which methylxanthines decrease ACh release remains obscure.
Some characteristics of the long‐latency component of the evoked muscle response induced by administration of catechol to the anaesthetized rat: a neurophysiological and neuropharmacological investigation
Authors: Dewhurst D.G.
Published: July 2012

Administration of catechol to rats anaesthetized with urethane produces a central excitatory state during which an EMG consisting of three temporally distinct components (M1, M2 and M3) can be recorded from forelimb and hindlimb muscles to electrical stimulation of cutaneous afferents.

The probability of occurrence of all three components was measured in flexor and extensor muscles of fore‐ and hindlimb and showed that the long latency component (M3) occurred less frequently in hindlimb muscles than forelimb and that its probability of occurrence in hindlimb extensors was significantly reduced as compared to flexors. A possible reflex pathway for this long latency component of the EMG is suggested.

Phenobarbitone (5 mg kg−1 i.v.) had no significant effect on the probability of occurrence of M1, M2 or M3.

These results suggest that the long latency component (M3) is not due to activation of a spino‐bulbo‐spinal reflex as has been previously suggested.

Cholinoceptor blocking drugs were found to reduce significantly the probability of occurrence of M2 and M3 and anticholinesterases to increase the probability of M2. None of the drugs was found to affect the short latency M1 component of the EMG. These results are discussed in relation to the possible reflex pathways of all three components of the EMG.
Pathophysiological mechanisms of sudden death induced by platelet activating factor
Authors: Lefer Allan M. , Müller Hugo F. , Smith J. Bryan
Published: July 2012

Platelet activating factor (Paf) (15–40 μg−1) kills male rabbits within 3 to 5 min. Intravenous injection of Paf at a dose of 15 μg kg−1 is uniformly lethal, and the rabbits died within 4.5 ± 0.4 min.

The sudden death is characterized by cessation of respiration, a marked decrease in mean arterial blood pressure (M.A.B.P.), and 8 fold increases in plasma thromboxane B2 (TxB2) concentrations with only modest elevation in plasma 6 keto‐prostaglandin F1α (6‐keto PGF1α) concentrations.

Pretreatment with the cyclo‐oxygenase inhibitor, ibuprofen (6.25 mg kg−1), or with the thromboxane synthetase inhibitors dazoxiben (2.5 mg kg−1), CGS‐13080, or OKY‐046 1 mg kg−1) increased survival rates to 83–100%.

Protected rabbits showed only modest changes in M.A.B.P. and no significant increase in plasma TxB2 concentrations. The protective drugs showed a dose‐related action on M.A.B.P., plasma TxB2 concentration and mortality rate in Paf‐induced sudden death.

The mechanisms of the protection appeared to be prevention of platelet aggregation (leading to pulmonary thrombosis) and pulmonary and coronary vasoconstriction. However, Paf does not appear to exert direct vasoconstrictor effects in isolated coronary or pulmonary arteries.

The effects of Paf in vivo appear to be mediated by TxA2 released by activated platelets in the absence of the protective effects of prostacyclin. Inhibition of thromboxane synthesis effectively prevents the Paf‐induced sudden death.