bluuebunny/crossref_metadata_2025 huggingface dataset:
An analysis of the action of pentobarbitone on the excitatory postsynaptic potentials and membrane properties of neurones in the guinea‐pig olfactory cortex
Authors: Richards C.D. , Strupinski K.
Published: July 2012

Intracellular recordings were made from neurones in slices of guinea‐pig olfactory cortex maintained in vitro at 37°C. The average membrane potential was 63 ± 12 mV and the input resistance of these cells was 42 ± 20 MΩ (mean ± s.d.). Stimulation of the lateral olfactory tract (l.o.t.) generated a transient depolarization in these cells which had the characteristics of an excitatory postsynaptic potential (e.p.s.p.). If the e.p.s.p. was of sufficient amplitude it culminated in an action potential. The e.p.s.p. was potentiated by repetitive stimulation at 10–50 Hz and showed post‐tetanic potentiation after a prolonged period of high frequency stimulation (50–100 Hz for 30–60 s).

Pentobarbitone (0.1‐0.5 mM) depressed the e.p.s.p. reversibly but was without effect on the resting membrane potential, input resistance or time constant of the neurones. Pentobarbitone did not inhibit potentiation of the e.p.s.p. by a preceding conditioning shock.

It is concluded that pentobarbitone does not affect the passive membrane properties of neurones in the olfactory cortex. The depressant action of pentobarbitone on synaptic transmission results from a decrease in the amount of transmitter released in response to a nerve impulse, or a decrease in the sensitivity of the postsynaptic membrane to the transmitter or a combination of both effects.
Behavioural and adrenocortical responses to nicotine measured in rats with selective lesions of the 5‐hydroxytryptaminergic fibres innervating the hippocampus
Authors: Balfour D.J.K. , Benwell M.E.M. , Graham C.A. , Vale A.L.
Published: July 2012

The effects of acute and subchronic (7) injections of nicotine (0.4 mg kg−1, s.c.) and of selective lesions of the 5‐hydroxytryptaminergic (5‐HTergic) pathways innervating the hippocampus on the spontaneous behaviour of rats in an elevated X‐maze composed of two open and two enclosed runways have been examined.

Subchronic, but not acute, nicotine increased total spontaneous activity. Neither acute nor subchronic nicotine altered the ratio of open:closed runway entries.

Destruction of the 5‐HTergic pathways innervating the hippocampus with 5,7‐dihydroxytryptamine caused a reduction in the ratio of open:enclosed runway entries.

Acute, but not subchronic, nicotine caused a significant increase in plasma corticosterone. The lesion had no effects on the plasma levels of this hormone.

No significant interactions between the lesion and the responses to nicotine were observed.

The data failed to provide any evidence that hippocampal 5‐HTergic systems may be implicated in the effects of nicotine on the spontaneous behaviour of the rat.
Effect of chronic treatment with 5‐HT1 agonist (8‐OH‐DPAT and RU 24969) and antagonist (isapirone) drugs on the behavioural responses of mice to 5‐HT1 and 5‐HT2 agonists
Authors: De Souza Rosemarie J. , Goodwin Guy M. , Green A. Richard , Heal David J.
Published: July 2012

The effects of chronic (14 day) administration to mice of the 5‐HT1 agonists 8‐hydroxy 2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and 5‐methoxy‐3 (1,2,3,6‐tetrahydropyridin‐4‐yl) IH indole (RU 24969) on the hypothermic response to 8‐OH‐DPAT and the locomotor response to RU 24969 have been examined.

Chronic administration of 8‐OH‐DPAT (5 mg kg−1, s.c.) resulted in an attenuated hypothermic response to this drug given subcutaneously (s.c.) or intracerebroventricularly (i.c.v.) but did not alter the locomotor response to RU 24969.

Chronic injection of RU 24969 (3 mg kg−1, i.p.) produced an attenuated locomotor response to this drug given i.p. or i.c.v. but not the hypothermic response to 8‐OH‐DPAT (0.5 mg kg−1, s.c).

Chronic administration of the putative presynaptic 5‐HT, antagonist isapirone (10 mg kg−1, i.p.) decreased the hypothermic response following 8‐OH‐DPAT injection but did not alter RU 24969‐induced locomotion.

Chronic treatment with 8‐OH‐DPAT (5 mg kg−1, s.c.) produced a modest enhancement of the 5‐HT2 receptor‐mediated head‐twitch behaviour initiated by 5‐hydroxytryptophan injection while chronic isapirone decreased this behavioural response. 5‐HT2 receptor number in frontal cortex was unaltered by isapirone treatment but markedly decreased (34%) by chronic 8‐OH‐DPAT.

These data suggest that chronic administration of the 5‐HT, agonists induces tolerance in their respective responses but not cross‐tolerance, while chronic isapirone may down‐regulate the 5‐HT1A site in a matter analogous to that seen by 5‐HT2 receptors following 5‐HT2 receptor antagonists.

The data further demonstrate that chronic treatment with 8‐OH‐DPAT and isapirone alter postsynaptic 5‐HT2 receptor function although 5‐HT2 receptor number in the frontal cortex did not correlate with the behavioural change.
Effects of α‐adrenoceptor agonists and antagonists on ouabain‐induced arrhythmias and cardiac arrest in guinea‐pig
Authors: Thomas George P. , Tripathi Rajit M.
Published: July 2012

Effects of α‐adrenoceptor agonists and antagonists with different affinity for α1‐ and α2‐receptors on ouabain‐induced arrhythmias in guinea‐pigs were studied.

Early arrhythmias, ventricular fibrillation and cardiac arrest were induced in anaesthetized guinea‐pigs by the slow intravenous infusion of ouabain.

Phenylephrine and yohimbine potentiated the cardiotoxicity of ouabain significantly whereas prazosin and clonidine showed significant antiarrhythmic effects and delayed the cardiac arrest.

It is concluded that selective α1‐receptor stimulation and α2‐receptor blockade increases the cardiotoxic effects of ouabain and selective α2‐receptor stimulation and α1‐receptor blockade inhibits ouabain‐induced arrhythmias and cardiac arrest in guinea‐pigs.
The inflammatory response of rabbit skin to topical arachidonic acid and its pharmacological modulation
Authors: Aked D. , Foster S.J. , Howarth A. , McCormick M.E. , Potts H.C.
Published: July 2012

The inflammatory reaction induced by the intradermal injection of arachidonic acid into the rabbit dermis has been investigated. Plasma extravasation was measured by the leakage of 125I‐albumin into the tissues and polymorphonuclear leukocyte (PMNL) accumulation was assessed histologically.

Arachidonic, 5,8,11,14,17‐eicosapentaenoic and 8,11,14‐eicosatrienoic acids, but not oleic, linoleic or linolenic acids, caused a concentration‐related plasma extravasation following their intra‐dermal injection. The plasma extravasation induced by arachidonic acid was dependent on PMNLs.

PMNL infiltration and plasma extravasation into arachidonic acid‐injected skin sites was inhibited by the mixed cyclo‐oxygenase‐lipoxygenase inhibitor, BW755C.

Arachidonic acid‐induced plasma extravasation was inhibited by cyclo‐oxygenase and 5‐lipoxygenase inhibitors but not by the Paf antagonist, kadsurenone.

The inflammation induced by arachidonic acid in the rabbit dermis may be a useful model for evaluating 5‐lipoxygenase inhibitors which could be potentially useful anti‐inflammatory agents for the treatment of psoriasis and other inflammatory diseases.
Mechanism of action of ketamine in the current and voltage clamped myelinated nerve fibre of the frog
Authors: Benoit E. , Carratù M.R. , Dubois J.M. , Mitolo‐Chieppa D.
Published: July 2012

The effects of the general anaesthetic ketamine, on the frog isolated node of Ranvier, were studied under current and voltage clamp conditions.

Ketamine (0.5 and 1 mM) reversibly decreased the amplitude of the action potential and increased both the duration of the action potential and the threshold potential. When the K current was blocked, spontaneous action potentials appeared after washout of the drug.

Ketamine rapidly blocked the Na current and more slowly modified a fraction of Na channels (about 10%) to give rise to a non‐inactivatable (late) Na current. After washout of the drug, the block reversed more rapidly than the ketamine‐induced late Na current disappeared.

Steady‐state outward, peak Na and ketamine‐induced late Na currents were rapidly and reversibly blocked by ketamine with an apparent dissociation constant of 0.7 mM.

Both peak Na and ketamine‐induced late Na currents were reversibly blocked by procaine.
The primary afferent depolarizing action of kainate in the rat
Authors: Agrawal S.G. , Evans R.H.
Published: July 2012

Dorsal roots (L3‐L7) isolated from immature (1–9 day old) rats were depolarized selectively by kainate (1–100 μM). L‐Glutamate (25–1000 μM), but not L‐aspartate, mimicked the action of kainate. N‐methylaspartate had no activity on these preparations and quisqualate was thirty times less active than kainate.

Depolarizations evoked by L‐glutamate (100–1000 μM) faded rapidly in the presence of L‐glutamate. Depolarizations evoked by kainate were depressed during the fade induced by L‐glutamate.

Certain electrically evoked C‐fibre volleys in dorsal roots or leg nerves of rats at any age were selectively depressed or abolished in the presence of kainate. The effect of kainate was more selective than that of γ‐aminobutyric acid or capsaicin.

Prolonged treatment of dorsal roots with kainate did not appear to be deleterious to C‐fibres.

It is suggested that certain primary afferent C‐fibres possess kainate receptors which may be activated physiologically by L‐glutamate released at their central terminations.
5‐Carboxamidotryptamine is a selective agonist at 5‐hydroxytryptamine receptors mediating vasodilatation and tachycardia in anaesthetized cats
Authors: Connor H.E. , Feniuk W. , Humphrey P.P.A. , Perren M.J.
Published: July 2012

We have attempted to characterize the 5‐hydroxytryptamine (5‐HT) receptors mediating bronchoconstriction, vasodilatation, vasodepression and tachycardia in anaesthetized cats following bilateral vagosympathectomy and β‐adrenoceptor blockade with propranolol.

5‐HT (1–100 μg kg−1 i.v.) caused dose‐related bronchoconstriction and tachycardia but variable and complex effects on diastolic blood pressure and carotid arterial vascular resistance.

In contrast, 5‐carboxamidotryptamine (5‐CT; 0.01–1 μg kg−1 i.v.) caused consistent, dose‐related decreases in diastolic blood pressure and carotid arterial vascular resistance and increases in heart rate. 5‐CT did not cause bronchoconstriction.

The 5‐HT‐induced bronchoconstriction was dose‐dependently antagonized by methiothepin, methysergide and ketanserin (10–100 μg kg−1 i.v.). The highest doses used of these antagonists did not antagonize bronchoconstriction induced by prostaglandin F2α. The high potency of all three antagonists indicate a 5‐HT2‐receptor mediated effect.

The 5‐HT‐ and 5‐CT‐induced tachycardia as well as the 5‐CT‐induced vasodepressor and carotid arterial vasodilator responses were dose‐dependently antagonized by low doses of methiothepin (10–100 μg kg−1 i.v.) and by high doses of methysergide (100–1000 μg kg−1 i.v.) but were little affected by ketanserin in doses up to 1000 μg kg−1 i.v. These selective effects of 5‐CT appear to be mediated by ‘5‐HT1‐like’ receptors.
Modulation of in vitro anaphylaxis of guinea‐pig isolated tracheal segments by azelastine, inhibitors of arachidonic acid metabolism and selected antiallergic drugs
Authors: Chand N. , Diamantis W. , Sofia R.D.
Published: July 2012

The ability of azelastine to influence antigen‐induced contractile responses (Schultz‐Dale phenomenon) in isolated tracheal segments of the guinea‐pig was investigated and compared with selected antiallergic drugs and inhibitors of arachidonic acid metabolism.

Indomethacin produced a significant leftward shift of the antigen concentration‐effect curve.

The inhibitory activity of azelastine on anaphylactic responses in guinea‐pig trachea was dependent on the duration of exposure (preincubation period).

The relative order of potency (antianaphylactic activity) at calculated IC50 level was as follows: FPL 55712 (a leukotriene receptor antagonist) > nordihydroguaiaretic acid (a lipoxygenase inhibitor) > p‐bromophenacyl bromide (a phospholipase A2 inhibitor) > BW 755c (a dual inhibitor of lipoxygenase and cyclo‐oxygenase) > theophylline (a phosphodiesterase inhibitor) > azelastine > diphenhydramine (H1 histamine‐receptor antagonist) > ketotifen > disodium cromoglycate. FPL 55712 (added 5 min before antigen challenge) was about 12 times as potent as azelastine (added 2 h before antigen challenge).

The incubation of tracheal segments with azelastine and BW 755c for a period of 30 min was found to inhibit indomethacin‐augmented anaphylactic responses. These observations seem to suggest that azelastine and BW 755c interfere with the synthesis/release of the products of lipoxygenase/leukotriene synthetase pathway (e.g., leukotrienes) in the mediation of allergic responses in airway smooth muscles.
Postsynaptic α1‐ and α2‐adrenoceptors in the vascular system of the herring gull, Larus argentatus
Authors: Hermansson Lars‐Erik , Johansson Pehr
Published: July 2012

The nature of the vascular α‐adrenoceptors has been studied in the herring gull, Larus argentatus.

In the anaesthetized herring gull, both phenylephrine and clonidine elicited dose‐dependent increases in arterial blood pressure.

The α1‐adrenoceptor antagonist prazosin was a better antagonist of phenylephrine than were the α2‐adrenoceptor antagonists yohimbine and rauwolscine.

Yohimbine and rauwolscine were better antagonists of clonidine than was prazosin.

The maximum response to phenylephrine, but not clonidine, was lower in reserpine‐treated birds, indicating that phenylephrine in high doses liberates endogenous catecholamines, which contribute to the effect.

It is concluded that the herring gull possesses postsynaptic, vascular α‐adrenoceptors, of both the α1‐ and α2‐subtypes, similar to those found in mammals.
In vitro effects of calcium entry blockers, chlorpromazine and fenoterol upon human pregnant myometrium contractility
Authors: Ballejo Gustavo , Calixto João B. , Medeiros Yara S.
Published: July 2012

The inhibitory effects of nifedipine, verapamil, cinnarizine (calcium entry blockers), chlorpromazine (a putative calmodulin antagonist) and fenoterol (a β2‐adrenoceptor agonist) on contractility in human isolated pregnant myometrium were studied.

Spontaneous contractions (present in 93% of the preparations) were inhibited in a concentration‐related manner by these compounds in the following order of potency: nifedipine > verapamil >> cinnarizine > chlorpromazine. Cinnarizine was effective only at a concentration greater than 100 μM. Fenoterol, at 10 μM, did not produce an inhibitory effect but decreased the frequency of spontaneous contractions.

All drugs, except fenoterol, produced a concentration‐dependent relaxation of K+‐induced contractions in the following order of sensitivity: nifedipine > verapamil >> chlorpromazine. Cinnarizine produced only about 40% of relaxation. Under these conditions nifedipine and verapamil were about 80 and 5 fold more potent respectively than when tested against spontaneous contractions. The potencies of chlorpromazine and cinnarizine did not differ in the two experimental conditions.

Both the spontaneous and K+‐induced contractions were inhibited in a time‐dependent manner in Ca2+‐free media and the responses were almost completely abolished in 70–100 min. Calcium addition to the medium rapidly restored both spontaneous or K+‐induced contractions.

To investigate further the role of intracellular calcium, K+‐depolarized preparations contracted by calcium 3 mM (40–60% of maximal contractions) were relaxed by these compounds. Nifedipine and verapamil showed a relaxation time course similar to that induced by calcium removal. Cinnarizine and fenoterol had no relaxant effect while chlorpromazine induced a slight and slow relaxation.

These findings suggest that calcium influx and calmodulin are involved in spontaneous contractions of pregnant human myometrium in vitro. Since nifedipine and verapamil were more potent against K+‐induced than spontaneous contractions, calcium channels activated by these conditions could be different. Finally, fenoterol, a β2‐adrenoceptor agonist, widely used as a tocolytic agent, blocked neither spontaneous nor K+‐induced contractions.
The mechanisms by which haemoglobin inhibits the relaxation of rabbit aorta induced by nitrovasodilators, nitric oxide, or bovine retractor penis inhibitory factor
Authors: Martin William , Smith Jerry A. , White David G.
Published: July 2012

The mechanisms by which haemoglobin and methaemoglobin inhibit the vasodilator actions of glyceryl trinitrate, sodium azide, nitric oxide, and the bovine retractor penis inhibitory factor (IF) were studied on rabbit endothelium‐denuded aortic rings.

Methaemoglobin was less effective than haemoglobin against each vasodilator, it was more effective at inhibiting the relaxation to azide than that to glyceryl trinitrate.

Glyceryl trinitrate was neither bound nor inactivated when passed through columns of haemoglobin‐agarose or methaemoglobin‐agarose. Azide was reversibly bound but less by haemoglobin‐agarose than by methaemoglobin‐agarose. Inhibition of the vasodilator actions of glyceryl trinitrate is not attributable therefore to a direct interaction with the haemoproteins, although a small part of the inhibition of azide‐induced relaxation by methaemoglobin is likely to be due to a direct interaction.

Columns of haemoglobin‐agarose were more effective than columns of methaemoglobin‐agarose in removing nitric oxide from solution. The greater ability of haemoglobin, compared to methaemoglobin, to inhibit vasodilatation induced by nitrovasodilators may therefore reflect the greater ability of haemoglobin to bind nitric oxide which is the active principle of the nitrovasodilators.

Neither the acid‐activated nor the inactive forms of IF were bound or inactivated when passed through columns of methaemoglobin‐agarose. Neither form of IF was retained on passage through colomns of haemoglobin‐agarose, but the resulting activity in the eluates was less than control, was unstable and, unlike the original activity, decayed rapidly on ice. The greater ability of haemoglobin, compared to methaemoglobin, to inhibit vasodilatation induced by IF might therefore reflect the greater ability of haemoglobin to interact with this vasodilator and inactivate it.
D2‐dopamine receptor‐mediated inhibition of intracellular Ca2+ mobilization and release of acetylcholine from guinea‐pig neostriatal slices
Authors: Fujiwara Hiroshi , Kato Noriko , Shuntoh Hisato , Tanaka Chikako
Published: July 2012

The effect of dopamine receptor activation on electrically‐or high K+ (30 mm)‐evoked neurotransmitter release and rise in intracellular Ca2+ concentration was investigated using slices of guinea‐pig neostriatum.

A specific D2‐dopamine receptor agonist, LY‐171555 (a laevorotatory enantiomer of LY‐141865: N‐propyl tricyclic pyrazole) at 10−6 m inhibited electrical stimulation‐and high K+‐evoked release of [3H]‐acetylcholine ([3H]‐ACh) to 47.7 ± 6.0% and 54.1 ± 5.0% of control, respectively. The maximal inhibition by LY‐171555 at 10−5 m was 54.8 ± 5.1% reduction of the control. The half‐maximal effective concentration (EC50) of LY‐171555 for the inhibition of [3H]‐ACh release was 2.3 × 10−7 m. A specific D2‐dopamine receptor antagonist, (−)‐sulpiride (10−7 m) reversed the inhibition of [3H]‐ACh release induced by LY‐171555. A specific D1‐dopamine receptor agonist, SK&F 38393 (2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐benzazepine) (10−5 m) had no effect on the release of [3H]‐ACh. LY‐171555 (10−6 m) also inhibited the high K+‐evoked endogenous glutamate release, by 47% of control. This inhibitory effect was reversed by (−)‐sulpiride (10−7 m).

We used a fluorescent, highly selective Ca2+ indicator, ‘quin 2’ to measure intracellular free Ca2+ concentrations ([Ca2+]i). Electrical stimulation of slices preloaded with quin 2 led to an elevation of relative fluorescence intensity and this response was reduced by the removal of Ca2+ from the bathing medium. These results indicate that the enhanced elevation in fluorescence intensity in the quin 2‐loaded slices reflects the increase of intracellular free Ca2+ concentration, [Ca2+]i.

The mixed D1‐and D2‐receptor agonist, apomorphine and LY‐171555 inhibited the increase of [Ca2+]i induced by electrical stimulation or high K+ medium, in a concentration‐dependent manner, while SK&F 38393 did not affect the increase of [Ca2+]i. The maximal inhibitory effect of LY‐171555 at 3 × 10−5 m was 35 ± 3% reduction in control values. The inhibitory effect of LY‐171555 was antagonized by (−)‐sulpiride (10−7 m).

There was a high correlation (r = 0.997, P < 0.05) between the D2‐receptor‐mediated inhibition of the stimulated rise of [Ca2+]i and [3H]‐ACh release.

When the slices were superfused with the Ca2+‐free medium containing EGTA (10−4 m) for 5 min, the rise in [Ca2+]i was markedly suppressed to 18.0% of control by LY‐171555 (10−6 m).

These data indicate that activation of the D2‐dopamine receptor suppresses the elevation of [Ca2+]i induced by depolarizing stimuli. This may be due to inhibition of mobilization of Ca2+ from the intracellullar store. We propose that the D2‐receptor‐mediated inhibition of transmitter release is probably due to a reduction in intracellular Ca2+ mobilization.
Electrophysiological effects of Ca antagonists, tetrodotoxin, [Ca]o and [Na]o on myocardium of hibernating chipmunks: possible involvement of Na‐Ca exchange mechanism
Authors: Kondo Noriaki
Published: July 2012

The electrophysiological performance of myocardium of hibernating chipmunks was investigated in the presence of Ca antagonists and tetrodotoxin, and the effects of high [Ca]o and low [Na]o were examined.

The action potential of the preparations was characterized by the low amplitude of the plateau phase (APp). Ca antagonists, nifedipine (10−6 m) and nitrendipine (2 × 10−6 m), did not significantly inhibit this APp or the contraction.

These nifedipine‐insensitive electromechanical responses were completely abolished by an internal Ca release inhibitor, ryanodine.

Both increasing [Ca]o and lowering [Na]o, by replacing Na by lithium or choline, also inhibited APp.

Tetrodotoxin (10−5 m) which markedly inhibited the initial rapid phase of the action potential slightly affected APp.

These results suggest that the plateau potential of the present preparations is controlled by a process linked to Ca release from internal stores, most likely the Na‐Ca exchange mechanism.
pH‐dependent stimulation by Ca2+ of prostacyclin synthesis in rat aortic rings: effects of drugs and inorganic ions
Authors: Ritter J.M. , Frazer C.E. , Taylor G.W.
Published: July 2012

Fresh rat aortic rings were incubated in HEPES‐buffered salt solutions. Extracellular Ca2+ stimulated the production of prostacyclin (PGI2), as determined by radioimmunoassay of its stable hydrolysis product 6‐oxo‐prostaglandin F1α. This action of Ca2+ was modified by H+ over the pH range 8.0–6.5. Stimulation by calcium ionophore A23187 was not pH‐dependent.

In parallel incubations of aortic rings with 45 Ca2+, followed by washing in the presence of La3+, tissue uptake of 45Ca2+ increased progressively as extracellular pH was increased from 6.5–8.0. Over this range intracellular pH, estimated by the distribution of [14C]‐dimethadione, varied from 5.9‐7.4.

Stimulation by Ca2+ of PGI2 synthesis was concentration‐dependent over the range 0.7–20 mm. The maximum effect was an increase of approx. 4 fold.

Nifedipine, but not verapamil or diltiazem, inhibited Ca2+‐stimulated PGI2 synthesis. A dihydropyridine compound that activates voltage‐dependent Ca2+ channels, Bay K 8644, did not increase PGI2 synthesis.

8‐(N, N‐diethylamino)‐octyl‐3,4,5 timethoxybenzoate (TMB‐8), an antagonist of intracellular Ca2+ mobilisation, inhibited basal and Ca2+‐stimulated PGI2 synthesis to a similar extent.

A solution containing 40 mm K+ reduced Ca2+‐stimulated PGI2 production. Mg2+ stimulated PGI2 synthesis in a pH‐dependent manner but was less potent than Ca2+. Other divalent cations (Mn2+, Ba2+ and Sr2+), and La3+ had little or no effect on basal or Ca2+‐stimulated PGI2 synthesis.
Effect of gastric secretagogues on the formation of inositol phosphates in isolated gastric cells of the rat
Authors: Puurunen Juhani , Schwabe Ulrich
Published: July 2012

The effects of compounds affecting gastric acid secretion were studied on the formation of inositol phosphates after prelabelling with [3H]‐inositol in enriched gastric parietal cells of the rat, prepared by isopycnic centrifugation with Percoll.

In cell preparations with 60 to 70% parietal cells, carbachol (10−6‐10−2 m) enhanced the accumulation of [3H]‐inositol monophosphate ([3H]‐IP1), [3H]‐inositol bisphosphate ([3H]‐IP2) and [3H]‐inositol trisphosphate ([3H]‐IP3) in a concentration‐dependent manner, an effect which was antagonized by 10−8 m atropine.

Li+ (0.5 − 30 mm) enhanced the basal and carbachol‐induced accumulation of all three [3H]‐inositol phosphates, the formation of [3H]‐IP1 being more sensitive to Li+ than those of [3H]‐IP2 and [3H]‐IP3.

The concentration of Ca2+ in the incubation medium did not affect the relative stimulation of the accumulation of [3H]‐inositol phosphates by carbachol, although the basal formation was higher in the presence of Ca2+ in the medium. In the absence of added Ca2+, the incorporation of [3H]‐inositol into phospholipids was increased—an effect which was further enhanced by the addition of EGTA to the medium.

Gastrin and pentagastrin (10−8 −10−5 m) enhanced the formation of [3H]‐inositol phosphates, although they were clearly less effective than carbachol. Histamine (10−6−10−3 m) had no effect of its own, but slightly attenuated the effect of carbachol. Cholecystokinin octapeptide (10−9−10−6 m) slightly increased the formation of [3H]‐inositol phosphates.

Indomethacin (10−4 m) had no consistent effect on the basal and carbachol‐induced accumulation of [3H]‐inositol phosphates, nor did prostaglandin E2 (10−5 m) modify it.

Adrenaline (10−3 m), 5‐hydroxytryptamine (10−3 m), forskolin (10−5 m), vasopressin (10−5 m), angiotensin II (10−5 m) and bombesin (10−9‐10−6 m) were all without effect.

We suggest that the hydrolysis of inositol phospholipids may be involved in the signal transduction mechanism by which the activation of the muscarinic and gastrin receptors on the parietal cells leads to Ca2+ mobilization and the stimulation of hydrogen ion secretion.
Effects of 5‐hydroxy‐propafenone in guinea‐pig atrial fibres
Authors: Delgado C. , Tamargo J. , Tejerina T. , Valenzuela C.
Published: July 2012

The effects of 5‐hydroxy‐propafenone (5‐OH‐P), an active metabolite of propafenone, were studied on isolated atrial muscle fibres obtained from non‐treated guinea‐pigs and from animals pretreated with 5‐OH‐P, 3 mg kg−1, for 28 days.

In untreated atria 5‐OH‐P, 10−8 m‐10−4 m, produced a dose‐dependent decrease in amplitude and df/dtmax and reduced the amplitude of the slow contractions induced by isoprenaline and histamine in high K+ media.

5‐OH‐P also produced a dose‐dependent decrease in atrial rate, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline.

In untreated atrial muscle fibres 5‐OH‐P depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (ADP) and the effective refractory period, lengthening the effective refractory period relative to APD.

Pretreatment with 5‐OH‐P reduced atrial rate and increased contractile force, but did not modify the action potential characteristics from the values obtained in untreated atria. Further addition of 5‐OH‐P produced similar but more marked changes than in untreated atria.

It is concluded that in guinea‐pig isolated atrial muscle fibres 5‐OH‐P, like propafenone, exhibits class I (membrane stabilizing), class II (antisympathetic) and class IV (Ca antagonistic) antiarrhythmic actions. Therefore, this metabolite could be responsible, at least in part, for some of the antiarrhythmic effects previously attributed to propafenone.
Cellular electrophysiological effects of d‐and dl‐sotalol in guinea‐pig sinoatrial node, atrium and ventricle and human atrium: differential tissue sensitivity
Authors: Campbell Terence J.
Published: July 2012

The effects of racemic dl‐sotalol and d‐sotalol on guinea‐pig sino‐atrial node, atrium and ventricle and on human atrium were studied using standard microelectrode techniques. Both compounds increased spontaneous sinus node cycle length largely by prolonging the repolarization phase of the action potentials. This effect was attributed to blockade of outward potassium current.

Ventricular action potential duration was similarly prolonged by dl‐sotalol at concentrations of 5–50 μm.

dl‐Sotalol 1–50 μm had no effect on guinea‐pig atrial action potential duration and d‐sotalol produced minor prolongation only at the highest concentration (50 μm).

Human atrial action potentials were, however, significantly prolonged by both dl‐AND d‐sotalol 10 μm. This indicates differential sensitivities to sotalol for human and guinea‐pig atrium and explains the ability of sotalol to prolong atrial monophasic action potential duration in clinical studies.
The role of blood vessels in the bioconversion of leukotrienes in the pig
Authors: Galton Simon A. , Piper Priscilla J.
Published: July 2012

Porcine pulmonary artery has the ability to convert leukotriene C4 (LTC4) to LTD4 and then to LTE4.

In this vessel, there appears to be no further metabolism beyond LTE4.

LTC4 (1 nm) is converted rapidly to LTD4, whereas the conversion of LTD4 to LTE4 is somewhat slower.

The conversion of LTC4 to LTD4 is inhibited by the γ‐glutamyl transpeptidase inhibitor, serine‐borate (45 mm).

The conversion of LTD4 to LTE4 is inhibited by the aminopeptidase inhibitor, l‐cysteine (10 mm).

LTB4 did not appear to be metabolized by porcine pulmonary artery.

These results suggest that the vessel wall may play a role in the early stages of leukotriene metabolism.
Effect of neomycin on post‐tetanic twitch tension of the mouse diaphragm preparation
Authors: Tsai M.C.
Published: July 2012

The effect of calcium (0.5–6 mm) and neomycin (0.1‐0.2 mm) on the maximum post‐tetanic twitch tension (MTT) and post‐tetanic depression (PTD) of the indirectly elicited twitch tension was studied on the mouse isolated phrenic nerve‐diaphragm preparation. The effect of neomycin on MTT of directly stimulated twitch tension was also tested in (+)‐tubocurarine pretreated preparations.

Three‐dimensional plots between MTT and frequency and duration of indirect tetanic stimulation revealed that the frequencies and durations inducing maximal MTT were 500 Hz for 20 s in 0.5 mm CaCl2, 100 Hz for 5 s in 2 mm CaCl2 and 100 Hz for 10 s in 6 mm CaCl2. The frequency and duration inducing maximal PTD was 100 Hz for 20 s in 0.5 mm CaCl2, but there was no PTD in 2 mm or 6 mm CaCl2.

Neomycin was associated with significantly greater MTT than in control if the duration of tetanic stimulation was 1 or 2 s, while it was associated with less MTT if the duration of tetanic stimulation was 10 or 20 s.

Neomycin caused PTD in 2 mm CaCl2; sometimes the depressive effect was so severe that twitch tension was abolished. The maximal depression effect was found after 100 Hz tetanic stimulation for 20 s. Increasing the extracellular calcium concentration to 6 mm antagonized the effects of neomycin on MTT and PTD, whereas neostigmine (1.6 μm) antagonized the effect partially.

Neomycin had no effect on the MTT or PTD of the directly stimulated twitch tension.

It is concluded that neomycin alters the conditions of tetanic stimulation inducing MTT.
Glutamate‐evoked release of endogenous brain dopamine: inhibition by an excitatory amino acid antagonist and an enkephalin analogue
Authors: Jhamandas Khem , Marien Marc
Published: July 2012

The present study examined the effect of a selective δ‐opioid receptor agonist [d‐Ala2‐d‐Leu5] enkephalin (DADL) on the spontaneous and the l‐glutamic acid (l‐Glu)‐evoked release of endogenous dopamine from superfused slices of rat caudate‐putamen. The amount of dopamine in slice superfusates was measured by a sensitive method employing high‐performance liquid chromatography with electrochemical detection (h.p.l.c.‐e.d.) after a two‐step separation procedure.

The spontaneous release of endogenous dopamine was (a) partially dependent on Ca2+, (b) enhanced in Mg2+‐free superfusion medium, (c) partially reduced by tetrodotoxin (TTX, 0.3 μm), (d) partially reduced by the putative excitatory amino acid receptor antagonist dl‐2‐amino‐7‐phosphonoheptanoic acid (dl‐APH, 1 mm), and (f) increased 10 fold by the dopamine uptake blocker, nomifensine (10 μm). DADL (5 and 50 nm) did not significantly affect spontaneous dopamine release.

l‐Glu (0.1–10 mm) produced a concentration‐dependent release of endogenous dopamine from slices of caudate‐putamen. This effect was (a) Ca2+‐dependent, (b) strongly inhibited by 1.2 mm Mg2+, (c) attenuated by dl‐APH (1 mm), (d) attenuated by TTX (0.3 μm), and (c) enhanced by nomifensine (10 μm). In the presence of nomifensine DADL (50 nm) reduced significantly the l‐Glu‐evoked release of endogenous dopamine by 20%. The inhibitory effect of DADL was blocked by 10 μm naloxone.

These results indicate tht l‐Glu stimulates the Ca2+‐dependent release of endogenous dopamine in the caudate‐putamen by activation of N‐methy‐d‐aspartate‐type of excitatory amino acid receptors. This release can be selectively modified by the δ‐opioid agonist DADL in a naloxone‐sensitive manner.
Four motor effects of capsaicin on guinea‐pig distal colon
Authors: Maggi Carlo Alberto , Meli Alberto , Santicioli Paolo
Published: July 2012

The motor effects of capsaicin on the guinea‐pig distal colon have been investigated in vivo and in vitro.

Capsaicin (0.1–10 μg kg−1 i.v.) produced a transient relaxation which was reduced by pretreatment with capsaicin itself, atropine, hexamethonium, phentolamine or guanethidine and almost abolished by tetrodotoxin (TTX). Topically applied capsaicin produced a transient inhibition of tone and spontaneous activity prevented by topically applied TTX.

In isolated preparations of distal colon, capsaicin produced a transient, TTX‐ and atropine‐sensitive contraction which was followed by a depression of the contractile activity. The depressant effect was unaffected by atropine plus guanethidine but was greatly reduced by TTX, indicating activation of intramural non‐adrenergic, non‐cholinergic (NANC) mechanisms. The depressant effect on the first exposure to capsaicin (1 μm) was greater than that produced by a second, third or fourth exposure.

In preparations excised from capsaicin‐pretreated animals, capsaicin (1 μm) only produced an inhibitory effect on spontaneous contractions. Desensitization did not occur to this inhibitory effect.

In preparations pre‐exposed to capsaicin (1 μm, 1 h before), capsaicin (1–30 μm) produced a concentration‐related inhibition of spontaneous contractions (IC50 = 19 μm) and of the high K+ ‐ induced tonic contraction (IC50 = 23 μm). A similar effect on spontaneous motility was produced by capsaicin in colonic segments excised from capsaicin‐pretreated guinea‐pigs (IC50 = 16 μm) or guinea‐pigs treated with TTX (IC50 = 20 μm).

It is concluded that, in vivo, capsaicin activates inhibitory reflexes, presumably due to stimulation of primary afferent fibres. This effect involves, at least in part, activation of sympathetic nerves to this organ. The contractile effect of capsaicin on the isolated colon involves activation of intramural cholinergic neurones, whereas the TTX‐sensitive component of the inhibitory effect involves either release of an inhibitory transmitter through an axon reflex arrangement or activation of NANC neurones. In addition, at high concentrations capsaicin produces a direct depression of smooth muscle contraction.
Evidence that locus coeruleus is the site where clonidine and drugs acting at α1‐ and α2‐adrenoceptors affect sleep and arousal mechanisms
Authors: De Sarro G.B. , Ascioti C. , Froio F. , Libri V. , Nisticò G.
Published: July 2012

The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline‐containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex).

The ECoG effects were continuously analysed and quantified by means of a Berg‐Fourier analyser as total power and as power in preselected bands of frequency.

Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose‐dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus.

Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex.

The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of α2‐adrenoceptors but not by α1‐adrenoceptor antagonists.

Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective α2‐adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after microinjection of phentolamine into the same sites.

No significant effects on behaviour and ECoG activity were evoked after intraventricular injection or microinfusion into the locus coeruleus of prazosin or methoxamine.
Stress induced ACTH release in capsaicin treated rats
Authors: Amann Rainer , Lembeck Fred
Published: July 2012

The plasma concentrations of adrenocorticotropic hormone (ACTH) in rats pretreated with capsaicin as neonates were compared with those of control rats pretreated with the capsaicin vehicle. Capsaicin pretreatment has been shown earlier to abolish the increase in plasma ACTH concentration induced by cold stress while not affecting that induced by restraint stress.

In the present experiments rats pretreated with capsaicin showed the same increase in plasma ACTH concentration in response to an i.v. infusion of ovine‐corticotropin releasing factor as control rats pretreated with the capsaicin vehicle.

Intraperitoneal injection of formalin, surgical stress and intravenous infusion of (–)‐isoprenaline increased plasma ACTH concentrations in control rats. In capsaicin pretreated rats the increase in plasma ACTH was significantly attenuated.

It is concluded that capsaicin‐sensitive sensory neurones mediate the activation of pituitary ACTH secretion in response to somatosensory stimuli. The function of the corticotroph cells of the anterior pituitary is not impaired by capsaicin treatment.
Activation of 5‐HT3 receptor subtypes causes rapid excitation of rabbit parasympathetic neurones
Authors: Akasu T. , Hasuo H. , Tokimasa T.
Published: July 2012

Intracellular recordings were made from parasympathetic neurones of the rabbit vesical pelvic ganglia maintained in vitro. 5‐Hydroxytryptamine (5‐HT) caused a membrane depolarization which was antagonized by ICS 205–930 ([3α‐tropanyl]‐1H‐indole‐3‐carboxylic acid ester) but not by methysergide. ICS 205–930 caused a parallel shift to the right of the dose‐response curve for 5‐HT. These results suggest that the 5‐HT3 receptor is involved in the membrane depolarization.
The protective effects of sulphasalazine against ethanol‐induced gastric damage in rats
Authors: Cho C.H. , Ogle C.W. , Sevilla E.L.
Published: July 2012

The inhibitory action of sulphasalazine on ethanol‐induced gastric damage was studied in rats.

Sulphasalazine (62.5 or 125 mg kg−1, s.c.) did not affect basal gastric acid secretion but increased pepsin output.

Ethanol (40% v/v, 10 ml kg−1, p.o.) produced severe gastric glandular mucosal damage and lessened the stomach emptying rate of resin pellets, but it increased the levels of prostaglandin E2 (PGE2)‐like activity in the glandular mucosa.

Sulphasalazine markedly prevented ethanol‐induced damage and significantly elevated gastric wall mucus levels both in basal conditions and in the presence of ethanol.

Sulphasalazine caused a small insignificant increase in mucosal PGE2 levels in both control and ethanol‐treated rats. The drug significantly increased mucosal PGE2 levels in indomethacin‐treated animals, but did not prevent indomethacin‐induced mucosal damage.

Sulphapyridine but not 5‐aminosalicylic acid, constituents of sulphasalazine, showed a similar antilesion action to the parent drug, and prevented gastric wall mucus depletion in ethanol‐treated animals.

This study elucidates the protective effects of sulphasalazine against ethanol‐induced gastric lesions. The antagonistic action appears to be mediated, at least partly, through the preservation of gastric wall mucus by sulphapyridine.
Positive inotropic and chronotropic effects of trypsin and some other proteolytic enzymes in the guinea‐pig heart
Authors: Imai Shoichi , Kawada Tomie , Kimura Takahito , Ohta Hideo , Nakazawa Mikio , Yoshida Yutaka
Published: July 2012

In atrial preparations of the young guinea‐pig (body weight 150–250 g), five proteolytic enzymes (trypsin, chymotrypsin, bacterial‐Al‐proteinase (nagarse), bromelain and kallikrein) produced concentration‐dependent positive inotropic and chronotropic effects, while they exerted only minimal effects on the papillary muscle preparations.

To characterize the effects, further experiments were conducted in atrial preparations using trypsin. There was a strong tendency for tachyphylaxis: a second exposure to the same concentration of trypsin resulted in considerably smaller positive inotropic and chronotropic effects. The positive inotropic and chronotropic effects of this substance were not affected by propranolol (5 × 10−7 m). However, an accumulation of cyclic AMP was observed and the positive inotropic and chronotropic effects were potentiated by aminophylline (10−4 m) in association with an augmentation of the accumulation of cyclic AMP. In preparations partially depolarized with high K+ (22 mm) medium (contractions ceased under this condition) trypsin 100 μg ml−1 reinstated the contraction. Treatment of the preparation with aprotinin (200 u ml−1) resulted in a strong inhibition of the positive inotropic and chronotropic effects.

Islet activating protein (IAP), a specific inhibitor of the ‘inhibition specific’ guanine nucleotide binding regulatory protein of the adenylate cyclase system, did not produce significant inhibition of the positive inotropic and chronotropic effects of trypsin, whereas it produced a complete inhibition of the negative inotropic and chronotropic effects of carbachol.

These results suggest that the positive inotropic and chronotropic effects of proteolytic enzymes are intimately connected with the proteolytic activities through which adenylate cyclase is activated to produce an accumulation of cyclic AMP within the myocardium. The destruction of the inhibition specific' guanine nucleotide regulatory protein of the adenylate cyclase was not substantiated as a mechanism of activation of the adenylate cyclase.
Apparent affinity of some 8‐phenyl‐substituted xanthines at adenosine receptors in guinea‐pig aorta and atria
Authors: Collis M.G. , Jacobson K.A. , Tomkins D.M.
Published: July 2012

Some 8‐phenyl‐substituted, 1,3 dipropyl xanthines have previously been demonstrated to have a 20–400 fold greater affinity for A1 binding sites in rat CNS membranes than for A2 adenosine receptors in intact CNS cells from guinea‐pigs. In the present study these compounds (1,3, dipropyl‐8‐phenylxanthine: DPPX; 1,3 dipropyl‐8‐(2 amino‐4‐chlorophenyl) xanthine: PACPX; 8‐(4‐(2‐aminoethyl)amino) carbonyl methyl oxyphenyl)‐1,3‐dipropylxanthine: XAC; and d‐Lys‐XAC) together with two that have not been reported to exhibit A1‐receptor selectivity (8‐(p‐sulphophenyl)theophylline: 8‐PST; 8‐(4‐carboxy methyl oxyphenyl)‐1,3‐dipropylxanthine: XCC) have been evaluated as antagonists of the effects of 2‐chloroadenosine in two isolated cardiovascular tissues.

The isolated tissues used were guinea‐pig atria (bradycardic response) and aorta (relaxation), which are thought to possess A1 and A2 adenosine receptors, respectively.

All the xanthines antagonized responses evoked by 2‐chloroadenosine in both tissues but did not affect responses evoked by acetylcholine (atria) or sodium nitrite (aorta).

The xanthines, 8‐PST, XAC, d‐Lys XAC, XCC and DPPX appeared to be competitive antagonists of the effects of 2‐chloroadenosine, as Schild plot slopes did not differ significantly from unity. The 1,3‐dipropyl substituted compounds had pA2 values from 6.5 to 7.4 and were more potent than the 1,3 dimethyl substituted 8‐PST (pA2 4.9 to 5).

For individual xanthines, there was no difference between pA2 values obtained in the atria and in the aorta.

Responses evoked by 2‐chloroadenosine in atria and aorta were antagonized to a similar degree by PACPX (1 μm). The agonist dose‐ratio evoked by 10 μm PACPX was no greater than that evoked by 1 μm of the xanthine in both tissues. This was probably a consequence of the limited aqueous solubility of PACPX.

These results fail to demonstrate A1 receptor selectivity for DPPX, XAC, d‐Lys XAC or PACPX in tissues from the guinea‐pig. The A1 selectivity previously found for these compounds may therefore be due to their high affinity for binding sites in rat CNS cell membranes.
The effects of nitroglycerin on exercise‐induced regional myocardial contractile dysfunction are not diminished by pretreatment with dihydroergotamine
Authors: Schneider W. , Krumpl G. , Mayer N. , Raberger G.
Published: July 2012

Because controversy exists regarding the effects of dihydroergotamine (DHE) on the performance of underperfused myocardium, the effects of DHE were investigated in a model of exercise‐induced regional myocardial dysfunction in conscious dogs.

We also investigated a possible functional antagonism between DHE and nitroglycerin that might reduce the latter drug's antianginal efficacy.

Investigations were carried out in conscious dogs. After stenosis of the circumflex branch of the left coronary artery that minimally affected resting myocardial function, treadmill exercise induced transient regional contractile dysfunction. Heart rate, arterial blood pressure, left ventricular dp/dtmax and left ventricular end‐diastolic pressure were registered. Regional contractile performance was assessed by ultrasonic distance measurement in the underperfused and in a normally perfused area.

DHE (5 μg kg−1, i.v.) induced a decrease in left ventricular dp/dtmax at rest and during exercise. DHE did not cause a deterioration in contractile function in the ischaemic myocardium, but led to a slight although not significant improvement in regional myocardial function.

After pretreatment with DHE, infusion of nitroglycerin (15 μg kg−1, i.v.) induced an improvement in the underperfused myocardial area during treadmill exercise, accompanied by a decrease in diastolic arterial pressure and left ventricular end‐diastolic pressure and an increase in left ventricular dp/dtmax.

These results suggest that DHE will not worsen exercise‐induced angina pectoris, and that the antianginal efficacy of nitroglycerin will not be neutralized by pretreatment with DHE.