bluuebunny/crossref_metadata_2025 huggingface dataset:
Converting enzyme inhibition in the rat by captopril is accompanied by potentiation of carrageenin‐induced inflammation
Authors: Boura A.L. A. , Svolmanis A.P.
Published: July 2012

Hind paw oedema in rats, measured by plethysmography or extravasation of Evans Blue dye into the skin, after subplantar injection of submaximal doses of carrageenin (1–100 μg) was significantly increased for 4 h during kininase II inhibition with captopril (1 mg kg−1, s.c.).

Submaximal oedema, as assessed by paw swelling, after subplantar bradykinin (0.1–1.0 μg) was also significantly increased after subcutaneous administration of this dose of captopril, whereas that in response to either histamine (2–20 μg) or prostaglandin E2 (2 μg) was unchanged.

The pain threshold of the paw, injected with carrageenin (1 μg) was lowered significantly after subcutaneous administration of captopril (1 mg kg−1).

Potentiation by captopril (1 mg kg−1, s.c.) of paw swelling in response to intraplantar carrageenin (100 μg) or bradykinin (1 μg) was reduced by prior subcutaneous administration of indomethacin (5 mg kg−1).

It is suggested that normally, tissue kininase II activity is sufficient to decrease the inflammatory response of the hind paw to carrageenin or bradykinin. After inhibition of kininase II with captopril, bradykinin levels are increased and interact with concomitantly released prostaglandins to potentiate inflammation.
Alterations to the electrical activity of atrial muscle isolated from the rat heart, produced by exposure in vitro to amiodarone
Authors: Northover B.J.
Published: July 2012

Glass microelectrodes were used to record transmembrane electrical activity from cells located just beneath the endocardial surface of the left atrial free wall of rat hearts during superfusion and electrical stimulation in vitro at 37°C.

Availability of the fast sodium channel for current flow was inferred from the maximum rate of rise of membrane potential during phase O of the action potential (V̇max).

Muscle exposed to polysorbate 80 (10 to 80 μg ml−1) showed a concentration‐dependent lengthening of action potential duration (APD) but no detectable change in V̇max.

Amiodarone (1 to 20 μg ml−1) was dissolved in physiological salt solution with the aid of polysorbate 80 (50 μg ml−1) and caused a concentration‐dependent prolongation of APD and a decrease in V̇max, both of which were slow to develop and extremely slow to wash‐out. The speed of onset of action of amiodarone varied with drug concentration and ranged from a few minutes with high concentrations to many hours with low concentrations.
Some effects of nicotine on food and water intake in undeprived rats
Authors: Clarke P.B.S. , Kumar R.
Published: July 2012

Undeprived rats were tested in their home cages for intake of water and powdered food, starting 15 min after subcutaneous (s.c.) injection of (−)−nicotine bitartrate or 0.9% w/v NaCl solution (saline). In the first 2 h, nicotine (0–0.4 mg kg−1 base) markedly reduced water intake in a dose‐related way, leaving food intake unchanged. Food and water intake up to 24 h after injection was unaffected.

Rats (n = 6 per group) were then injected daily with nicotine (0.4 mg kg−1 base, s.c.) or saline for one month. Intermittent tests with saline (in place of nicotine) during this period did not reveal any signs of abstinence. A dose‐response study similar to the first was then carried out, and little or no tolerance was found to the hypodipsic action of nicotine. Nicotine also reduced food intake, irrespective of chronic treatment. Subsequently, daily injections were discontinued, and spontaneous intake did not differ in rats previously maintained on nicotine, relative to control animals.

Mecamylamine (0.3, 1.5 mg kg−1, s.c.) prevented nicotine‐induced hypodipsia, whereas chlorisondamine (0.02, 0.1 mg kg−1 s.c.) was ineffective. Both ganglion blockers reduced food intake.

Nicotine did not reduce drinking in rats preloaded with a hypertonic saline solution.

It is suggested that nicotine reduces water intake in undeprived rats, probably by acting centrally. Since this action changes little with repeated testing, it may provide a useful index of one or more central actions of the drug.
Substance P can contract the longitudinal muscle of the guinea‐pig small intestine by releasing intracellular calcium
Authors: Holzer P. , Lippe Irmgard Th.
Published: July 2012

The contraction of the longitudinal muscle of the guinea‐pig isolated ileum in response to substance P (SP) in high [K+] medium and in Ca2+‐free solution which contained EGTA has been investigated in order to examine whether excitation‐contraction coupling involves the release of Ca2+ from an intracellular store.

In tissues contracted by K+, high concentrations of SP (> 0.1 μM) were still capable of causing a slight, transient contraction.

Bathing the ileum in a Ca2+‐free medium for 2.5 min greatly diminished the potency and efficacy of SP in contracting the longitudinal muscle but concentrations of 2.2–22 μM SP were still able to produce a response 30–40% of maximal.

The responsiveness to SP was completely lost within 10 min of bathing in Ca2+‐free medium but was partially restored by a brief exposure (0.5–2 min) to high concentrations of Ca2+ (9–72 mM). The restorative effect of Ca2+ depended on the concentration of Ca2+ and on the time for which the tissue was exposed to this Ca2+ concentration.

The fact that high concentrations of SP were able to elicit a contraction in media containing high [K+] or no Ca2+, suggested that they may do so by releasing Ca2+ from an intracellular store which is not as sensitive to removal of extracellular Ca2+ or as easily accessible to EGTA as the extracellular space of the muscle. The location of this store is not known; it may be associated with the internal side of the cell membrane.

There is apparently an overlap between the Ca2+ pool associated with the action of SP and the Ca2+ pools utilized by acetylcholine, histamine or tetraethylammonium, which accounts for the cross‐desensitization observed between these agonists. It was not possible to determine whether autodesensitization to SP also results from depletion of an intracellular Ca2+ store.
The dependence of excitatory junction potential amplitude on the external calcium concentration in mouse vas deferens during narcotic withdrawal
Authors: Einstein R. , Lavidis N. A.
Published: July 2012

The dependence of neurotransmitter release on calcium was evaluated in adrenergic terminals from mice that were acutely withdrawn from chronic morphine treatment (CMT).

A two fold increase in the number of writhes in response to an i.p. injection of acetylcholine was induced in mice by CMT and subsequent withdrawal.

A shift to the left in the relationship between the excitatory junction potential (e.j.p.) amplitude and extracellular calcium concentration ([Ca]o) was induced in vasa deferentia from CMT‐withdrawn mice.

A reduction in the degree of facilitation of transmitter release during a short low‐frequency train of impulses and an increase in the amount of transmitter release during a high‐frequency train of impulses was induced in vasa deferentia from CMT‐withdrawn mice.

The adaptive mechanism of the terminals to the sustained presence of morphine may involve an increase in the probability that the release sites will release transmitter either via increase in calcium influx or an increase in the affinity of calcium to the hypothetical X‐receptor.
Energy conservation by nisoldipine in ischaemic heart
Authors: De Jong Jan W. , Huizer Tom , Tijssen Jan G.P.
Published: July 2012

We studied the effect of the calcium entry blocker nisoldipine on ATP catabolism in the rat heart, perfused according to Langendorff. Even 1 nM nisoldipine induced vasodilatation; concentrations of 30 nM and higher caused significant negative inotropy.

The drug had a very strong affinity for silicon rubber tubing.

Myocardial ischaemia was induced by lowering the perfusion pressure, which reduced flow without nisoldipine by 85%. The efflux of purine nucleosides and oxypurines rose 14 fold. Nisoldipine reduced this efflux of ATP catabolites dose‐dependently. The highest concentration, 300 nM, suppressed ischaemic purine production completely.

The action of the drug was antagonized by an increase in Ca2+‐concentration in the perfusion fluid.

We also showed the protective effect of nisoldipine on adenine nucleotides in freeze‐clamped hearts. A concentration of 20 nM partially prevented the reduction of ATP and adenylate energy charge due to ischaemia.

We conclude that relatively low doses of nisoldipine effectively prevent ATP breakdown in ischaemic rat heart.
Effect of exposure to radiation on the inflammatory process and its influence by diclofenac
Authors: El‐Ghazaly M. , Kenawy S. , Khayyal M.T. , Roushdy H. , Saleh S.
Published: July 2012

The effect of radiation exposure on the inflammatory process was studied in rats using the carrageenan‐induced paw oedema and adjuvant‐induced arthritis tests.

Irradiation (0.5,1 and 2 Grays) resulted in a significant augmentation of the tissue response to carrageenan and the early phase of adjuvant‐induced arthritis, but suppressed the late phase.

Diclofenac (1–5 mg kg−1) effectively reduced the exaggerated inflammatory response in irradiated animals in both the carrageenan paw oedema and adjuvant‐induced arthritis tests. The drug also had a prophylactic value in guarding against the induction of radiation damage.

The inflammatory responses produced by irradiation and the benefits obtained by drug treatment may be related to changes in tissue prostaglandin levels and/or changes in the immune system.
The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret
Authors: Gwathmey Judith K. , Morgan James P.
Published: July 2012

The effects of milrinone and piroximone were compared to those of isoprenaline, dibutyryl adenosine 3′:5′‐cyclic monophosphate (dibutyryl cyclic AMP), forskolin, isobutylmethylxanthine, increased extracellular calcium ([Ca2+]o) and caffeine in ferret right ventricular papillary muscles that were loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium.

The positive inotropic action of each drug, except caffeine, was associated with an increase in the peak amplitude of the aequorin light signal (i.e. intracellular Ca2+ transient) reflecting an increased amount of calcium available for excitation‐contraction coupling; the positive inotropic effect of caffeine appears to occur by other mechanisms.

The time courses of the aequorin light signal and corresponding tension response were shortened by isoprenaline, forskolin, isobutylmethylxanthine, dibutyryl cyclic AMP, milrinone and piroximone; unchanged by increased [Ca2+]o and prolonged by caffeine, suggesting that the rates of Ca2+ release and uptake by the sarcoplasmic reticulum were respectively increased, unchanged or decreased by these groups of drugs.

Relative to changes in [Ca2+]o, the ratio of the peak of the aequorin light signal to the peak of the tension response was increased by isoprenaline, milrinone and piroximone, and decreased by caffeine, indicating that the Ca2+‐sensitivity of the myofilaments was respectively decreased, and increased by these drugs.

The effects of milrinone and piroximone on the amplitude and time course of the aequorin light signal, as they relate to changes in uptake and release of calcium from the sarcoplasmic reticulum and to changes in the sensitivity of the myofilaments to Ca2+, are consistent with the findings that positive inotropic doses of these agents act by increasing intracellular concentrations of cyclic AMP.

Higher doses of milrinone and piroximone produced negative inotropic effects that were characterized by diminution of developed tension but no change or an increase in the amplitude of the aequorin light signal, suggesting a decrease in the sensitivity of the contractile elements to Ca2+.

Toxic doses of milrinone, piroximone and isoprenaline were associated with development of a Ca2+‐overload state characterized by the presence of after‐glimmers, after‐contractions and dysrhythmias, and by decreased amplitude of both the aequorin light signal and tension response.

The negative inotropic and toxic effects of milrinone and piroximone can be explained only in part by increased intracellular concentrations of cyclic AMP; we suggest that these drugs may have other cardiac actions.
Clonidine and presynaptic adrenoceptor theory
Authors: Kalsner Stanley
Published: July 2012

The effects of clonidine, a presumed selective presynaptic α2‐adrenoceptor agonist or partial agonist, were examined in guinea‐pig atria.

Split left atrial preparations were stimulated transmurally at 2 Hz with 100 pulses of 0.5 ms duration and the efflux of 3H‐transmitter determined.

Clonidine inhibited efflux at 3 × 10−8 M to 3 × 10−7 M by about 30%. Yohimbine, at a concentration (10−6 M) which caused a 3 fold increase in the release of 3H‐transmitter during field stimulation, did not alter the ability of clonidine to inhibit transmitter efflux.

At 10−6 M clonidine alone had no significant effect on the stimulation‐induced efflux of 3H‐transmitter, but in the presence of yohimbine (10−6 M), inhibited efflux by over 50%.

The inhibitory effect of noradrenaline (10−6M) on 3H‐transmitter efflux was antagonized by clonidine at 10−6M but not at 10−8M, although neither concentration of clonidine alone inhibited transmitter efflux.

The present findings indicate that the effects of clonidine on the efflux of noradrenaline from sympathetic nerves cannot be accommodated within the currently held view that the compound is an agonist or partial agonist on presynaptic α2‐adrenoceptors. It appears that clonidine has multiple sites of action few of which are antagonized by a concentration of the prototypical presynaptic antagonist yohimbine, which enhances efflux 3 fold.
Age‐related changes in the sensitivity to verapamil and sodium nitroprusside of vascular smooth muscle of rabbit aorta
Authors: Karaki H. , Nakagawa H. , Urakawa N.
Published: July 2012

Age‐related changes in the sensitivity to verapamil and sodium nitroprusside were examined in isolated aortic strips of the rabbit.

In the aortae of newborn rabbits within 10 days of birth, the resting tone of the muscle was strongly reduced by sodium nitroprusside but not by either Ca‐deficient solution or by verapamil. High It‐induced contraction and noradrenaline‐induced contraction were both inhibited by verapamil or sodium nitroprusside.

In the aortae of 24 day‐old rabbits, resting tension was slightly reduced by sodium nitroprusside but not by verapamil. High K‐induced contraction was less sensitive to sodium nitroprusside than to verapamil whereas noradrenaline‐induced contraction was less sensitive to verapamil than to sodium nitroprusside.

In the aortae isolated from 60 day‐old or older rabbits, resting tension was not affected by either sodium nitroprusside or verapamil. High K‐induced contraction was inhibited by verapamil whereas sodium nitroprusside showed only a weak inhibitory effect. Noradrenaline‐induced contraction was inhibited by sodium nitroprusside although verapamil had only a slight inhibitory effect.

In the aortae of 1 day‐old and also in adult rabbits, noradrenaline induced an additional increase in muscle tension when applied during the sustained contraction induced by high K.

It is suggested that, in the newborn rabbit aorta, the voltage‐dependent Ca channel is sensitive to both verapamil and sodium nitroprusside and the sensitivity to sodium nitroprusside gradually decreases during maturation whereas the receptor‐linked Ca channel is also sensitive to both of the inhibitors at birth but the sensitivity to verapamil gradually decreases with age.
A comparison of several calcium antagonists on uterine, vascular and cardiac muscles from the rat
Authors: Granger Susan E. , Hollingsworth M. , Weston A.H.
Published: July 2012

An assessment was made of the potencies of nifedipine, gallopamil, diltiazem, cinnarizine and salbutamol as inhibitors of tension development by the uterus and cardiovascular tissues from the term pregnant rat.

The rank order of potency was nifedipine > gallopamil > diltiazem for those preparations on which these compounds were potent, viz. spontaneous and oxytocin‐induced tension development of the uterus, spontaneous tension development of hepatic portal vein, potassium chloride (KCl)‐induced pressure rises of perfused mesenteric bed and electrically‐stimulated (0.5 Hz) ventricular muscle.

The rank order of potency of nifedipine, gallopamil and diltiazem was different for those preparations on which they exhibited low potency, viz. noradrenaline‐induced pressure rises of perfused mesenteric bed and tension development of aorta.

Gallopamil and diltiazem, but not nifedipine, were more potent against tension development by ventricular muscle stimulated at 2.5 Hz than at 0.5 Hz, suggesting that nifedipine interacts at a different site from the other compounds.

Cinnarizine was less potent than the other calcium antagonists on the uterus and portal vein, was the second most potent compound against KCl‐induced pressure rises of the mesenteric bed and was equipotent against responses to noradrenaline and KCl of the mesenteric bed (unlike the other compounds). This suggests that the site of action of cinnarizine differs from that of the other calcium antagonists.

Nifedipine, gallopamil and diltiazem, like salbutamol, exhibited selectivity for inhibition of tension development by the uterus relative to the cardiovascular tissues.
The effect of diltiazem on noradrenaline release
Authors: Wolchinsky Camille , Zsotér Thomas T.
Published: July 2012

The effects of diltiazem in rat tail arteries and guinea‐pig vasa deferentia have been investigated.

Superfusion of the rat tail artery with diltiazem (10−6–10−4 M) resulted in a dose‐related increase in 3H‐overflow (P < 0.001) both in Wistar Kyoto (WKY) and in spontaneously hypertensive (SHR) rats. Release of 3H by transmural stimulation (1 Hz, 2 ms, 10 V) was also much greater in vessels perfused with diltiazem; this effect was dose‐dependent.

Diltiazem did not significantly alter the proportion of noradrenaline and its metabolites in 3H‐overflow, as analysed by column chromatography.

In the vasa deferentia of guinea‐pigs, diltiazem (10−9–10−5 M) increased spontaneous 3H‐release.

The results indicate that diltiazem acts on sympathetic nerves and causes the release of noradrenaline.
Potentiation by TRH of the effect of imipramine on the forced‐swimming test
Authors: Reny‐Palasse Véronique , Rips Richard
Published: July 2012

Discovery of the potentiation of thyrotropin releasing hormone (TRH)‐induced hyperthermia in mice by antidepressants which activate α‐adrenergic systems instigated investigation of other relations between TRH and antidepressants.

For this study the forced‐swimming test using mice was chosen since this test is more sensitive for selection of antidepressants which modify catecholaminergic systems than for those affecting 5‐hydroxytryptaminergic systems.

The effects of imipramine were potentiated by TRH. The involvement of α‐adrenergic systems was then investigated in this effect since it is already known that these systems are directly implicated in the potentiation of TRH‐induced hyperthermia by some antidepressants. Then the involvement of opiate systems was investigated since endogenous opiates are implicated in the action of some antidepressants, and some interactions between TRH and opiate systems are known to exist.

TRH made effective a completely inactive dose of imipramine as small as 2 mg kg−1 (i.p.) or 1 μg per mouse (i.c.v.). Pretreatment by both α1‐ and α2‐adrenoceptor antagonists (phenoxybenzamine, 8 mg kg−1 i.p; phentolamine, 4 mg kg−1 i.p.) or by a α1‐adrenoceptor antagonist (prazosin, 2 mg kg−1 i.p.) did not prevent this potentiation. In contrast the α2‐adrenoceptor antagonist (Yohimbine, 2 mg kg−1 i.p.) blocked the TRH effect. The imipramine potentiation by TRH was blocked by pretreatment with an opiate antagonist (naloxone, 1 mg kg−1 i.p.) and the potentiation was decreased in morphine‐tolerant mice.

These data indicate that potentiation of the effects of imipramine on the forced‐swimming test does not seem to be associated with an increase of effective levels of noradrenaline in the synaptic clefts and suggest an interaction between TRH and the opiate systems.
Mode of stimulatory actions of cadmium ion on the mouse diaphragm
Authors: Fu W.M. , Lin‐Shiau S.Y.
Published: July 2012

Effects of Cd2+ on the phrenic nerve‐diaphragm preparation of the mouse varied markedly in media containing various Ca2+ concentrations. In normal 2.5 mM Ca2+ medium, Cd2+ inhibited acetylcholine release from nerve endings without appreciable effect on the muscle membrane. However, Cd2+ elicited stimulatory effects on the muscle membrane in low Ca2+ medium (10−3–1 mM). These stimulatory effects included the induction of spontaneous contractions, augmentation of twitch responses to direct electrical stimulation and potentiation of the muscle contracture induced by acetylcholine, carbachol and high K+. By contrast, caffeine contracture was not affected by Cd2+.

Tetrodotoxin, procaine, cysteine and glycerol pretreatment abolished these stimulatory effects of Cd2+. Moreover, changing the ionic composition of the bathing medium to one containing low Na+, high K+, high Mg2+ or high Ca2+ also antagonized these effects of Cd2+. In contrast, low Mg2+ markedly potentiated the frequency of spontaneous contractions induced by Cd2+.

(+)‐Tubocurarine and β‐bungarotoxin had no effect on Cd2+‐induced spontaneous contractions indicating that they may be myogenic rather than neurogenic in origin.

By use of conventional microelectrodes, it was found that Cd2+ not only depolarized the muscle membrane but also induced spontaneous action potentials at a high frequency (173 ± 17 Hz).

It is concluded that increased Na+ permeability of the muscle membrane is the essential step bringing about spontaneous contractions. The binding of Cd2+ to ‐SH groups of the membrane is closely related to the induction of these effects.
Histamine‐induced inositol phospholipid breakdown in the longitudinal smooth muscle of guinea‐pig ileum
Authors: Donaldson J. , Hill S.J.
Published: July 2012

The characteristics of histamine‐stimulated inositol phospholipid breakdown in slices of guinea‐pig ileal smooth muscle and cerebellum have been investigated.

In cerebellar slices the inhibition of the inositol phospholipid response to histamine by mepyramine was consistent with competitive antagonism of histamine H1‐receptors.

In slices of the longitudinal smooth muscle of guinea‐pig ileum, mepyramine produced only a weak inhibition of the response to histamine, at concentrations up to 1 μM. This was in striking contrast to the potent competitive antagonism of the H1‐mediated contractile responses obtained with mepyramine in this tissue.

The H1‐receptor antagonists (+)‐chlorpheniramine and promethazine similarly had no effect on the EC50 value for histamine in guinea‐pig ileum, while promethazine competitively antagonized the muscarinic receptor‐mediated inositol phospholipid response in this tissue (Ka 3.6 × 107 M−1).

Cimetidine, on its own, did not significantly inhibit the inositol phosphate accumulation elicited by histamine in ileum. In the presence of 0.2 μM mepyramine, cimetidine (0.1 mM) produced a small parallel shift of the histamine concentration‐response curve (Ka 3 × 104 M−1). This inhibition, however, was not consistent with antagonism of an H2‐receptor‐mediated response.

The effect of a range of histamine analogues on inositol phospholipid breakdown was determined. Dose‐response curves were constructed and characterized in terms of the EC50, slope and maximal response attainable relative to histamine.

The H1‐agonists, Nα, Nα‐dimethylhistamine, Nα‐methylhistamine, 2‐pyridylethylamine and 2‐thiazolylethylamine produced the largest accumulations of [3H]‐inositol‐1‐phosphate. A very weak response was produced by the H2‐selective agonist impromidine, while dimaprit (also H2‐selective) was without significant effect.

Mepyramine appeared to antagonize competitively the response to the H1‐selective agonist 2‐pyridylethylamine. This was in contrast to the data obtained with other H1‐agonists, where mepyramine produced only a small dextral shift of the agonist curves at low agonist concentrations and an increase in the Hill coefficient. This was particularly striking in the case of 2‐methylhistamine.

The results suggest that an H1‐receptor component in guinea‐pig ileum, may coexist with a larger inositol phospholipid response to histamine which is independent of the activation of H1‐ or H2‐receptors.
Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit
Authors: Hamilton Carlene A. , Reid John L. , Vincent John
Published: July 2012

The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit.

Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]‐prazosin from specific binding sites. However, the lower pA2 value for doxazosin at α1‐adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin.

The dose‐related pressor effects of intravenous phenylephrine were used to assess vascular α1‐adrenoceptor antagonism in vivo. There was a close agreement between α1‐adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The α1‐adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin.

Studies using either radioligand binding or pressor responses to B‐HT 920 showed that doxazosin did not show any significant affinity for the α2‐adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium.

Doxazosin has a longer terminal elimination half‐life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined.

Following pharmacological ‘autonomic blockade’ and treatment with prazosin, doxazosin did not cause any further fall in blood pressure.

These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through α1‐adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained α1‐adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has α1‐adrenoceptor blocking properties.
Effects of pinaverium bromide and verapamil on the motility of the rat isolated colon
Authors: Baumgartner A. , Drack E. , Halter F. , Scheurer U.
Published: July 2012

Pinaverium bromide was 30 times less potent than verapamil in inhibiting intraluminal pressure responses of in vitro rat colonic segments to barium chloride, acetylcholine, FK 33–824 or field stimulation.

The inhibitory effects of both verapamil and pinaverium bromide on the pressure responses to field stimulation were antagonized similarly by exogenous calcium administration.

These results support the concept that pinaverium bromide acts on calcium channels in the smooth muscle cell membrane.
Effects of noradrenaline, vasopressin and angiotensin on the Na‐K pump in rat isolated liver cells
Authors: Berthon Brigitte , Capiod Thierry , Claret Michel
Published: July 2012

The effects of noradenaline (via α1‐adrenoceptors) and of the peptidic hormones vasopressin and angiotensin on the Na‐K pump have been studied in rat isolated liver cells.

The three hormones increased the cytosolic Ca concentration, stimulated the Na‐K pump and decreased the internal Na concentration of the cells. The effects were dose‐dependent and were blocked by the corresponding antagonists.

The simultaneous addition of maximal doses of noradrenaline and angiotensin or vasopressin were not additive suggesting that the hormones use a common mechanism to stimulate the carrier.

Incubating the cells in Ca‐free medium for long periods (Ca‐depletion) increased the Na‐K pump activity and reduced the stimulatory action of vasopressin, angiotensin and noradrenaline.

The effect of the Ca indicator quin2, used as an intracellular Ca chelator, was also studied. The cells were loaded with a maximal concentration of [3H]‐quin2 acetoxymethyl ester in the presence of external Ca for 6 min. The final cell content was 3.1 nmol quin2 mg−1 cell dry wt. In these cells the cytosolic Ca, as monitored from the fluorescence emission of the indicator, was about 200 nM and Na‐K pump activity was normal and the cells remained responsive to the three hormones.

Loading the cells with quin2 in the absence of external Ca reduced the [Ca]i from 200 nM to about 40 nM and increased the Na‐K pump activity but not as a result of a rise in internal Na concentration. In addition, the rat hepatocytes were no longer sensitive to the hormones.

It is proposed that Ca inhibits the Na‐K pump by binding the internal sites and that vasopressin, angiotensin and noradrenaline stimulate the carrier by interfering with the inhibitory Ca sites.
Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation
Authors: Izumi Hidetaka
Published: July 2012

Changes in the mechanical properties of the longitudinal and circular muscle tissues of the rat myometrium during gestation were investigated.

In isolated longitudinal and circular muscles of the rat myometrium, spontaneous contractions and contractions per unit cross‐sectional area induced by 128 mM K+ and 1 × 10−5 M acetylcholine (ACh) increased with the progress of gestation. These increases appeared in longitudinal muscles to a greater extent than in circular muscles.

ACh induced the largest contraction for both intact muscle tissues, at all stages of gestation. In both muscle layers, the ACh‐induced contraction reached the same amplitude as the 1 × 10−5 M Ca‐induced contraction of skinned muscles, except for the longitudinal muscle at the 22nd day of gestation.

In Ca‐free solution containing 2 mM EGTA, ACh produced contraction in both intact muscle tissues at all stages and the amplitude was increased during the progress of gestation, whereas the It‐induced and spontaneous contractions ceased.

In saponin‐treated skinned muscles of both layers, the free Ca concentration required to produce contraction was lowered, the maximum amplitudes of the contraction were increased and the pCa‐tension relationships shifted to the left during the progress of gestation.

The results indicate that during the progress of gestation, Ca sensitivity of the contractile proteins and mechanical responses to agonists increased and that the properties of the intracellular Ca store site were also altered in both muscle layers.
Determination of the receptor selectivity of opioid agonists in the guinea‐pig ileum and mouse vas deferens by use of β‐funaltrexamine
Authors: Hayes A.G. , Sheehan M.J. , Tyers M.B.
Published: July 2012

The irreversible inhibitor of μ‐opioid receptor‐mediated effects, β‐funaltrexamine (β‐FNA), was used to investigate the selectivity of various opioid agonists at μ‐opioid receptors in the electrically stimulated guinea‐pig ileum and mouse vas deferens preparations in vitro.

In the guinea‐pig ileum, pretreatment with β‐FNA (3 × 10−8 − 3 × 10−6 M) produced a concentration‐dependent antagonism of the inhibitory effect produced by the μ‐opioid receptor agonist [D‐Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of β‐FNA (3 × 10−6 − 1 × 10−5 M) also antagonized the inhibitory effects of the K‐opioid agonist U50488.

Pretreatment of guinea‐pig ileum with β‐FNA at 1 × 10−6 M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration‐response curves, and hence the greatest μ/k opioid receptor selectivity, were nalbuphine, [D‐Ser2, Leu5]enkephalinyl‐Thr6(DSLET), morphine, DAGO and normophine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by β‐FNA.

In the mouse vas deferens, pre‐treatment with β‐FNA (1 × 10−6 M) produced a similar shift in the dose‐response curves for normophine as in the guinea‐pig ileum. The concentration‐response curves for the δ‐receptor agonists [D‐Ala2, D‐Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that β‐FNA will also block δ‐opioid receptors.

Since β‐FNA does not block k‐opioid receptor‐mediated effects, it can be used in the guinea‐pig ileum preparation as a selective μ‐receptor inhibitor. However, its lack of selectivity between μ‐ and δ‐opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.
Potentiation of morphine analgesia by caffeine
Authors: Misra Anand L. , Pontani Ronald B. , Vadlamani Narasimham L.
Published: July 2012

Significant potentiation of morphine (5mg kg−1 s.c. or 1 mg kg−1 i.v.) analgesia (tail‐withdrawal reflex at 55°C) was observed in caffeine‐treated (100 mg kg−1 i.p.) rats as compared to the control group and lower doses of caffeine (2mg kg−1 i.p.) did not show this effect. Potentiated analgesia was reversed by naloxone. Pharmacokinetic or dispositional factors appear to be involved in part in this potentiation.
Actions of adenine dinucleotides in the guinea‐pig taenia coli: NAD acts indirectly on P1purinoceptors; NADP acts like a P2‐purinoceptor agonist
Authors: Burnstock Geoffrey , Hoyle Charles H.V.
Published: July 2012

The actions of the adenine dinucleotides β‐nicotinamide adenine dinucleotide (NAD) and β‐nicotinamide adenine dinucleotide phosphate (NADP) were examined on the carbachol‐contracted taenia coli of the guinea‐pig.

Both were capable of inducing full relaxations in a concentration‐dependent manner; NADP was 21.4 times more effective than NAD at EC50; the threshold for NADP was approximately 0.1 μm and for NAD approximately 1.0 μm.

The P1‐purinoceptor antagonist, 8‐phenyltheophylline (10 μm), produced a large parallel rightward shift in the NAD concentration‐response curve; in contrast it produced a small parallel leftward shift in the NADP concentration‐response curve.

Dipyridamole (0.2 μm), a purine nucleoside uptake inhibitor, markedly potentiated responses to NAD and slightly potentiated NADP. 8‐Phenyltheophylline antagonized the dipyridamole potentiation of both NAD and NADP.

By use of high performance liquid chromatography it was shown that the action of NAD involves a breakdown to adenosine.

Apamin, a K+ channel blocker, which antagonizes P2‐purinoceptor activation in the intestine, abolished responses to NADP but not to NAD.

The α‐ and β‐adrenoceptor antagonists, phentolamine (1 μm) and propranolol (1 μm), did not affect responses to NAD or NADP.

Tetrodotoxin, a neurotoxin, did not abolish responses to either NAD or NADP.

It is concluded that NAD acts largely indirectly as a P1‐purinoceptor agonist following its breakdown to adenosine by ectoenzymes, while NADP acts in a similar manner to a P2‐purinoceptor agonist.
Baclofen activates voltage‐dependent and 4‐aminopyridine sensitive K+ conductance in guinea‐pig hippocampal pyramidal cells maintained in vitro
Authors: Inoue Masumi , Matsuo Tadashi , Ogata Nobukuni
Published: July 2012

The ionic mechanism underlying the effect of (—)‐baclofen in the hippocampus was investigated using guinea‐pig brain slices.

(—)‐Baclofen either perfused or applied directly by microiontophoresis hyperpolarized the membrane and decreased the membrane input resistance of pyramidal cells in a dose‐dependent manner.

The value of the reversal potential for the baclofen‐induced hyperpolarization, as estimated from the current‐voltage relationships, was about −95 mV.

The reversal potential of the baclofen‐induced hyperpolarization measured directly coincided with that for the post‐burst hyperpolarization which is known to result from an activation of Ca2+‐activated K+ conductance.

The amplitude of the baclofen‐induced hyperpolarization was increased in low K+ (1.24 mm) medium whereas the hyperpolarization was decreased or abolished in high K+ (12.4 and 25 mm). Low Cl− (10.2 mm) medium had no noticeable effect on the baclofen‐induced hyperpolarization.

The effect of baclofen was antagonized by a low dose of 4‐aminopyridine (5 × 10−6 m) whereas it was unaffected by Picrotoxin (2 × 105m).

These results strongly suggest that the effect of baclofen is mediated by an increase in K+ conductance.
Dopamine autoreceptors and the effects of drugs on locomotion and dopamine synthesis
Authors: Brown Frank , Campbell William , Mitchell Paul J. , Randall Karl
Published: July 2012

Criteria for distinguishing dopamine autoreceptor agonism from other mechanisms of inhibiting locomotion were examined, together with the relationship between inhibition of locomotion and dopamine synthesis.

ED50 potencies to inhibit locomotion of mice were established for drugs from a number of categories. Spiperone 0.02 mg kg−1 significantly (P<0.05) reversed inhibition of locomotion by known dopamine agonists but not that by the other types of drug. Idazoxan antagonized inhibition of locomotion due to α2‐agonists but not dopamine agonists. RU 24926 (N‐propyl‐N,N‐di[2‐(3‐hydroxyphenyl)ethyl]amine) was antagonized by both spiperone and idazoxan.

Only for dopamine agonists was there good correlation (r = 0.97) between potencies to inhibit locomotion in mice and 1‐dihydroxyphenylalanine (1‐DOPA) accumulation in the nucleus accumbens of rats treated with γ‐butyrolactone and 3‐hydroxybenzylhydrazine. The specific dopamine D1‐agonist, SK&F 38393 (2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐3‐benzazepine), was inactive in both tests at doses up to 10 mg kg−1. The mixed dopamine agonist/antagonist, (—)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine, commonly known as (—)‐3‐PPP, acted as a dopamine agonist in both tests but inhibited locomotion more potently than 1‐DOPA accumulation.

The inhibitory effects of dopamine agonists on locomotion were not prevented by α‐methyl‐p‐tyrosine pretreatment.

The data suggest that spiperone‐reversible inhibition of locomotion in mice is a good criterion for dopamine autoreceptor agonists. The receptors involved are affected by low doses of both dopamine agonists and antagonists and seem similar to those involved in the autoreceptor mediated inhibition of dopamine synthesis. However, inhibition of locomotion is not due simply to suppression of dopamine release brought about as a secondary consequence of effects on synthesis; a separate mechanism for inhibiting dopamine release is probably involved.
Some effects of nifedipine in guinea‐pig isolated trachealis
Authors: Ahmed F. , Foster R.W. , Small R.C.
Published: July 2012

In trachealis depolarized by a K+‐rich medium, nifedipine (0.001–1 μmol 1−1) caused concentration‐dependent antagonism of CaCl2‐induced increase in tension, moving the CaCl2 log concentration‐effect curve to the right and depressing the maximal response.

In trachealis in normal Krebs solution, similar concentrations of nifedipine had marked antispasmogenic activity against the responses to potassium chloride (KCl) and tetraethylammonium (TEA). However, nifedipine had little, if any, antispasmogenic activity against the responses to acetylcholine or histamine.

Nifedipine 1 μmol 1−1 was tested for spasmolytic activity in tissues generating tension in response to the EC50 of acetylcholine, KCl or CaCl2. In producing spasmolysis nifedipine was most effective against CaCl2 and least effective against acetylcholine.

Nifedipine (0.01–1 μmol−1) had little or no effect on the tone of trachealis in normal Krebs solution.

Intracellular electrophysiological recording showed that nifedipine 1 μmol 1−1 could abolish spontaneous slow wave activity. This was associated with very minor depolarization and little or no loss of mechanical tone. In tissues treated with TEA (8 mmol 1−1) nifedipine abolished spike and slow wave discharge and reduced mechanical activity to the pre‐TEA level.

It is concluded that nifedipine prevents KCl‐ or TEA‐induced spasm by inhibition of Ca2+ influx. Spasm evoked by acetylcholine or histamine and the maintenance of spontaneous tone depend largely on mechanisms for increasing the cytoplasmic concentration of free Ca2+ which are resistant to nifedipine.
Tryptamine‐induced vasoconstrictor responses in rat caudal arteries are mediated predominantly via 5‐hydroxytryptamine receptors
Authors: Bradley P.B. , Humphrey P.P.A. , Williams R.H.
Published: July 2012

It has been suggested that tryptamine can stimulate specific receptors distinct from those for 5‐hydroxytryptamine (5‐HT). We have examined this possibility in the rat isolated caudal artery, paying particular attention to the involvement of monoamine oxidase metabolism and α‐adrenoceptors, two factors that can complicate the quantification of antagonist potencies at 5‐HT receptors.

5‐HT and tryptamine were agonists over the concentration‐ranges 3.0 × 10−8 − 3.0 × 10−5 moll−1 and 1.0 × 10−6−3.0 × 10−4 moll−1 respectively. The sensitivity of the caudal artery to tryptamine was increased by about 44 fold in the presence of iproniazid (5.0 × 10−5 moll−1) and about 17 fold in the presence of pargyline (1.0 × 10−5 moll−1), while responses to 5‐HT and methoxamine were unaffected.

In the absence of iproniazid, ketanserin and methysergide were potent antagonists of responses to 5‐HT with pA2 values of 9.08 and 9.11 and slopes of the Schild regressions of 1.15 and 1.00 respectively. However, against tryptamine the antagonists were weaker such that pA2 values were similar to those against 5‐HT but the slopes of the Schild regressions were 0.47 and 0.47.

In the presence of iproniazid (or pargyline), the 5‐HT antagonists were more potent against tryptamine such that the pA2 values and the slopes of the Schild regressions were not significantly different from those against 5‐HT. Phentolamine was a weak antagonist of responses to both 5‐HT and tryptamine in the presence of iproniazid.

The findings in this study suggest that the contractile action of tryptamine in rat caudal artery is mediated predominantly by the same receptor as 5‐HT and that the differential inactivation of tryptamine by monoamine oxidase enzymes largely accounts for the different susceptibilities of 5‐HT and tryptamine to the antagonists examined.
The use of [3H]‐[d‐Pen2,d‐Pen5]enkephalin as a highly selective ligand for the δ‐binding site
Authors: Cotton R. , Kosterlitz H.W. , Paterson S.J. , Rance M.J. , Traynor J.R.
Published: July 2012

The characteristics of the binding of [3H]‐[d‐Pen2,d‐Pen5]enkephalin were determined in homogenates of guinea‐pig and rat brain.

In the guinea‐pig, the maximum binding capacity for [3H]‐[d‐Pen2,d‐Pen5]enkephalin was 4.19 pmol g−1 and the KD 1.61 nm. In the rat, the corresponding values were 2.47 pmol g−1 and 5.42 nm. In both species, the maximum binding capacity and the affinity were not altered when μ‐binding was suppressed with [d‐Ala2, MePhe4, Gly‐ol5]enkephalin.

The μ‐agonists, [d‐Ala2, MePhe4, Gly‐ol5]enkephalin and morphine, displaced a small portion of the binding of [3H]‐[d‐Pen2,d‐Pen5]enkephalin with high affinities.
Kinin‐induced prostaglandin release in rat colon does not display serosal/mucosal ‘sidedness' after epithelial removal
Authors: Hoult J.R.S. , Phillips J.A.
Published: July 2012

Release of prostaglandin E2 (PGE2) from rat colon in response to 1 μM lysylbradykinin (LBk) displayed ‘sidedness’ in preparations with an intact epithelial cell layer (PGE2 release, sensitivity to LBk and inhibition by indomethacin all occurred on the serosal side only). Preparations with histologically‐verified removal of the epithelial layer and which were impermeable to prostaglandins (i.e. intact) continued to demonstrate LBk‐induced PGE2 generation, but this and indomethacin inhibition did not display sidedness. The results show that kinin‐induced PGE2 derives principally from cells in the lamina propria and not from the epithelial cells as previously supposed, and that the apparent sidedness of LBk responsiveness, PGE2 generation and its inhibition by indomethacin results from the barrier property of the epithelial cells and is not indicative of an asymmetric response.
Postganglionic muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea‐pig
Authors: Faulkner D. , Fryer Allison D. , Maclagan Jennifer
Published: July 2012

The location of neuronal inhibitory muscarinic receptors in pulmonary parasympathetic nerves was investigated in vivo and in vitro. The effects of an agonist for neuronal muscarinic receptors (pilocarpine) and an antagonist (gallamine) were tested on contractions of airway smooth muscle induced by pre‐ and postganglionic cholinergic nerve stimulation.

In anaesthetized guinea‐pigs, gallamine potentiated constriction of the tracheal tube and smaller airways induced by preganglionic stimulation. Gallamine also potentiated postganglionic stimulation induced by transmural stimulation of the tracheal tube and by 1‐1‐dimethyl‐4‐phenylpiperazinium iodide in the rest of the lung.

Bronchoconstriction and contraction of the tracheal tube induced by intravenous acetylcholine were not potentiated by gallamine, indicating that postjunctional muscarinic receptors in airway smooth muscle were not involved in the potentiation.

The muscarinic agonist, pilocarpine, had the opposite effect to gallamine and inhibited contractions of the tracheal tube induced by both types of nerve stimulation.

In vitro, the inhibitory effect of pilocarpine was demonstrated in the tracheal tube preparation stimulated both pre‐ and postganglionically. The effect of pilocarpine was antagonized by gallamine.

Because gallamine and pilocarpine affected the responses to postganglionic stimulation, the inhibitory muscarinic receptors must be located on the postganglionic neurones of the parasympathetic nerves innervating the trachea and the smaller airways. However, these experiments cannot exclude the possibility that muscarinic receptors may also be located on the soma of the ganglion cells.
Effect of long term amineptine treatment on pre‐ and postsynaptic mechanisms in rat brain
Authors: Ceci A. , Garattini S. , Gobbi M. , Mennini T.
Published: July 2012

The effect of amineptine and its two metabolites on monoamine uptake, release and receptor binding was studied in vitro.

Amineptine and its two metabolities did not displace labelled ligands for known neurotransmitters and drug receptor sites.

Amineptine and its two metabolities did not influence [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) uptake or release by rat brain synaptosomes. Amineptine inhibited [3H]‐dopamine and [3H]‐noradrenaline ([3H]‐NA) accumulation, with IC50 values of 1.4 and 10 μM, respectively. The effect was retained, though with lower efficacy, by the two metabolites.

Amineptine released [3H]‐dopamine from preloaded synaptosomes. Metabolite 1 had no effect on catecholamine release, and metabolite 2 was about half as active as the parent compound on [3H]‐dopamine release.

The releasing effect of amineptine on [3H]‐dopamine was potentiated by reserpine pretreatment, suggesting that the drug acts on the cytoplasmic neurotransmitter pool.

Chronic treatment with amineptine (20 mg kg−1, twice daily for 15 days followed by a 3 days drug withdrawal period) resulted in a decrease of [3H]‐spiperone binding sites in striatum, and of [3H]‐dihyroalprenolol and [3H]‐clonidine in cortex.

Chronic treatment with amineptine reduced basal [3H]‐dopamine accumulation in striatal synaptosomes, without affecting [3H]‐NA or [3H]‐5‐HT accumulation.

The adaptive changes in the pre‐ and postsynaptic dopamine mechanisms observed after long term treatment with amineptine are consistent with the drug acting as an indirect dopamine agonist.

The down regulation of β‐ and α2‐noradrenoceptors observed after long term amineptine treatment may play a role in the antidepressant activity of the drug.