bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo and in vitro activity of selective 5‐hydroxytryptamine2 receptor antagonists
Authors: Conolan Sean , Quinn Michael J. , Taylor David A. 
Published: July 2012

The abilities of ketanserin, ritanserin, R56413 and LY53857 to inhibit 5‐hydroxytryptamine (5‐ HT) and noradrenaline‐induced vasoconstrictor responses both in vitro and in vivo and to lower blood pressure in the rat, were compared.
In the isolated perfused mesenteric artery preparation of the rat all of the compounds tested were found to be potent inhibitors of 5‐HT‐induced vasoconstrictor responses. Ritanserin was the most potent compound, producing more than 50% inhibition of a near maximal response to 5‐HT at a concentration of 10−11 M. All four compounds were found to be competitive antagonists of noradrenaline; ketanserin being the most potent with a pA2 value of 7.64 ± 0.06.
5‐HT‐induced pressor responses in the pithed rat were inhibited by low doses (0.3–10 μg kg−1) of the four compounds. Ketanserin, at doses of 0.1–3.0 mg kg−1, resulted in rightward shifts of the control dose‐response curve to noradrenaline in the pithed rat. None of the other compounds had any significant effect on the noradrenaline‐induced pressor responses.
Ketanserin (0.1–1 mg kg−1) produced a dose‐dependent decrease in the mean arterial blood pressure of anaesthetized rats. The maximum decrease in blood pressure observed following a dose of 1 mg kg−1 ketanserin was 73.7 ± 4.7 mmHg. The other compounds at doses of 1.0–3.0 mg kg−1 produced a decrease in blood pressure of a lesser magnitude than that following ketanserin. In addition, this effect did not appear to be dose‐dependent.
It is suggested that the acute hypotensive effect of ketanserin results predominantly from α1‐adrenoceptor blockade. The involvement of antagonism of 5‐HT2 receptors in the hypotensive effect of the other compounds tested cannot be excluded.
Electrophysiological analysis of neurogenic vasodilatation in the isolated lingual artery of the rabbit
Authors: Brayden J.E. , Large W.A. 
Published: July 2012

The nature of neurogenic vasodilatation was investigated in isolated segments of rabbit lingual artery. In separate experiments membrane responses to nerve stimulation were studied by use of microelectrodes.
In the presence of guanethidine to block constrictor responses and noradrenaline to induce tone, field stimulation with trains of pulses (8 Hz for 0.5 to 4 s) produced vasodilatation. Atropine (10−6 M) reduced the relaxations to about 50% of the control values while the induced vasodilatations were potentiated by physostigmine. Tetrodotoxin (TTX, 10−7 M) blocked all nerve‐evoked responses. These data suggest that there is a cholinergic and a non‐cholinergic component of the vasodilatation produced by nerve stimulation in the rabbit lingual artery.
Single stimuli did not evoke electrophysiological responses. With parameters similar to those used in the mechanical studies, periarterial stimulation in the presence of guanethidine evoked membrane hyperpolarizations which achieved amplitudes of up to 11 mV. The ionophoretic application of acetylcholine (ACh) produced hyperpolarization.
The inhibitory junction potentials (i.j.ps) but not the ionophoretic‐induced responses were blocked by TTX. The nerve‐evoked and the ACh‐induced hyperpolarizations were potentiated by physostigmine (5 × 10−7 M) and totally blocked by atropine (10−7 M).
I.j.ps and hyperpolarization to ionophoresis of ACh were recorded from arteries in which the endothelium had been removed by mechanical rubbing. Mechanical relaxation to field stimulation and ACh was observed in preparations without endothelium.
These data suggest that the cholinergic component of the neurogenic vasodilatation in the rabbit lingual artery is accompanied by hyperpolarization. The non‐cholinergic component does not appear to possess an electrophysiological correlate. In addition, it seems that the action of nerve‐released ACh is mediated by muscarinic receptors which are situated directly on the vascular smooth muscle cells.
Biphasic actions of L‐DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices
Authors: Goshima Yoshio , Kubo Takao , Misu Yoshimi 
Published: July 2012

Effects of L‐DOPA on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices evoked by electrical field stimulation at 5 Hz were investigated in the absence and presence of p‐bromobenzyloxyamine (NSD‐1055), a DOPA‐decarboxylase inhibitor.
In the absence of NSD‐1055, L‐DOPA produced a facilitation of impulse‐evoked release of noradrenaline at 0.1 μM but not at 1 and 10 μM, and had no effect on the spontaneous release. On the other hand, L‐DOPA 0.1 to 10 μM dose‐dependently increased the spontaneous release of dopamine and the highest concentration only increased the evoked release and tissue content of dopamine.
In the presence of NSD‐1055 10 μM, the increase in the spontaneous release of dopamine was prevented and L‐DOPA produced biphasic regulatory effects on the evoked release of noradrenaline and dopamine, a facilitation at 0.1 μM and an inhibition at 1 μM. The facilitation was antagonized by (‐)‐propranolol 0.1 μM, but not by the (+)‐isomer, whereas the inhibition was antagonized by S‐sulpiride 1 nM, but not by the R‐isomer.
In conclusion, L‐DOPA appears to produce biphasic actions on the release of endogenous noradrenaline and dopamine from rat hypothalamic slices, not through its conversion to dopamine but through presynaptic regulatory mechanisms, an inhibition via dopamine receptors at a micromolar concentration and a facilitation via β‐adrenoceptors at the lower concentration.
Bremazocine is an agonist at K‐opioid receptors and an antagonist at μ‐opioid receptors in the guinea‐pig myenteric plexus
Authors: Corbett A.D. , Kosterlitz H.W. 
Published: July 2012

The agonist and antagonist activity of bremazocine at opioid receptors in the guinea‐pig myenteric plexus preparation was determined in untreated tissues and in tissues in which either μ‐ or k‐opioid receptors were blocked preferentially.
After pretreatment of the tissue with β‐funaltrexamine for 90 min followed by washing out, the IC50 value of the selective μ‐ligand [D‐Ala2,MePhe4,Gly‐ol5]enkephalin was increased 67 fold whereas the IC50 values of the selective k‐ligand U‐69,593 and of the non‐selective k‐ligand bremazocine were not significantly changed. In this experimental design bremazocine acted only on k‐receptors.
After pretreatment of the tissue with β‐chlornaltrexamine and 10 μM of the μ‐ligand for 30 min followed by washout, the IC50 value of the μ‐ligand was increased 2 fold whereas the IC50 value of the selective k‐ligand was increased 32 fold and that of bremazocine 62 fold. Under these experimental conditions, it was shown that bremazocine is an antagonist against [D‐Ala2,MePhe4,Gly‐ol5]enkephalin at the μ‐receptor (Ke. = 1.6 nM). The residual agonist activity of bremazocine is at the k‐receptor.
In naive myenteric plexus preparations the μ‐antagonist activity of bremazocine cannot be demonstrated because its potency at the k‐receptor is very high. This dual action may be of importance for the responses of bremazocine in other peripheral and central tissues.
Activation and desensitization of presynaptic α2‐adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens
Authors: García‐Sevilla J.A. , Zubieta J.K. 
Published: July 2012

The isolated field‐stimulated vas deferens of the rat (0.1 Hz, 3 ms, 30–40 V) was used to study the relationship between the in vivo inhibition of neuronal uptake of noradrenaline (NA) by cyclic antidepressant drugs and the subsequent activation/desensitization of presynaptic α2‐adrenoceptors. Receptor activation was indirectly measured by quantifying the ability of each drug to inhibit basal twitch responses after their acute administration. Receptor desensitization was also indirectly measured by quantifying the ability of the drugs to reduce the inhibitory effects of selective α2‐adrenoceptor agonists on the electrically‐induced twitch responses after their long‐term administration.
The acute in vivo administration of desipramine and other antidepressants (0.5–10 mg kg−1; i.p.; 2 h) resulted in dose‐dependent inhibitions of the basal twitch responses which were rapidly reversed to control values by idazoxan (10−5 M). In vitro, desipramine and other antidepressants also inhibited in a concentration‐dependent manner (10−9 − 10−5 M) the twitch responses. In rats pretreated 12 h earlier with reserpine (1 mg kg−1; i.p.) or oxypertine (4 mg kg−1; i.p.), desipramine (10 mg kg−1; 2 h) did not induce inhibition of the basal twitch responses or it induced a smaller effect, respectively.
For the various antidepressants the degree of inhibition of the basal twitch responses (desipramine > protriptyline > nortriptyline > maprotiline = imipramine > amitriptyline > viloxazine > iprindole > zimelidine) was highly correlated (r = 0.914) with the potency for blockade of [3H]‐NA uptake into rat brain synaptosomes.
Clonidine and xylazine inhibited in a concentration‐dependent manner (10−9 − 10−6 M) the twitch responses. The long‐term (7–14 days) administration of antidepressants or cocaine (10 mg kg−1, i.p.) resulted in significant decreases in sensitivity to clonidine or xylazine. Short‐term (3 days) treatment with desipramine did not reduce the sensitivity to clonidine.
The results indicate that the acute in vivo inhibition of NA neuronal uptake by antidepressants leads to the activation (through endogenous NA) of presynaptic inhibitory α2‐adrenoceptors which results in inhibition of the twitch responses. In contrast, prolonged in vivo inhibition of NA reuptake is followed by a slow desensitization process of the same receptors which results in a reduction of sensitivity to clonidine.
The role of the sympathetic nervous system in oestrogen‐induced hypertension in rats
Authors: Bhatt J.D. , Gulati O.D. 
Published: July 2012

Albino rats of either sex received chronic ethinyl oestradiol (EO) treatment (1.5 mg kg−1 daily, i.m.) for 3 weeks. Untreated control rats received arachis oil vehicle alone.
Chronic EO treatment resulted in elevation of blood pressure in both sexes. Female rats exhibited significantly greater elevation in blood pressure than males.
In chronic EO‐treated rats pressor responses to low doses (0.5 μg kg−1) of noradrenaline were significantly increased, while those to angiotensin II, acetylcholine and isoprenaline were unaltered. Chronic EO treatment also sensitized the vascular bed of the rats' hindquarters to noradrenaline.
EO‐induced hypertension was associated with significant increase in dopamine‐β‐hydroxylase activity of adrenal glands.
Complete bilateral adrenalectomy or chemical sympathectomy prevented the development of EO‐induced hypertension.
It is suggested that chronic treatment of rats with EO induces and maintains hypertension. The peripheral sympathetic system plays an important role in this phenomenon.
Nerve membrane sodium channels as the target site of brevetoxins at neuromuscular junctions
Authors: Atchison William D. , Luke Virginia Scruggs , Narahashi Toshio , Vogel Stephen M. 
Published: July 2012

Actions of two structurally related toxins, T‐17 and brevetoxin‐B, isolated from the red‐tide dinoflagellate, Ptychodiscus brevis, were studied on the giant axon of the squid and the neuromuscular junctions of the frog and rat.
T‐17 toxin caused a large increase in the frequency of miniature endplate potentials at nanomolar concentrations. In one typical case with a frog endplate, the frequency increased from 1.9 s−1 before application of 3.5 nM T‐17 to 69.3 s−1 within 5 min after application. In the rat muscle, the mean frequency increased from 1.39 s−1 in control to 11.93 s−1 after application of 23.2 nM T‐17.
The increase in miniature endplate potential frequency was reversed by the addition of 1 μM tetrodotoxin, and was not observed in a solution containing elevated Mg2+ and reduced Ca2+ concentrations.
External or internal application of T‐17 toxin (2–5 μM) or brevetoxin‐B (10–30 μM) to intact or internally perfused squid axons caused a depolarization of the membrane. This depolarization was abolished by the removal of external Na+ or by addition of tetrodotoxin to the external solution.
In voltage clamped squid giant axons, exposure to T‐17 toxin or brevetoxin‐B increased the non‐ inactivating component of the tetrodotoxin‐sensitive sodium current. The sodium current was activated at potentials 15 to 40 mV more negative than control.
It is proposed that these toxins modify a fraction of the sodium channels to a form which opens at potentials more negative than normal and which inactivates to a lesser extent. This mechanism would predict a depolarization of the nerve membrane at the neuromuscular junction, thus explaining the increased discharge of transmitter.
The relationship between noradrenaline‐induced contraction and 45Ca efflux stimulation in rabbit mesenteric artery
Authors: Leijten Paul A.A. , van Breemen Cornelis 
Published: July 2012

Cellular Ca2+ recycling in a branch of the rabbit mesenteric artery was investigated by measuring the time‐ and concentration‐dependent effects of noradrenaline (NA) on contraction and 45Ca efflux in Ca2+‐free solution.
When NA was present continuously (15 min), both force development and 45Ca efflux stimulation consisted of a fast and a slow (often oscillatory) component. These components were sensitive to caffeine and are probably both related to Ca2+ release from the intracellular Ca2+ store, presumably sarcoplasmic reticulum (s.r.).
When NA was applied for shorter time periods, both tension and stimulated 45Ca efflux decreased similarly.
Repetitive short (30 s) NA applications resulted in repeated contractions and stimulations of 45Ca efflux.
The NA‐stimulated 45Ca efflux was not inhibited when external Ca2+ was present or in Na+‐free medium.
Loading the cell with Ca2+ (with physiological salt solution for 3 h or with a high K+ depolarizing solution) increases the number of subsequent NA‐induced repeated contractions in Ca2+‐free solution.
The Ca2 + content of the sarcoplasmic reticulum (s.r.) in the smooth muscle cells of this small artery was estimated to be at least 50 μmol kg−1 wet weight, corresponding to an s.r. Ca2+ concentration of about 3.1 mM.
These results indicate that the NA‐induced increase in cytosolic free Ca2+ (as measured by force development) is accompanied by an increase in Ca2+ extrusion (as measured by stimulation of 45Ca efflux). This suggests that at least part of the activator Ca2+ cycles through the extracellular space during hormone‐induced activation of vascular smooth muscle.
Interactions between noradrenaline and α2‐adrenoceptor agonists in the superior mesenteric arterial bed of the rat
Authors: Hiley C. Robin , Nichols Andrew J. , Thomas G. Roger 
Published: July 2012

Interactions between α2‐agonists and noradrenaline vasoconstrictor responses were studied in the superior mesenteric arterial bed of the rat by use of perfusion both in situ with blood and in vitro with Krebs‐Henseleit solution.
Xylazine (1.9 × 10−6 mol) administered into the perfusion circuit reduced the maxium response to noradrenaline in the in situ preparation by 35% and decreased the pD50 for noradrenaline from 8.5 ±0.01 to 7.9 ±0.13 (n = 7). Yohimbine (1 mg kg−1, i.v.) gave a small parallel shift in the noradrenaline log dose‐response curve and prevented the reduction in the maximum response by subsequent administration of xylazine.
In vitro, xylazine (1.9 × 10−6 mol) also gave a long‐lasting reduction of 37% in the maximum response but did not affect the mid‐point sensitivity to noradrenaline. Yohimbine (10−6 M) did not change either of these effects.
Clonidine (1.9 × 10−6 mol) did not affect the maximum response to noradrenaline in vitro but did reduce the pD50 from 7.72 ± 0.17 to 6.9 ± 0.17 (n = 6). Yohimbine did not change these effects.
Guanfacine (1.8 × 10−6 mol) had no effect on the sensitivity of the in vitro preparation to noradrenaline but did reduce the maximum response by 20%. Yohimbine (10−6 M) prevented the depression of the maximum response.
It is concluded xylazine and clonidine interfere with noradrenaline induced vasoconstriction only to a limited extent through their interaction with α2‐adrenoceptors and that some other, as yet uncharacterised mechanism which may be activated by their aryl amidine structure, is responsible for their in vitro effects.
Effect of somatostatin on 45Ca fluxes in guinea‐pig isolated atria
Authors: Díez Juan , Tamargo Juan 
Published: July 2012

The effect of somatostatin (SS, 10−6 m and 5 × 10−6 m) was studied on 45Ca fluxes in guinea‐pig isolated atria.
SS produced a dose‐dependent decrease in 45Ca uptake, this effect being dependent on the stimulation rate and Ca concentration in the bathing media.
The decrease in 45Ca uptake was more evident at faster (60 and 180 beats min−1) than at slower frequencies (15 beats min−1) and was less evident in high Ca (5.4 mm).
SS had no effect on 45Ca efflux.
These results suggest that SS inhibits the slow inward Ca current in guinea‐pig atrial fibres.
Sodium‐dependence of the non‐specific desensitization of the guinea‐pig ileum induced by acetylcholine and histamine
Authors: Aboulafia J. , Capocci H. , Paiva A.C.M. , Paiva T.B. 
Published: July 2012

The isometric maximal responses of the guinea‐pig ileum to acetylcholine and to histamine (but not those to prostaglandin E2 and to high K+) exhibited a secondary transient increase in tonus during the tonic component of the contraction.
After desensitizing treatment with acetylcholine or histamine, the isometric responses to either agonist showed decreased phasic and enhanced tonic components, whereas both components of the response to prostaglandin E2 were markedly depressed.
During the desensitizing treatment the degree of desensitization went through a maximum that coincided with the occurrence of the secondary tonic increment.
In low‐Na+ medium, or in ouabain‐treated tissues, the responses to the three agonists were similar to the respective responses in the desensitized state.
It is concluded that the non‐specific desensitization is due to changes in Na+ translocation and that the increased tonic component of the isometric response is due to a reduced Na+ gradient across the cell membrane and consequent increase in Ca2+ loading.
P2‐purinoceptors of two subtypes in the rabbit mesenteric artery: reactive blue 2 selectively inhibits responses mediated via the P2y‐ but not the P2x‐purinoceptor
Authors: Burnstock Geoffrey , Warland Jennifer J.I. 
Published: July 2012

α,β‐Methylene ATP and ATP both produced concentration‐dependent contractions of the isolated mesenteric artery of the rabbit that were not inhibited by reactive blue 2.
In preparations where the tone had been raised with noradrenaline, ATP and 2‐methylthio ATP, but not α,β‐methylene ATP, produced relaxations of the vessel. These relaxations were inhibited in the presence of reactive blue 2.
Reactive blue 2 did not inhibit the contractions to noradrenaline, and only slightly inhibited relaxations to adenosine and acetylcholine.
The rank order of potency of purine nucleotide analogues in contracting the vessel was: α,β‐methylene ATP > β,γ‐methylene ATP = 2‐methylthio ATP > ATP, and in relaxing the vessel at raised tone was: 2‐methylthio ATP > ATP > β,γ‐methylene ATP > α,β‐methylene ATP.
It is concluded from this study that in the isolated mesenteric artery of the rabbit, purine nucleotides act via P2y‐purinoceptors to cause the muscle to relax and via P2x‐purinoceptors to cause the muscle to contract. The results also suggest that reactive blue 2 selectively inhibits responses mediated via the P2y‐purinoceptor, at least within a limited concentration range.
Uptake inhibitors potentiate γ‐aminobutyric acid‐induced contractile responses in the isolated ileum of the guinea‐pig
Authors: Ong Jennifer 
Published: July 2012

The γ‐aminobutyric acid (GABA)‐induced contractile responses in the guinea‐pig isolated ileum, maintained in Krebs‐bicarbonate solution (pH 7.4, 37°C), were significantly potentiated by inhibitors of GABA uptake, with a greater potentiation of the responses in the presence of (±)‐cis‐3‐aminocyclohexane‐carboxylic acid (ACHC) > l‐2,4‐diaminobutyric acid (DABA) > (±)‐nipecotic acid > β‐alanine, whilst simultaneous addition of DABA with β‐alanine caused a greater potentiation of the GABA‐induced responses than did nipecotic acid with β‐alanine, or any of the uptake blockers applied alone.
The concentration‐response curves for the GABA‐induced ileal contraction were shifted to the left in the presence of the uptake inhibitors, this shift being more prominent over the lower concentration range of GABA (1–20 μm). By contrast, contractile responses to muscimol or 3‐amino‐1‐propanesulphonic acid (3APS) were not potentiated by the uptake blockers, neither were their concentration‐response curves altered.
Bicuculline methochloride shifted the GABA concentration‐response curve to the right, whilst picrotoxinin both shifted the concentration‐response curve for GABA to the right and depressed the maximum response. In the presence of the uptake inhibitors, the rightward shift of the concentration‐response curves for GABA induced by bicuculline was less than that induced by bicuculline alone. The rightward shift with picrotoxinin was similarly reduced in the presence of the uptake inhibitors, without altering the depression of the maximum by picrotoxinin.
Bicuculline caused a rightward shift of the concentration‐response curves for 3APS and muscimol, with the curve for 3APS most affected. Picrotoxinin similarly shifted the concentration‐response curves for 3APS and muscimol but depressed the maximum, with the curve for 3APS again being most affected. None of the inhibitors of GABA uptake influenced the concentration‐response curves for 3APS or muscimol in the presence of bicuculline or picrotoxinin.
In conclusion, a saturable GABA uptake system is present in the enteric nervous system of the guinea‐pig intestine, where neuronal GABA uptake appears to predominate over glial uptake.
Effect of omeprazole on eicosanoid formation in and release from guinea‐pig gastric mucosal cells
Authors: Hell M. , Sewing K.‐Fr. 
Published: July 2012

Guinea‐pig gastric mucosal cells isolated by collagenase and pronase digestion were used to study the release of prostanoids prostaglandin I2 (PGI2; measured as 6‐keto PGF1α), PGE2, PGF2α and thromboxane A2 (TXA2; measured as TXB2). Lysophosphatide acyltransferase (LAT) and phospholipase A2 (PLA2) were measured in the microsomal fraction of isolated but not separated gastric cells and isolated and enriched parietal and mucous cells.
In all cell preparations PLA2 activity was approximately 5 times higher than that of LAT.
Acid‐activated omeprazole inhibited LAT in a concentration‐dependent manner with similar IC50 values in gastric, parietal and mucous cells. It had no effect on PLA2.
Gastric cells constantly produced PGI2, PGE2, PGF2α and TXA2. The main prostaglandins released were PGI2 and PGE2. PGF2α and TXA2 were released in smaller quantities.
Omeprazole dissolved in polyethylene glycol 400 (PEG) pH 2 inhibited spontaneous PGI2 release in a concentration‐dependent manner with an IC50 of 14.3 ± 4.8 μm. Only concentrations as high as 100 μm produced a significant reduction in PGE2 release by 60%. No significant changes could be detected in the spontaneous release of PGF2α and TXA2.
Omeprazole dissolved in PEG pH 7 had no effect on PGI2 release except at 100 μm which led to an insignificant decrease by 40%.
These data suggest that omeprazole beyond its inhibitory effect on parietal cell K+/H+‐ATPase also affects gastric mucosal prostanoid formation and release. The inhibitory effect on PGI2 does not support the view that omeprazole protects the gastric mucosa by increasing prostanoid formation.