bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological characterization of 5‐hydroxytryptamine‐induced hyperpolarization of the rat superior cervical ganglion
Authors: Ireland S.J. , Jordan C.C. 
Published: July 2012

A study has been made of the pharmacology of 5‐hydroxytryptamine (5‐HT)‐induced hyperpolarization responses recorded extracellularly from the rat isolated superior cervical ganglion (SCG).
Hyperpolarization responses induced by 5‐HT (1 × 10−8‐1 × 10−4 m) in the presence of MDL 72222 (1 × 10−5 m) were not antagonized by phentolamine (1 × 10−6 m), prazosin (1 × 10−7‐3 × 10−7 m), haloperidol (1 × 10−6 m) or ketanserin (1 × 10−7‐1 × 10−6 m). However, the latter two compounds both potentiated and increased the persistence of the hyperpolarization induced by moderate to high concentrations of 5‐HT. Spiperone (1 × 10−7 m) caused similar effects. All further experiments were performed in the presence of ketanserin (1 × 10−6 m) as well as MDL 72222.
8‐Hydroxy‐2(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT; 1 × 10−7‐1 × 10−4 m) and ipsapirone (3 × 10−5‐3 × 10−4 m) behaved as weak hyperpolarizing agonists on the SCG. However, at concentrations below those required to produce hyperpolarization, both compounds acted as unsurmountable antagonists of 5‐HT‐induced hyperpolarization.
5‐Carboxamidotryptamine (5‐CT; 1 × 10−9‐1 × 10−5 m) mimicked the hyperpolarizing activity of 5‐HT on the SCG. The EC50 for 5‐CT was approximately 9 fold lower than that for 5‐HT.
Spiperone (1 × 10−7‐1 × 10−5 m) behaved as a reversible competitive antagonist of hyperpolarization responses induced by 5‐HT with a pKB value of 7.40 ± 0.09. Spiperone (1 × 10−7‐1 × 10−6 m) also caused concentration‐dependent rightward displacement of the 5‐CT concentration‐hyperpolarization response curve. In this case, the pKB was 7.80 ± 0.05.
(±)‐Cyanopindolol (3 × 10−7‐3 × 10−6 m) caused non‐parallel rightward displacements of the 5‐HT concentration‐response curve. Against 5‐CT, (±)‐cyanopindolol (3 × 10−7‐3 × 10−6 m) caused a concentration‐independent rightward displacement of the concentration‐response curve, accompanied by a large increase in the maximum response. 5‐CT‐induced hyperpolarization recorded in the presence of (±)‐cyanopindolol (3 × 10−7 m) was not significantly antagonized by methiothepin (1 × 10−6 m) or methysergide (1 × 10−6 m).
It is concluded that 5‐HT‐induced hyperpolarization of the rat SCG is mediated via a 5‐HT1‐like receptor which resembles the 5‐HT1A binding site. However, a lack of selective drugs precludes more definitive characterization of this receptor.
Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand
Authors: Spedding Michael , Mir Anis K. 
Published: July 2012

Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca2+ channel activator, Bay K 8644, in K+‐depolarized smooth muscle. Palmitoyl carnitine caused concentration‐dependent (1–1000 μmol l−1) augmentations in the sensitivity to Ca2+ of K+‐depolarized taenia preparations from the guinea‐pig caecum. The (±)‐isomer was equieffective with the (–)‐isomer, whereas carnitine was ineffective and palmitic acid relaxed the tissues. The shift to the left of Ca2+ concentration‐response curves induced by palmitoyl carnitine (100 μmol l−1) was additive with that of Bay K 8644 (1 μmol l−1).
The interactions of palmitoyl carnitine with the different classes of calcium‐antagonist were similar to those seen with Bay K 8644. Schild plots of the calcium‐antagonist effects of nifedipine were shifted to the right following preincubation of the taenia with palmitoyl carnitine (30–300 μmol l−1). The inhibitory effects of verapamil were especially sensitive to palmitoyl carnitine (100 μmol l−1). Whereas the potency of diltiazem as a calcium‐antagonist was reduced by palmitoyl carnitine (100 μmol l−1), the inhibitory effects of the lipophilic class III calcium‐antagonists, cinnarizine and flunarizine, were entirely resistant to palmitoyl carnitine (100 μmol l−1).
Although palmitoyl carnitine has detergent properties in high concentrations and lyses red blood cells, these effects were not Ca2+‐dependent, nor were they modified by calcium‐antagonists. Other detergents did not have selective interactions with Ca2+ channels.
Palmitoyl carnitine inhibited [3H]‐nitrendipine, [3H]‐verapamil and [3H]‐diltiazem binding to rat cortical membranes with IC50 values (μmol l−1) of 120 ± 1, 95 ± 17 and 120 ± 15 μmol l−1 respectively. The inhibition showed little temperature‐dependence, in contrast to that of Bay K 8644, except for a small reduction in the IC50 value for [3H]‐verapamil binding at 37°C (42 ± 5 μmol l−1). Palmitoyl carnitine interacted selectively with the Ca2+ channel, in that effects on ligand binding to α‐adrenoceptors, β‐adrenoceptors and 5‐HT1A receptors occurred only at 5–10 fold higher concentrations.
It is concluded that palmitoyl carnitine, at concentrations which have previously been shown to occur in the cytoplasm during myocardial ischaemia, may interact directly with Ca2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.
Clonidine and morphine increase [3H]‐noradrenaline overflow in mouse vas deferens
Authors: Forsyth Karyn M. , Pollock David 
Published: July 2012

Field stimulation of mouse isolated vas deferens produced a biphasic contraction that consisted of an initial brief non‐adrenergic, non‐cholinergic (NANC) twitch, followed by a more prolonged noradrenergic component.
Field stimulation of vasa, previously loaded with [3H]‐noradrenaline ([3H]‐NA), increased the amount of radioactivity in the Krebs bathing solution; 77% of this radioactivity was derived from [3H]‐NA.
Tetrodotoxin (3 × 10−6 m) abolished the biphasic motor response to field stimulation and the accompanying increased overflow of [3H]‐NA.
Morphine (10−7‐10−5 m) inhibited the initial NANC component but potentiated the secondary noradrenergic component of the motor response to field stimulation. Morphine also increased the field stimulation‐induced overflow of radioactivity. Naloxone (10−6 m) antagonized the effects of morphine on the motor response and also on the overflow of radioactivity.
Clonidine (10−9‐10−7 m) inhibited the initial NANC component but potentiated the secondary noradrenergic component of the motor response to field stimulation. Clonidine also increased the field stimulation‐induced overflow of radioactivity.
The ability of morphine (10−7 m) and of clonidine (10−9 m) to potentiate the field stimulation‐induced overflow of radioactivity persisted in the presence of a combination of tranylcypromine (10−5 m), desmethylimipramine (10−5 m) and 17‐β‐oestradiol (10−5 m).
The inhibition of the initial NANC component of the motor response to field stimulation produced by morphine and clonidine may be related to the ability of these drugs to potentiate both the secondary noradrenergic component and the overflow of radioactivity, if the NANC transmitter is involved in regulating NA release.
Zolantidine (SK&F 95282) is a potent selective brain‐penetrating histamine H2‐receptor antagonist
Authors: Calcutt C.R. , Ganellin C.R. , Griffiths R. , Leigh B.K. , Maguire J.P. , Mitchell R.C. , Mylek M.E. , Parsons M.E. , Smith I.R. , Young R.C. 
Published: July 2012

The novel benzthiazole derivative zolantidine (SK&F 95282) is a potent antagonist of histamine at H2‐receptors in guinea‐pig atrium and rat uterus. Only apparent pA2 values of 7.46 and 7.26 respectively could be calculated since the slopes of the Schild plots were significantly less than unity.
Zolantidine is equally potent as an antagonist at histamine H2‐receptors in guinea‐pig brain. The compound inhibited histamine stimulated adenylate cyclase (pKi 7.3) and dimaprit stimulated adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) accumulation (approx pA2 7.63), and competed with [3H]‐tiotidine binding (pKi 7.17).
Zolantidine is at least 30 fold more potent at H2‐receptors than at other peripheral and central receptors investigated.
Infusion of zolantidine into rats produces a brain concentration greater than the plateau blood concentration (brain/blood ratio 1.45).
Zolantidine is thus characterized as a potent selective brain‐penetrating H2‐receptor antagonist, and will be a valuable pharmacological tool for investigating possible physiological and pathological roles for histamine in the central nervous system.
A possible role of airway epithelium in modulating hyperresponsiveness
Authors: Aizawa H. , Miyazaki N. , Shigematsu N. , Tomooka M. 
Published: July 2012

In order to examine the role of airway epithelium in the responsiveness of smooth muscle in man, we measured the contractile responses to acetylcholine (ACh), histamine, and prostaglandin F2α (PGF2α) and the relaxation response to isoprenaline (Isop), in 48 bronchi obtained from 10 patients who received surgery. Responses were measured in the presence and absence of the epithelium.
Removal of epithelium (by rubbing the mucosa gently with forceps) significantly increased the contractile responses evoked by ACh, histamine and PGF2α.
In contrast, removal of epithelium did not alter the relaxation response to Isop.
To clarify the mechanism underlying this epithelial inhibitory effect on smooth muscle contraction, we measured the contractile responses of dog trachea with the epithelium removed to increasing concentrations of ACh. After measuring the control response, we added about 0.1 g of the chopped epithelium in the organ chamber, and measured the response again.
After adding airway epithelium and incubating with tracheal strips, the contractile response of tracheal strips decreased significantly as compared to the control response.
These results show that airway epithelium possesses the ability to decrease the smooth muscle contraction to ACh, histamine and PGF2α in man and dogs.
The mechanism of this inhibitory effect of the airway epithelium is not explained by a change in mechanical property of the airway nor the change in diffusion of these drugs to the smooth muscle across the epithelium. Thus, these results suggest that airway epithelium may have an important role in modulating smooth muscle tone, possibly by inactivation of these mediators, or by releasing an epithelium‐derived relaxing factor.
Interactions of the imidazodiazepine Ro 15–4513 with chemical convulsants
Authors: Lister Richard G. , Nutt David J. 
Published: July 2012

The proconvulsant effects of the imidazodiazepine Ro 15–4513, were investigated in mice by use of intravenous infusion of a variety of convulsant drugs.
Dose‐response and time course studies of Ro 15–4513 against γ‐aminobutyric acid (GABA) antagonists were performed. On the basis of these studies a maximally effective dose of 5 mg kg−1 was administered 5 min before the determination of seizure thresholds in subsequent experiments.
Ro 15–4513 (5 mg kg−1) significantly lowered seizure thresholds to pentylenetetrazole, bicuculline and the convulsant benzodiazepine Ro 5–3663, but failed to alter seizure thresholds to picrotoxin, strychnine, caffeine and quipazine.
Ro 15–4513 significantly raised seizure threshold to the benzodiazepine receptor inverse agonist methyl 6,7‐dimethoxy‐4 ethyl‐β‐carboline‐3‐carboxylate (DMCM).
These results are discussed in relation to other studies investigating the proconvulsant and alcohol‐antagonizing effects of Ro 15–4513.
Gastric mucosal damage induced by local intra‐arterial administration of Paf in the rat
Authors: Esplugues J.V. , Whittle B.J.R. 
Published: July 2012

A technique for the close‐arterial administration of substances to the rat stomach in vivo has been developed.
Intra‐arterial infusion of platelet‐activating factor (Paf, 10–50 ng kg−1 min−1 for 10 min) induced macroscopically assessed damage in the corpus mucosa, characterized as vasocongestion and necrosis.
The threshold intra‐arterial doses of Paf that induced histologically assessed damage in the antrum and corpus of the stomach (10 and 5 ng kg−1 min−1, respectively) produced minimal systemic hypotension (< 20 mmHg) suggesting a dissociation between these events.
Pretreatment with the Paf‐antagonist, L‐652,731 (2.5 mg kg−1 i.v.) prevented the gastric damage induced by local infusion of Paf.
Intravenous infusion of Paf (25 ng kg−1 min−1) did not significantly damage the gastric mucosa, in contrast to the same dose infused locally, yet Paf administered by either route produced a comparable degree of hypotension. Such findings suggest minimal metabolism of Paf during its passage through the gastric circulation.
Local intra‐arterial infusion of Paf in doses as low as 0.25 ng kg−1 min−1, which had no systemic hypotensive actions, significantly induced gastric damage in the presence of intragastric 20% ethanol.
These observations support a local role for Paf in the pathogenesis of gastric irritation and ulceration, such as that observed during endotoxin shock or bacterial infection. The present technique is thus useful for the study of locally administered substances on gastric function and integrity.
The effects of prenylamine on single ventricular myocytes of guinea‐pig
Authors: Shimoni Y. , Posner P. , Spindler A.J. , Noble D. 
Published: July 2012

The action of prenylamine, an antianginal drug, was studied in single ventricular guinea‐pig myocytes. In concentrations of 10–50 μm, prenylamine significantly (P < 0.01) shortened action potentials, and significantly (P < 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor‐blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action.
Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time‐dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time‐independent potassium conductance.
It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.
Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats
Authors: Sim M.F. , Yates D.B. , Parkinson R. , Cooling M.J. 
Published: July 2012

Flosequinan (BTS 49 465, 7‐fluoro‐l‐methyl‐3‐methylsulphinyl‐4‐quinolone) a novel arteriovenous dilator agent was orally effective in conscious renal hypertensive dogs and normotensive cats. The hypotensive potency of flosequinan was approximately ten times less than that of hydralazine in renal hypertensive dogs, 10 mg kg−1 and 20 mg kg−1 flosequinan causing similar falls in mean blood pressure to 1 mg kg−1 and 3 mg kg−1 hydralazine respectively. In normotensive cats, 5 mg kg−1 flosequinan caused similar falls to 0.5 and l.0 mg kg−1 hydralazine. The onset of hypotensive effect after flosequinan appeared to be slightly slower than after hydralazine in the dog and slightly faster than hydralazine in the cat.
The degree of tachycardia and increase in plasma renin activity (PRA) for equivalent falls in mean blood pressure in both species was significantly less for flosequinan than for hydralazine (P < 0.05).
In normotensive dogs, flosequinan, 10 and 20 mg kg−1 orally, caused a small but non‐significant increase in sodium and chloride excretion and had little effect on urine volume whereas hydralazine, 1 and 3 mg kg−1 orally, caused a marked retention of sodium and chloride ions and a reduction in urine volume (P < 0.01).
Neither flosequinan, 10 mg kg−1 orally, nor hydralazine 1 mg kg−1 orally, affected either glomerular filtration rate measured as creatinine clearance or effective renal plasma flow measured as p‐aminohippuric acid clearance in normotensive dogs.
The lesser degree of tachycardia and increase in plasma renin activity together with a lack of sodium retaining activity associated with flosequinan suggest that this agent may have potential advantages over existing therapy as an antihypertensive in man.
Effects of the calcium channel activator Bay K 8644 on general anaesthetic potency in mice
Authors: Dolin S.J. , Halsey M.J. , Little H.J. 
Published: July 2012

The effects of the calcium channel activator, Bay K 8644, on the anaesthetic potencies of ethanol, argon and pentobarbitone were examined in mice.
Bay K 8644, at 1 mg kg−1 i.p., significantly antagonized the general anaesthetic potencies of ethanol and argon, but at 5 and 10 mg kg−1 this compound increased the general anaesthetic potency of these drugs.
At doses of 1, 5 and 10 mg kg−1 Bay K 8644 antagonized the anaesthetic effects of pentobarbitone.
Bay K 8644, at the highest dose used, did not alter the brain concentrations of pentobarbitone or the blood concentrations of ethanol.
The effects of the different doses of Bay K 8644 on the actions of ethanol and of argon are compatible with the known partial agonist properties of this compound on calcium channels in vitro.
The actions of Bay K 8644 on the anaesthetic effects of pentobarbitone suggests that specific interactions may be involved in the anaesthetic actions of this compound.
Effects of cadmium on the slow inward current of frog heart muscle in relation to a lowering of pH in external solution
Authors: Pater Christine , Sauviat Martin‐Pierre 
Published: July 2012

The effect of cadmium (Cd) on the slow inward current (Isi) of frog atrial fibres was studied by the double sucrose gap technique.
Cd (5μm) depressed Isi in a voltage‐dependent manner without alteration of the apparent reversal potential for Isi.
Dose‐response curves indicated an apparent dissociation constant for the Cd blocking effect of 4.5 μm at 0 mV, with a one to one relationship between Cd and the slow channel.
Increasing the external concentration of Ca ions ([Ca]0) in the tetrodotoxin (TTX)‐containing Ringer solution antagonized the block of Isi by Cd. Double reciprocal plots for Isi versus [Ca]0 drawn in the presence or in the absence of Cd intersected at the ordinate, indicating that Cd competes with Ca for a common binding site.
Lowering the external pH from 7.3 to 6.3 depressed Isi. The block caused by H was voltage‐dependent. Double reciprocal plots for Isi versus [Ca]o drawn at pH 7.3 and 6.3 intersected at the abscissa, and indicated that H and Ca did not compete for a common site.
Lowering the external pH did not change the ability of Cd to inhibit Isi.
The data suggested the existence of two different sites within the slow channel in frog atrial fibres, one of them being H‐sensitive and the other cadmium‐sensitive.
Effects of halothane on membrane currents associated with contraction in single myocytes isolated from Guinea‐pig ventricle
Authors: Terrar D.A. , Victory J.G.G. 
Published: July 2012

The effects of halothane on electrical activity and contraction were investigated in single myocytes isolated from guinea‐pig ventricle.
Halothane depressed the plateau and shortened the duration of action potentials.
Halothane also reduced the amplitude of inward calcium currents and of additional inward current activated by cytosolic calcium under voltage‐clamp conditions.
Contractions (measured by an optical technique) accompanying either action potentials or calcium currents were reduced by halothane. However, the extent of attenuation of contraction was greater than when a similar level of calcium channel blockade was induced by application of verapamil.
Actions of halothane on calcium‐activated tail currents in double‐pulse experiments were consistent with reduction by halothane of the cytosolic calcium transient, perhaps as a consequence of reduced uptake of calcium into sarcoplasmic reticulum stores.
It is concluded that the actions of halothane on inward currents contribute to its effects on action potentials. The reduction in contraction caused by halothane may result partly from a reduced influx of calcium to trigger contraction, and partly by a reduced release of calcium from sarcoplasmic reticulum stores.
Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea‐pigs
Authors: Payne A.N. , Garland L.G. , Lees I.W. , Salmon J.A. 
Published: July 2012

The effect of a novel series of orally‐active acetohydroxamic acid inhibitors of arachidonate 5‐lipoxygenase on ‘leukotriene‐dependent’ anaphylactic bronchoconstriction has been investigated in anaesthetized, pump‐ventilated guinea‐pigs actively sensitized to ovalbumin (OA). In a complementary series of experiments, the pharmacokinetics of these compounds in the plasma compartment following oral administration to guinea‐pigs has also been investigated.
In animals pretreated with mepyramine (2 mg kg−1 i.v.) and indomethacin (l0 mg kg−1 i.v.) and challenged with antigen aerosol (OA 10 mg ml−1; 5s) compounds BW A4C, BW A137C and BW A797C (10–200 mg kg−1, p.o., 1 h pre‐challenge) markedly reduced that component of anaphylactic bronchoconstriction shown to be ‘leukotriene‐dependent’.
The maximum degree of inhibition (up to 75%) of ‘leukotriene‐dependent’ anaphylactic bronchoconstriction by these three compounds was equivalent to that seen with the leukotriene antagonist FPL 55712 (10 mg kg−1, i.v.).
The peak levels of unchanged acetohydroxamic adds in the plasma compartment occurred 0.5 h after their oral administration and were as follows: BW A4C: 11.3 ± 3.9; BW A137C: 7.6 ± 2.4; BW A797C: 3.9 ± 1.3 μg ml−1 plasma.
The inhibition by BW A4C and BW A137C (50 mg kg−1, p.o.) of ‘leukotriene‐dependent’ anaphylactic bronchospasm persisted for up to 3 and 4h respectively but did not extend to 6h. The decline in inhibitory activity paralleled the fall in the concentration of unchanged drug in the plasma compartment over this time period.
The results of the present study are consistent with BW A4C, BW A137C and BW A797C attenuating ‘leukotriene‐dependent’ bronchial anaphylaxis in anaesthetized guinea‐pigs by selective inhibition of arachidonate 5‐lipoxygenase.
The action of prostanoid receptor agonists and antagonists on smooth muscle and platelets
Authors: Eglen R.M. , Whiting R.L. 
Published: July 2012

Prostanoid receptors have been characterized in a range of guinea‐pig and rat smooth muscle and platelets, according to the scheme of Coleman et al., (1985a), using agonists (prostaglandin D2 (PGD2), PGE1, PGE2, 16,16 dimethyl PGE2, PGF2α, PGI2 and U46619) and putative selective antagonists (AH 6809 and SQ 29,548).
The ileum possesses EP1‐ and IP‐receptors; the trachea, EP1‐EP2‐ and TP‐receptors; the oesophageal muscularis mucosa, EP1‐ and TP‐receptors; the aorta and the portal vein TP‐receptors. The rat colon possesses IP‐, FP‐ and TP‐receptors.
Guinea‐pig platelets possess both IP and DP receptors mediating an inhibition of aggregation and TP receptors mediating proaggregation responses. No evidence was found for the presence of EP1‐, EP2‐ or FP‐receptors.
Misoprostol and fenprostalene were characterized using the above preparations. Misoprostol acts as a selective EP1‐agonist, and has little or no DP, FP, IP and TP activity. In the trachea precontracted with carbachol no evidence of EP2‐receptor stimulation was observed. Fenprostalene possesses FP and TP activity but no EP1, EP2, DP or IP activity.