bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation into the cardioregulatory properties of the α1‐adrenoceptor blocker indoramin
Authors: Pierce Vanessa , Shepperson N.B. , Todd M.H. , Waterfall J.F. 
Published: July 2012

The cardioregulatory properties of the α1‐adrenoceptor blocker indoramin have been compared with those of prazosin in the anaesthetized rat. The effects of autonomic blockade on heart rate responses evoked by these two agents and their effects on blood pressure and heart rate after peripheral or central administration have been compared.
Cumulative administration of indoramin (0.8–25.6 mg kg−1 i.v.) evoked significant decreases in arterial blood pressure and a concomitant bradycardia. Pithing or autonomic blockade, by pretreatment with a combination of practolol and bilateral vagotomy, prevented the bradycardia evoked by indoramin (0.8–3.2 mg kg−1 i.v.). Atropine sulphate pretreatment abolished the bradycardia until a cumulative dose of 25.6 mg kg−1 (i.v.) of indoramin had been reached. Bilateral vagotomy, intravenous administration of atropine methylnitrate or practolol pretreatment attenuated the bradycardia.
Prazosin (0.02–0.64 mg kg−1 i.v.) evoked a fall in arterial blood pressure of similar magnitude to that observed following indoramin. A bradycardia was evoked only at a relatively high dose (0.64 mg kg−1 i.v.).
Intracisternal injection of indoramin or prazosin evoked bradycardia and hypotension at a dose which had no effect after intravenous injection (25 μg). Intracerebroventricular injection of indoramin (25 μg) had no significant effect on heart rate or blood pressure compared to control values, whereas prazosin (25 μg) evoked a significant tachycardia and hypotension.
It is concluded that the bradycardia evoked by indoramin in the rat is not due to a direct action on the heart except possibly at high doses. Central α1‐adrenoceptor blockade, possibly in the brainstem region, results in a bradycardia and this may explain the lack of reflex tachycardia following the administration of indoramin.
Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant
Authors: Black J.W. , Gerskowitch V.P. , Left P. , Shankley N. P. 
Published: July 2012

In this paper, pharmacological resultant is defined as the net effect of a single compound resulting from the simultaneous expression of two or more specific actions.
The principles of concentration‐ratio analysis are extended to develop a method for detecting and quantifying competitive antagonism when this property is a component of a pharmacological resultant. The method is general to the extent that it allows analysis of competitive antagonism in combination with all types of post‐receptor intervention. Essentially it depends on the altered expression of competition by a reference antagonist. It incorporates tests for validating its application and it is independent of agonist concentration‐effect curve shape: in these respects the method is analogous to Schild plot‐analysis of simple competition.
The methodology for the practical application of the analysis is exemplified by studying the net effect of a combination of a phosphodiesterase inhibitor (isobutylmethylxanthine) and histamine H2‐ receptor antagonist (metiamide) on histamine‐stimulated tachycardia in guinea‐pig, isolated, right atrium. Cimetidine was used as the reference antagonist.
The equation used in this analysis is similar in form to one recently described by Hughes & Mackay (1985) to elucidate the situation when competitive antagonism occurs in combination with functional interactions. The relation between their method and the present analysis is discussed.
Nicotinic antagonists produce differing amounts of tetanic fade in the isolated diaphragm of the rat
Authors: Gibb A. J. , Marshall I.G. 
Published: July 2012

The effects of nicotine antagonists on single twitches, trains of four twitches and tetanic contractions of the isolated diaphragm of the rat were examined.
Different drugs were found to produce different amounts of tetanic fade relative to depression of twitch tension.
The order of activity from most able, to least able to produce fade was: hexamethonium> trimetaphan = atracurium = tubocurarine>pancuronium>erabutoxin b.
The effect of erabutoxin b was distinctive for its almost complete lack of tetanic fade.
3,4‐Diaminopyridine increased tetanic fade produced by tubocurarine, atracurium and hexamethonium, but not that produced by erabutoxin b.
It is concluded that nicotinic antagonists act at more than one site at the neuromuscular junction. Assuming block of the postjunctional acetylcholine receptor produces tension depression, a second or third site must be involved in producing tetanic fade.
The possibility that tetanic fade results from block of the ion channel associated with the postjunctional acetycholine receptor or from the block of a prejunctional nicotinic receptor is discussed.
Stimulation of α1‐adrenoceptors in rat kidney mediates increased inositol phospholipid hydrolysis
Authors: Neylon Craig B. , Summers Roger J. 
Published: July 2012

The molecular events which follow activation of α1‐adrenoceptors in rat kidney were investigated by measuring inositol phospholipid hydrolysis. Slices were labelled with [3H]‐inositol (0.25 μm) and the accumulation of [3H]‐inositol phosphates ([3H]‐IP's) was measured after stimulation with α‐adrenoceptor agonists.
Phospholipid labelling was both time‐and Ca2+‐dependent. In kidney, Ca2+ (1 mm) increased the incorporation of [3H]‐inositol by 49% and in cerebral cortex reduced it by 46%.
Following addition of noradrenaline (NA, 1 mm), accumulation of [3H]‐IP's increased linearly for at least 60 min. In Ca2+‐free buffers a 2.1 fold increase in [3H]‐IP accumulation was observed and further increases in stimulated and control levels were produced in the presence of Ca2+ (2.5 mm). These responses were attenuated by the inclusion of indomethacin (10 μm) and abolished in the presence of EGTA (0.5 mm). Responses to (−)‐NA were more than 4 fold higher in the renal cortex than in the medulla.
Separation of the IP's which accumulate after α‐adrenoceptor agonists showed that after 60 min stimulation the major products were glycerophosphoinositol and inositol‐phosphate with smaller amounts of inositol‐bisphosphate and inositol‐trisphosphate.
The most effective agonists tested for stimulation of accumulation of [3H]‐IP's were (–)‐ NA > phenylephrine > methoxamine, (+)‐NA. Clonidine and (–)‐isoprenaline were ineffective at concentrations up to 100 μm. The order of effectiveness of α‐adrenoceptor antagonists was prazosin > BE2254 > phentolamine > idazoxan > rauwolscine.
The results indicate that α1‐adrenoceptors in rat kidney are linked to phosphoinositide hydrolysis and that this response is localized mainly to the renal cortex.
Interaction of phorbol esters with Ca2+ channels in smooth muscle
Authors: Spedding Michael 
Published: July 2012

The phorbol ester 12‐O‐tetradecanoyl phorbol‐13‐acetate (TPA), a selective activator of protein kinase C, had no effect on the sensitivity to Ca2+ or verapamil of K+‐depolarized taenia preparations from the guinea‐pig caecum, despite the use of high concentrations (1 μm for 3 h); this preparation is sensitive to Ca2+ channel activators and antagonists.
TPA (0.03‐3 μm) caused a slow contraction of rat aorta preparations; the contractions were resistant to the calcium‐antagonists nifedipine (0.01 μm), verapamil (10 μm), diltiazem (10 μm) and cinnarizine (10 μm), but were antagonized by N‐(6‐aminohexyl)‐5‐chloro −1‐naphthalensulphonamide (W‐7, 50–200 μm). Prolonged exposure to TPA (> 2h) resulted in spontaneous contractions which were sensitive to verapamil (1 μm).
Isoprenaline and sodium nitroprusside relaxed phenylephrine‐induced contractions in rat aorta preparations. TPA (0.3 μm) blocked the maximal response to isoprenaline but not to sodium nitroprusside indicating that TPA did selectively activate protein kinase C under these experimental conditions.
These findings indicate that protein kinase C activation does not result in direct effects on Ca2+ channel function, but may exert effects indirectly (e.g. by modifying intracellular sensitivity to Ca2+, Ca2+ extrusion, or cellular depolarization).
Effects of nipradilol on myocardial ischaemia produced by coronary stenosis in dogs
Authors: Noguchi Katsuhiko , Sakanashi Matao 
Published: July 2012

Effects of nipradilol which is a new β‐adrenoceptor blocking agent endowed with nitroglycerin‐like vasodilator actions, its denitrated derivative (denitro nipradilol) and propranolol on abnormalities of regional myocardial shortening produced by partial occlusion of the left circumflex coronary artery (LCX) were studied in anaesthetized open‐chest dogs.
In the presence of LCX stenosis, nipradilol (0.1 mg kg−1, i.v.) produced marked decreases in heart rate and LV dP/dt without a significant increase in left ventricular end‐diastolic pressure (LVEDP). It improved impaired myocardial segment shortening and restored normal cardiac lactate metabolism.
Denitro nipradilol (0.2 mg kg−1 i.v.) and propranolol (0.2 mg kg−1 i.v.) both caused similar haemodynamic changes to nipradilol but also produced a significant increase in LVEDP. However, improvement by these two agents of regional dysfunction in the ischaemic myocardium was comparable to those seen with nipradilol.
All three agents markedly inhibited isoprenaline‐induced tachycardia, but vehicle did not.
Atrial pacing abolished the beneficial effect of nipradilol on myocardial shortening in the ischaemic region without affecting other haemodynamic parameters.
These results indicate that nipradilol alleviates acute myocardial ischaemia produced by coronary stenosis with similar efficacy to denitro nipradilol and propranolol suggesting, that a major part of the beneficial effect of nipradilol may be attributable to its β‐adrenoceptor blocking action.
Electrophysiological effects of diclofurime on rabbit and frog atrial heart muscle
Authors: Gautier Patrick , Guiraudou Pierre , Sauviat Martin‐Pierre 
Published: July 2012

The effects of diclofurime on the electrical activity of the rabbit sinus node, rabbit atria and frog atrial fibres were studied using microelectrode and the double sucrose gap voltage‐clamp techniques respectively.
In rabbit sinus node, diclofurime (10−7 m to 10−6 m) decreased the action potential (AP) amplitude and maximum rate of depolarization , increased the AP duration and slowed the sinus rate.
In rabbit atria, the drug reduced the amplitude of the depolarizing phase and , lengthened the AP duration and decreased the resting membrane potential.
In frog atrial fibres, the drug (10−5 m) depolarized the resting membrane potential, decreased as well as the plateau amplitude. It inhibited the sodium current (INa) with a dissociation constant of 3.7 × 10−6 M and a one to one relationship between the drug molecule and the Na channel. Diclofurime did not alter the apparent reversal potential for the fast Na current (ENa) but it inhibited the sodium conductance (GNa) in a frequency‐dependent manner.
Diclofurime also blocked the slow inward current (Islow) without alteration of Eslow. The block of Islow occurred with a dissociation constant of 2 × 10−5 m and unity stoichiometry.
The data suggest that diclofurime might be effective in the control of cardiac arrythmias since it exhibited both local anaesthetic‐like and calcium antagonistic properties.
Neuroleptic‐induced hypothermia in mice: lack of evidence for a central mechanism
Authors: Boschi Gabrielle , Launay Nicole , Rips Richard 
Published: July 2012

The present study investigated the ability of neuroleptic drugs to induce hypothermia in mice when they were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.).
Twelve neuroleptics belonging to five chemical classes including phenothiazines, butyrophenones, benzamides, thioxanthenes and diphenylbutylpiperidines were injected i.p. All of them, except benzamides, induced a dose‐dependent decrease in rectal temperature.
Neuroleptics were administered i.c.v. via cannulae previously implanted in mice to determine whether this response might have a central origin. None of the drugs tested induced hypothermia at doses which did not produce toxic effects. These negative results suggest that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism.
Since some neuroleptics possess α‐adrenolytic properties which could induce hypothermia by promoting vasodilatation, we attempted to antagonize the hypothermia produced by peripheral administration of two neuroleptics with phenylephrine, an α‐adrenoceptor agonist that does not cross the blood‐brain barrier. The hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral α‐adrenoceptors may mediate neuroleptic‐induced hypothermia.
The actions of the peptides, neuropeptide Y and peptide YY, on the vascular and capsular smooth muscle of the isolated, blood‐perfused spleen of the dog
Authors: Corder R. , Lowry P.J. , Withrington P.G. 
Published: July 2012

The two peptides, neuropeptide Y (NPY) and peptide YY (PYY) were compared for potency on the vascular and extravascular smooth muscle of the isolated, blood‐perfused spleen of the dog.
The only vascular response to both NPY and PYY was vasoconstriction; the maximum effect was to arrest splenic arterial blood flow completely.
On a molar basis both NPY and PYY were significantly more potent (P < 0.01) as splenic arterial vasoconstrictors than the transmitter noradrenaline (NA).
PYY was approximately 7 times more potent as a vasoconstrictor than NPY.
In contrast to their potency on the vascular smooth muscle, NPY and PYY were significantly (P < 0.01) less potent than NA in causing contraction of the splenic capsule. The two peptides were equipotent in eliciting this contraction.
Inhibition of GABA release from slices prepared from several brain regions of rats at various times following a convulsion
Authors: Green A. Richard , Minchin Michael C.W. , Vincent Nigel D. 
Published: July 2012

A method is described for the measurement of the K+‐evoked release of endogenous γ‐aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum.
In tissue prepared 30 min following an electroconvulsive shock, K+‐evoked GABA release (above basal release) was inhibited by 45% in cortex, 50% in hippocampus and 75% in striatum. A similar inhibition of release was observed with slices prepared from rats in which a convulsion had been induced by flurothyl. There was no change in spontaneous (basal) release following either procedure.
An inhibition of K+‐evoked endogenous GABA release was also seen in tissue prepared 4 min postictally but not 2 h after the seizure.
No difference was observed in the release of [3H]‐GABA from preloaded cortical slices prepared from rats given a single electroconvulsive shock.
It is proposed that a convulsion results in an inhibition of GABA release and that this inhibition may in turn inhibit GABA synthesis as described in the preceding paper.
It is also proposed that changes in the endogenous releasable pool of GABA may not be detected by preloading slices with [3H]‐GABA.
Effects of calcium entry blockers on calcium‐dependent contractions of rat portal vein
Authors: Dacquet C. , Mironneau C. , Mironneau J. 
Published: July 2012

The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200‐110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high‐K+ solutions, noradrenaline, acetylcholine and caffeine.
The rank order of potency was PN 200‐110>nicardipine = nifedipine = D888>D600>diltiazem from experiments on spontaneous contractions and high‐K+ induced contractions. With depolarized preparations, the concentration‐response curves for nicardipine, PN 200‐110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage‐dependent inhibitory properties. This effect was not significant with D888 and diltiazem.
All the calcium entry blockers strongly reduced the noradrenaline (NA)‐ and acetylcholine (ACh)‐induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine‐induced contractions.
In Ca2+‐free, EGTA‐containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug‐sensitive calcium store. The filling of the calcium store was maximal after 10–12 min of calcium loading in 2.1 mm Ca2+, while the depletion was complete after 4–6 min of perfusion in Ca2+‐free solution.
At concentrations which abolished spontaneous contractions, PN 200‐110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+‐free solutions by ACh, NA and caffeine. When added in Ca2+‐containing solutions diltiazem and, to a lesser extent, nicardipine strongly reduced the contractions evoked in Ca2+‐free solutions, suggesting that they inhibited the filling of the internal calcium store.
These results indicate that the six calcium entry blockers are potent inhibitors of calcium influx through voltage‐dependent calcium channels. Two of them (diltiazem and nicardipine) may exert an additional effect to depress contractions dependent on intracellular calcium release.
Relaxation of guinea‐pig tracheal smooth muscle to arachidonate is converted to contraction following epithelium removal
Authors: Farmer Stephen G. , Hay Douglas W.P. , Raeburn David , Fedan Jeffrey S. 
Published: July 2012

The effect of epithelium removal on responses of guinea‐pig isolated trachealis to sodium arachidonate has been examined.
Arachidonate (100 μm) caused relaxation of epithelium‐intact preparations, but following epithelium removal, the response to arachidonate was converted to contraction. In the presence of indomethacin (1 μm), arachidonate caused contraction in intact and denuded trachea.
Arachidonate also produced concentration‐dependent effects, the qualitative nature of which varied with the presence or absence of the epithelium. In the presence of indomethacin, tracheal strips contracted in a concentration‐dependent manner whether or not the epithelium had been removed.
Nordihydroguaiaretic acid (NDGA; 11 μm) markedly inhibited the contractile response of denuded strips to arachidonate. In intact tissues this lipoxygenase inhibitor converted the arachidonate‐induced relaxation to a concentration‐dependent contraction. The contraction to arachidonate, in the presence of NDGA, was epithelium‐dependent. In the presence of both indomethacin and NDGA, responses to arachidonate were abolished.
It is concluded that the relaxation of guinea‐pig trachea to arachidonic acid is epithelium‐dependent and is mediated by an inhibitory product of the cyclo‐oxygenase metabolic pathway. The contraction in denuded trachea, and trachea in the presence of indomethacin, may be mediated by lipoxygenase products of arachidonic acid metabolism, i.e. peptidoleukotrienes. The mediator of the epithelium‐dependent contraction in NDGA‐treated tissues is unknown.
Studies on the induction of pharmacological responses to des‐Arg9‐bradykinin in vitro and in vivo
Authors: Bouthillier Johanne , Deblois Denis , Marceau François 
Published: July 2012

The mechanisms by which agents modulate the induction of kinin B1‐receptors were investigated by studying the effects of kinins in vitro, by use of the rabbit isolated aorta, and in vivo by measuring the blood pressure of anaesthetized rabbits.
The contractile response of the rabbit isolated aorta to kinins increased in a time‐dependent manner in vitro. This effect was abolished by continuous exposure to the protein synthesis inhibitor cycloheximide (71 μm).
Several substances were found to increase specifically the rate of sensitization to des‐Arg9‐bradykinin (des‐Arg9‐Bk), when applied continuously in vitro to tissues isolated from normal animals: bacterial lipopolysaccharide (LPS; 1 μg ml−1), muramyl‐dipeptide (MDP; 2 μg ml−1), phorbol myristate acetate (PMA; 320 nm), epidermal growth factor (EGF; 100 ng ml−1) and endothelial cell growth factor (150 μg ml−1).
The protease inhibitors phenylmethylsulphonyl fluoride and aprotinin, a non‐adjuvant isomer of MDP, rabbit purified leukocyte interferon, fibroblast growth factor and the chemotactic peptide N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanine (FMLP) did not have this effect.
It has been demonstrated that LPS induces B1‐receptors in rabbits enabling des‐Arg9‐Bk to act as a hypotensive agent. In these experiments neutropenia induced by nitrogen mustard, did not prevent the in vivo effect of LPS. MDP (300 μg) and PMA (100 μg) were also found to induce a state of responsiveness to des‐Arg9‐Bk in vivo. FMLP (1 mg i.v.) induced a temporary decrease in blood neutrophil counts but had no effect on the induction of responses to des‐Arg9‐Bk.
The development of responses mediated by the B1‐receptor in the two experimental systems seems to be unrelated to the activation of neutrophil leukocytes, but may be related to the activation of tissue macrophages. Approximately 3% of cultured adherent cells derived from rabbit aorta strips following protease digestion were stained for non‐specific esterase, supporting such a possibility.
Differential effects of epithelium removal on the responsiveness of guinea‐pig tracheal smooth muscle to bronchoconstrictors
Authors: Hay D.W.P. , Farmer S.G. , Raeburn D. , Muccitelli R.M. , Wilson K.A. , Fedan J.S. 
Published: July 2012

The influence of the epithelium on contractions produced by the peptidoleukotrienes, 5‐hydroxytryptamine (5‐HT) and the thromboxane mimetic, U‐44069, was examined in trachea from control and ovalbumin‐sensitized guinea‐pigs.
In control tissues removal of the epithelium produced an approximately 2 to 4 fold leftward shift in leukotriene C4 (LTC4) and LTD4 concentration‐response curves, but no effect on LTE4‐induced contractions. Similar results were obtained in preparations from ovalbumin‐sensitized animals.
Responses produced by 5‐HT or U‐44069 were similar in the presence and absence of the epithelium in control guinea‐pigs.
Indomethacin produced contrasting effects on leukotriene‐induced contractions in control guinea‐pigs: an increase in sensitivity to LTC4 in the presence but not absence of the epithelium, no effect on LTD4‐induced contractions and a decrease in sensitivity to LTE4 in both epithelium‐containing and epithelium‐free preparations.
These results indicate that there is selectivity in the effects of epithelium removal on agonist‐induced contractions of the guinea‐pig trachea. This provides further evidence for the modulatory influence of the epithelium on the reactivity of mammalian airway smooth muscle and supports the postulated existence of an epithelium‐derived inhibitory factor. The observation that in intact trachea indomethacin mimics the effects of epithelium removal on LTC4‐induced responses, suggests the involvement of a prostanoid(s) in this phenomenon.