bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the prostaglandin E (EP‐) receptor subtype mediating relaxation of the rabbit jugular vein
Authors: Lawrence Ruth A. , Jones R.L. 
Published: July 2012

Prostaglandin E2 (PGE2) relaxes circular smooth muscle of the rabbit isolated jugular vein at very low concentrations (mean pIC50 against histamine‐induced contraction = 9.34). This effect is not blocked by the EP1‐receptor antagonist, AH 6809 (2 μm).
From a group of prostaglandin E analogues examined, 16,16‐dimethyl PGE2, misoprostol, 11‐deoxy PGE2‐1‐alcohol and 11‐deoxy PGE1 were highly potent relaxant agents, whereas 17‐phenyl‐ω‐trinor PGE2, MB 28767 and butaprost had low potency and sulprostone and oxoprostol were virtually inactive.
Comparison of the jugular vein data with published data for inhibitory agonist potencies on the cat trachea (EP2 preparation) and the field‐stimulated guinea‐pig vas deferens (EP3) indicates that the EP‐receptor in the rabbit jugular vein is closest to the EP2 subtype. However, the correlation is not entirely convincing. For example, butaprost, 16,16‐dimethyl PGE2 and 11‐deoxy PGE1 are of similar potency on the cat trachea, whereas butaprost is about 300 times less potent than the other two analogues on the jugular vein. The existence of more than one EP2‐receptor appears possible.
It was felt that the activity of butaprost required further investigation in view of the claim that it is a specific EP2‐receptor agonist. We have shown that butaprost has very low inhibitory activity on the guinea‐pig vas deferens, a very sensitive EP3‐receptor containing preparation. However, on the chick ileum, the original EP3 preparation, butaprost showed potent contractile activity (pEC25 ˜ 8.0). In addition, its maximum response was lower than that of PGE2; lower maxima were also found for sulprostone, MB 28767 and oxoprostol, but not for ICI 80205, 16,16‐dimethyl PGE2 and 17‐phenyl‐ω‐trinor PGE2. The maximal response to a combination of either sulprostone and butaprost or sulprostone and PGE2 was similar to that achieved by PGE2 alone. Analysis of the interaction between sulprostone and PGE2 appears to exclude a partial agonist action for sulprostone. Furthermore neither sulprostone nor butaprost appear to have inhibitory activity on the ileum. AH 6809 at 2 μm produced only a small shift of the PGE2 log concentration‐response curve.
It is likely that contraction of the longitudinal smooth muscle of the chick ileum is mediated by (at least) two EP‐receptor subtypes; activation of only one receptor system does not induce the maximum response (i.e. the acetylcholine maximum) of the preparation. One receptor could be an EP3 subtype, at which sulprostone exerts a selective agonist action. The other receptor is unlikely to be an EP1 subtype, because of the high agonist potency of butaprost, the low agonist potency of iloprost, and the low antagonist potency of AH 6809. An alternative hypothesis is that the chick ileum contains a novel EP‐receptor subtype in addition to an EP3‐receptor.
Involvement of β2‐adrenoceptors in the regional haemodynamic responses to bradykinin in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T. , Bose C. , Foulkes R. , Hughes B. 
Published: July 2012

Bradykinin can release neuronal calcitonin gene‐related peptide (CGRP) and adrenal medullary catecholamines, both of which could contribute to its cardiovascular effects in vivo. Therefore, in the main experiment, regional haemodynamic responses to bolus injections of bradykinin (3 nmol kg−1, i.v.) were assessed in the same chronically‐instrumented, conscious, Long Evans rats in the absence and in the presence of human α‐CGRP [8–37] or ICI 118551, antagonists of CGRP1‐receptors and β2‐adrenoceptors, respectively. The selected doses of these antagonists caused specific inhibition of responses mediated by exogenous human α‐CGRP and β2‐adrenoceptor agonists, respectively.
Bradykinin administered alone as an i.v. bolus had a slight pressor effect accompanied by a marked tachycardia. There were early (at about 30 s) increases in flow and conductance in the mesenteric vascular bed, and delayed (at about 90 s), but qualitatively similar, changes in the hindquarters vascular bed. There were only slight increases in flow and conductance in the renal vascular bed.
Human α‐CGRP [8–37] had no statistically significant effects on the responses to bolus doses of bradykinin. However, in the presence of ICI 118551, the pressor effect of bradykinin was significantly enhanced while its tachycardic effect was significantly suppressed. The hindquarters vasodilator effect of bradykinin was converted to a vasoconstriction and there was a slight renal vasoconstriction, but the mesenteric vasodilator effect of bradykinin was unchanged by ICI 118551.
In subsidiary experiments, in other animals, it was found that infusion of bradykinin (36 nmol kg−1 min−1) elicited a pattern of haemodynamic responses similar to that seen with bolus injections and, as in the latter case, the hindquarters hyperaemic vasodilatation was inhibited by ICI 118551. In the presence of mecamylamine (at a dose sufficient to block reflex heart rate responses to rises or falls in arterial blood pressure) bolus injection or infusion of bradykinin still elicited increases in renal, mesenteric and hindquarters blood flow. However, in additional experiments in adrenal demedullated rats (n = 4) the hindquarters hyperaemic effect of bradykinin was absent, although the mesenteric hyperaemic effect remained.
The results indicate that the increase in hindquarters blood flow following administration of bradykinin in vivo is largely due to activation of β2‐adrenoceptors by catecholamines released subsequent to direct stimulation of the adrenal medulla by the peptide. However, the bradykinin‐induced increase in mesenteric blood flow does not depend on this mechanism.
Neuroendocrine response to clonidine and 8‐OH‐DPAT in rats following chronic administration of desipramine or sertraline
Authors: O'Donnell J.M. , Grealy M. 
Published: July 2012

Rats were administered either desipramine (DMI) or sertraline daily at doses 7.5 mg kg−1 or 10 mg kg−1, i.p., respectively and the effects on the functional state of hypothalamic neuroendocrine control mechanisms assessed by measurements of plasma hormones following acute drug challenge. The effects of treatment on gross behaviour and brain adrenoceptor density were also determined.
Both DMI and sertraline caused significant reduction in activity measured as ambulation and rearing at 14 days of treatment.
All animals were chronically cannulated after 14 days of treatment and tested for neuroendocrine response to acute i.v. clonidine (50 μg kg−1) or 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT, 250 μg kg−1) after 21 or more days of treatment.
Rats treated with DMI but not sertraline showed a virtually complete suppression of the growth hormone (GH) secretion elicited by clonidine in controls, while the secretion of corticosterone was augmented.
Treatment with DMI but not sertraline led to a significantly greater 8‐OH‐DPAT‐induced secretion of prolactin than in the control rats, while the plasma concentrations of corticosterone following 8‐OH‐DPAT were not influenced by either DMI or sertraline treatment.
The density (but not the affinity) of cerebral cortical binding of [3H]‐dihydroalprenolol was significantly reduced by DMI treatment.
These results show that DMI treatment blunted the sensitivity of post‐synaptic α2‐adrenoceptors, accompanied by complex interactions manifested as increased responsiveness of α1‐adrenoceptors and 5‐HT1A receptors. Sertraline had no significant neurendocrine effects at a dose which significantly reduced gross activity.
Effects of purines on the longitudinal muscle of the rat colon
Authors: Bailey S.J. , Hourani S.M.O. 
Published: July 2012

Adenosine and adenosine 5′‐triphosphate (ATP) have been reported to cause relaxation of the rat colon longitudinal muscle preparation; the purinoceptors mediating this effect were investigated by use of a series of agonists and antagonists.
The tissue was precontracted with carbachol (1 μm), and the purines induced reversible relaxations with a potency order of 5′‐N‐ethylcarboxamidoadenosine (NECA) >N6‐cyclopentyladenosine (CPA) = adenosine 5′‐(α,β‐methylene) triphosphonate (AMPCPP) >adenosine = adenylyl 5′‐(β,γ‐methylene) disphosphonate (AMPPCP) = ATP. The P1‐selective antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) (3 μm) shifted to the right the log concentration‐response curves of all these agonists except for AMPCPP, indicating that they all act via P1‐purinoceptors. The order of potency of the adenosine analogues and the relatively high concentrations of the antagonist required indicated that these receptors are of the A2 subtype. The P2‐selective antagonist suramin (300 μm) inhibited responses to AMPCPP, but not to the other agonists.
The dephosphorylation of the nucleotides was studied by high performance liquid chromatography following incubation with the longitudinal muscle preparation for up to 30 min. ATP was rapidly degraded, largely to adenosine, and AMPPCP and AMPCPP were also degraded, although more slowly, to adenosine and adenosine 5′‐(α,β‐methylene) diphosphonate (AMPCP) respectively. AMPCP, like AMPCPP, caused relaxations by acting on P2‐purinoceptors, as it was also inhibited by suramin (300 μm). Incubation of the tissue with adenosine deaminase abolished responses to adenosine, reduced those to ATP and AMPPCP, but had no effect on those to AMPCPP. ATP and AMPPCP therefore appear to be acting on the A2 receptors in this tissue largely via their degradation product adenosine.
The longitudinal muscle of the rat colon therefore contains both P1‐ and P2‐purinoceptors, which both mediate relaxation. The P1‐purinoceptors are of the A2 subtype and the P2‐purinoceptors are probably of the P2Y subtype, although the rapid degradation of the nucleotides means that it is difficult to classify them with certainty.
Correlation between airway epithelium‐induced relaxation of rat aorta in the co‐axial bioassay and cyclic nucleotide levels
Authors: Hay D.W.P. , Muccitelli R.M. , Page C.P. , Spina D. 
Published: July 2012

In co‐axial bioassays, in the presence of indomethacin, addition of histamine (100 μm) or methacholine (100 μm) to guinea‐pig trachea produced an epithelium‐dependent relaxation of precontracted rat aorta which was associated with an approximately 2 fold elevation in tissue levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). Removal of the airway epithelium abolished the histamine‐induced relaxation of rat aorta and the associated increase in intracellular cyclic GMP.
Epithelium‐dependent relaxation was not associated with altered adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels in rat aorta. Unstimulated intact or denuded guinea‐pig trachea also did not affect the levels of cyclic AMP or cyclic GMP in rat aorta.
Methylene blue (10 μm) abolished the methacholine‐induced, endothelium‐derived relaxing factor (EDRF)‐mediated rise in intracellular cyclic GMP in rat endothelium‐intact aorta alone. In contrast, methylene blue (10 μm) did not affect the methacholine‐induced epithelium‐dependent rise in intracellular cyclic GMP in rat endothelium‐denuded aorta in the co‐axial bioassay.
Relaxation of the rat aorta without endothelium was associated with increased levels of cyclic GMP (but not cyclic AMP) in response to sodium nitroprusside (5 nm) and of cyclic AMP (but not cyclic GMP) in response to isoprenaline (1 μm).
These results provide evidence that the postulated epithelium‐derived inhibitory factor (EpDIF) may produce relaxation of vascular tissue via elevation in cyclic GMP levels. Furthermore, some data suggest that EpDIF may act by stimulation of the particulate, rather than the soluble form of guanylate cyclase.
Bronchodilatation by tachykinins and capsaicin in the mouse main bronchus
Authors: Manzini Stefano 
Published: July 2012

The effect of sensory neuropeptides and capsaicin on basal and stimulated tone of mouse bronchial smooth muscle has been evaluated.
In basal conditions neither sensory neuropeptides (subtance P, neurokinin A or calcitonin gene‐related peptide (CGRP)) nor capsaicin exerted any contractile effects. However, when a tonic contraction was induced with carbachol (1 μm) a prompt relaxation was induced by substance P (1– 100 nm) and by neurokinin A (1– 100 nm), with substance P being more potent. A second application of substance P was without effect. CGRP (10 nm) produced only a very small and erratic relaxation. Relaxation was also induced by capsaicin (1 μm), and this response could be evoked only once in each preparation. In 4 out of 6 preparations a cross‐desensitization between substance P and capsaicin was observed.
The selective NK1 tachykinin agonist, [Pro9]‐SP sulphone (1 μm), exerted potent bronchodilator actions on carbachol‐contracted mouse bronchial preparations. In contrast, neither [β Ala8]‐NKA (4–10) nor [MePhe7]‐NKB (both at a concentration of 1 μm), selective synthetic agonists for NK2 and NK3 receptors, exerted significant relaxant effects. Furthermore, the selective NK1 tachykinin antagonist, (±)‐CP 96,345 (1 μm), abolished substance P (1 nm)‐ but not isoprenaline (0.1 μm)‐induced relaxations.
Application of electrical field stimulation (EFS) (20 Hz, supramaximal voltage, 0.5 ms for 10 s) to carbachol‐contracted preparations evoked a transient contraction followed by a relaxation. The tetrodotoxin‐sensitive slow component of this relaxation was reduced following capsaicin desensitization.
In the presence of indomethacin (5 μm) the relaxation induced by substance P, capsaicin or EFS was suppressed.
In conclusion, the mouse main bronchus appears to be a monoreceptorial tissue containing only NK1 receptors which subserve bronchodilator functions. Such receptors could be activated by exogenous or endogenously (capsaicin or EFS) released tachykinins and the consequent relaxation is probably mediated by the generation of prostanoids.
The 5‐HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP‐dependent protein kinase
Authors: Fagni L. , Dumuis A. , Sebben M. , Bockaert J. 
Published: July 2012

The aim of the present study was to examine the effect of 5‐hydroxytryptamine (5‐HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5‐HT receptor subtype that could be involved in this effect.
The voltage‐activated K+ current of the neurones was partially blocked by 8‐bromo adenosine 3′:5′‐cyclic monophosphate (8‐bromo‐cyclic AMP). This effect was mimicked by 5‐HT and the action of 5‐HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP‐dependent protein kinase blocker.
A similar cyclic AMP‐dependent blockade of the K+ current was found with renzapride (BRL 24 924) and other 5‐HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5‐methoxytryptamine (5‐MeOT). ICS 205 930, the classical 5‐HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5‐HT4 receptor antagonist, DAU 6285 blocked the effects of 5‐HT and renzapride on the K+ current.
The current was insensitive to the 5‐HT1 and 5‐HT3 receptor agonists (8‐hydroxy‐2‐(di‐n‐propylamino) tetralin, RU 24 969, carboxamidotryptamine, 2‐CH3‐5‐HT) as well as to 5‐HT1, 5‐HT2 and 5‐HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38 032]). Moreover, these antagonists did not affect the actions of the tested 5‐HT4 receptor agonists.
The present results show that part of the voltage‐activated K+ current in mouse colliculi neurones is cyclic AMP‐sensitive and the blockade of the current by 5‐HT involves the 5‐HT4 receptor subtype. The putative implication of 5‐HT4 receptors in neuronal plasticity, via a blockade of K+ channels, is discussed.
Inhibitory effects of certain enantiomeric cannabinoids in the mouse vas deferens and the myenteric plexus preparation of guinea‐pig small intestine
Authors: Pertwee R.G. , Stevenson L.A. , Elrick D.B. , Mechoulam R. , Corbett A.D. 
Published: July 2012

The psychoactive cannabinoids (−)‐Δ9‐tetrahydrocannabinol ((−)‐Δ9‐THC) and the 1,1‐dimethylheptyl homologue of (−)‐11‐hydroxy‐Δ8‐tetrahydrocannabinol ((−)‐DMH) both inhibited electrically‐evoked contractions of the mouse isolated vas deferens and the myenteric plexus‐longitudinal muscle preparation of the guinea‐pig small intestine.
Concentrations of (−)‐Δ9‐THC and (−)‐DMH that decreased twitch heights by 50% were 6.3 and 0.15 nm respectively in the mouse vas deferens and 60 nm and 1.4 nm respectively in the myenteric plexus preparation. (−)‐DMH was about 40 times more potent than (−)‐Δ9‐THC in both preparations, supporting the notion that their mode of action in each tissue is the same.
The psychically inactive cannabinoid, (+)‐DMH, had no inhibitory effect in the mouse vas deferens at a concentration of 30 nm, showing it to be at least 1000 times less potent than (−)‐DMH. In the myenteric plexus preparation, (+)‐DMH was about 500 times less potent than its (−)‐enantiomer.
The inhibitory effects of sub‐maximal concentrations of (−)‐Δ9‐THC were not attenuated by 300 nm naloxone.
The findings that (−)‐Δ9‐THC and (−)‐DMH are highly potent as inhibitors of the twitch response of the mouse vas deferens and guinea‐pig myenteric plexus preparation and that DMH shows considerable stereoselectivity suggest that the inhibitory effects of cannabinoids in these preparations are mediated by cannabinoid receptors.
Comparative effects of BRL 38227, nitrendipine and isoprenaline on carbachol‐ and histamine‐stimulated phosphoinositide metabolism in airway smooth muscle
Authors: Challiss R.A. John , Patel Neela , Arch Jonathan R.S. 
Published: July 2012

The ability of BRL 38227 and nitrendipine to affect muscarinic agonist and histamine‐stimulated [3H]‐inositol phosphate accumulation in slices of bovine tracheal smooth muscle has been studied and compared with the established inhibitory effects of isoprenaline on this pathway.
Pre‐addition of BRL 38227 (5 μm), nitrendipine (1 μm) or isoprenaline (10 μm) significantly inhibited the subsequent inositol phosphate response to histamine at all concentrations studied (10– 1000 μm). BRL 38227 and nitrendipine also significantly inhibited the [3H]‐inositol phosphate response to low (1 μm), but not high (100 μm) concentrations of carbachol. Isoprenaline had no effect at any concentration of carbachol studied.
Nitrendipine (IC50 = 95 nm) and BRL 38227 (IC50 = 322 nm) caused concentration‐related inhibitions of the inositol phosphate response to histamine (100 μm). Similar maximal inhibitions were caused by each agent (55– 58%). Inhibitory effect of BRL 38227 was reduced in potency (IC50 = 5.5 μm), but not magnitude, in the presence of glibenclamide (0.5 μm).
Time‐course studies comparing the effects of BRL 38227 addition 15 min before, and 10 min after histamine challenge showed that for pre‐addition a distinct (< 2 min) lag occurred following histamine addition before the inhibitory effect of BRL 38227 was manifest. In contrast, when BRL 38227 was added 10 min after histamine, an inhibitory effect was immediately apparent.
Further evidence for an initial, ‘protected’ phase of inositol phosphate accumulation was provided by the finding that BRL 38227 pre‐addition had no effect on the early (0–300 s) time‐course of inositol 1,4,5‐trisphosphate mass accumulation.
The inhibitory effect of BRL 38227, but not that of nitrendipine or isoprenaline, on histamine‐stimulated [3H]‐inositol phosphate accumulation was completely prevented in the presence of an elevated extracellular K+ (65 mm) concentration.
The results demonstrate that membrane hyperpolarization, and/or blockade of voltage‐operated Ca2+‐channels can regulate agonist‐stimulated phosphoinositide metabolism in airway smooth muscle. The possible contribution of this regulatory mechanism to the relaxant properties of these agents is discussed.
Noradrenaline modulates smooth muscle activity of the isolated intravesical ureter of the pig through different types of adrenoceptors
Authors: Hernández M. , Prieto D. , Simonsen U. , Rivera L. , Barahona M.V. , García‐Sacristán A. 
Published: July 2012

We have studied the effects of α‐ and β‐adrenoceptor agonists and antagonists on both phasic peristaltic activity and basal tone of the isolated intravesical ureter of the pig by means of isometric techniques in vitro.
Spontaneous phasic activity was exhibited by 21% of pig intravesical ureter preparations manifested as rhythmic contractions with average frequency and amplitude of 2.54 ± 0.18 min−1 and 1.48 ± 0.16 g (n = 31), respectively.
Adrenaline, noradrenaline and phenylephrine induced concentration‐dependent increases in both phasic activity and basal tone of ureteral preparations, all three agonists being more potent in modifying ureteral phasic activity than baseline tone. B‐HT 920, B‐HT 933 and clonidine had no significant effect.
Phentolamine (10−9 − 10−7 m) and prazosin (3 × 10−11 − 3 × 10−8 m) significantly inhibited increases in both frequency of phasic activity and baseline tone induced by a submaximal dose of noradrenaline. Rauwolscine (10−9 − 10−7 m) affected only the tone evoked by noradrenaline and higher concentrations of this antagonist were needed to block phasic activity.
Pretreatment of ureteral strips with the β‐adrenoceptor antagonist, propranolol (10−6 m), significantly increased the maximum contraction evoked by noradrenaline. After incubation with phentolamine (10−6 m), noradrenaline (10−7 − 10−6 m) decreased phasic activity induced by prostaglandin F2α (10−5 m). Isoprenaline and salbutamol also abolished PGF2α‐induced phasic activity. Pafenolol (10−6 m) and butoxamine (10−6 m) blocked the inhibitory effect of noradrenaline, isoprenaline, and salbutamol on PGF2α‐induced phasic activity.
These results suggest that noradrenaline may modulate both phasic peristaltic activity and basal tone of pig intravesical ureter through both α‐ and β‐adrenoceptors.
Guinea‐pig treatment with pertussis toxin suppresses macrophage‐dependent bronchoconstriction by fMLP and fails to inhibit the effects of PAF
Authors: Kadiri Chakir , Leduc Dominique , Lefort Jean , Imaizumi Atsushi , Vargaftig B. Boris 
Published: July 2012

Bronchoconstriction and thromboxane B2 (TxB2) release following the intra‐tracheal administration of the secretagogue N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanine (fMLP) to lungs from pertussis toxin‐treated guinea‐pigs in vivo and in vitro were inhibited as compared to saline‐treated animals, under conditions where the responses to PAF were modified less effectively.
The cell target accounting for bronchoconstriction by fMLP and for inhibition by pertussis toxin is located in the airways and is probably the alveolar macrophage. Indeed (a) fMLP‐induced superoxide anions and TxB2 formation by alveolar macrophages were inhibited by pertussis toxin given in vivo; (b) Gi proteins of membranes from alveolar macrophages were ADP‐ribosylated in vivo by pertussis toxin and (c) bronchoconstriction and TxB2 release in response to the intra‐tracheal administration of fMLP to lungs from pertussis toxin‐treated animals were restored when alveolar macrophages from control guinea‐pigs were transferred into the airways of pertussis toxin‐treated animals before lung isolation.
Pertussis toxin administered to guinea‐pigs in vivo, reduced the subsequent TxB2 formation and superoxide anion release by alveolar macrophages stimulated with PAF, but failed to inhibit PAF‐induced bronchoconstriction.
Formation of TxB2 by alveolar macrophages following the intra‐tracheal administration of fMLP accounts for bronchoconstriction and requires pertussis toxin‐sensitive Gi proteins. PAF operates via a different mechanism, which is independent of Gi‐like protein and involves mediators other than TxB2 and superoxide anions.