bluuebunny/crossref_metadata_2025_split huggingface dataset:
α2‐Adrenoceptors in the enteric nervous system: a study in α2A‐adrenoceptor‐deficient mice
Authors: Scheibner Jens , Trendelenburg Anne‐Ulrike , Hein Lutz , Starke Klaus , Blandizzi Corrado 
Published: January 2005

Mammals possess three types of α2‐adrenoceptor, α2A, α2B and α2C. Our aim was to determine the type of α2‐adrenoceptor involved in the control of gastrointestinal motility.
In transmitter overflow experiments, myenteric plexus longitudinal muscle (MPLM) preparations of the ileum were preincubated with [3H]‐choline and then superfused. The α2‐adrenoceptor agonist medetomidine reduced the electrically evoked overflow of tritium from preparations taken from wild type but not α2A‐adrenoceptor‐knockout mice.
In a second series of overflow experiments, MPLM preparations were preincubated with [3H]‐noradrenaline and then superfused. Again medetomidine reduced the electrically evoked overflow of tritium from wild type but not α2A‐knockout preparations.
In organ bath experiments, medetomidine reduced electrically evoked contractions of segments of the ileum from wild type but not α2A‐knockout mice.
In each of these three series, phentolamine antagonized the effect of medetomidine in wild‐type preparations with greater potency than rauwolscine.
In conscious mice, gastrointestinal transit was assessed by means of an intragastric charcoal bolus. In α2A‐knockout mice, the speed of gastrointestinal transit was doubled compared to wild‐type. Medetomidine, injected intraperitoneally, slowed gastrointestinal transit in wild type but not α2A‐knockout mice.
We conclude that the cholinergic motor neurons of the enteric nervous system of mice possess α2‐heteroreceptors which mediate inhibition of acetylcholine release, of neurogenic contractions and of gastrointestinal transit. The noradrenergic axons innervating the intestine possess α2‐autoreceptors. Both hetero‐ and autoreceptors are exclusively α2A. It is the α2A‐adrenoceptor which in vivo mediates the inhibition of intestinal motility by the sympathetic nervous system.

British Journal of Pharmacology (2002) 135, 697–704; doi:10.1038/sj.bjp.0704512
Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine‐mediated blood pressure reaction
Authors: Raasch Walter , Schäfer Ulrich , Qadri Fatimunnisa , Dominiak Peter 
Published: January 2005

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS‐induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR.
Intravenously‐administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg−1, respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose‐response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium‐denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms.
Agmatine reduces noradrenaline release in pithed SHR while α2‐adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I1‐binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate.
Finally, CDS‐like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR.

British Journal of Pharmacology (2002) 135, 663–672; doi:10.1038/sj.bjp.0704513
Evidence for an atypical receptor mediating the augmented bronchoconstrictor response to adenosine induced by allergen challenge in actively sensitized Brown Norway rats
Authors: Hannon J P , Tigani B , Wolber C , Williams I , Mazzoni L , Howes C , Fozard J R 
Published: January 2005

The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response.
Like adenosine, the broad‐spectrum adenosine receptor agonist, NECA, induced dose‐related bronchoconstriction in actively sensitized, OA‐challenged animals. In contrast, CPA, CGS 21680 and 2‐Cl‐IB‐MECA, agonists selective for A1 A2A and A3 receptors, respectively, induced no, or minimal, bronchoconstriction.
Neither the selective A1 receptor antagonist, DPCPX, nor the selective A2A receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine.
MRS 1754, which has similar affinity for rat A2B and A1 receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A1 receptor‐mediated bradycardia induced by NECA.
8‐SPT and CGS 15943, antagonists at A1, A2A, and A2B but not A3 receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the KB value at the rat A2B receptor, respectively.
Adenosine and NECA, but not CPA, CGS 21680 or 2‐Cl‐IB‐MECA, induced contraction of parenchymal strip preparations from actively sensitized OA‐challenged animals. Responses to adenosine could not be antagonized by 8‐SPT or MRS 1754 at concentrations >50 times their affinities at the rat A2B receptor.
The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes.

British Journal of Pharmacology (2002) 135, 685–696; doi:10.1038/sj.bjp.0704516
Caffeine‐induced immobilization of gating charges in isolated guinea‐pig ventricular heart cells
Authors: Leroy Jérôme , Lignon Jacques M , Gannier François , Argibay Jorge A , Malécot Claire O 
Published: January 2005

The effects of 10 mM caffeine (CAF) on intramembrane charge movements (ICM) were studied in isolated guinea‐pig ventricular heart cells with the whole‐cell patch‐clamp technique.
In the presence of CAF, the properties (voltage dependence, maximum QON[Qmax], availability with voltage) of QON charge activated from −110 mV were barely affected. Following a 100 ms prepulse to −50 mV to decrease the participation of charges originating from Na channels, the voltage dependence of QON was shifted by 5 mV (negative component) and by 10 mV (positive component) towards negative potentials, and Qmax was depressed by 16.5%.
CAF drastically reduced in a time‐ and voltage‐dependent manner QOFF on repolarization to −50 mV, the effects being greater at positive potentials.
CAF‐induced QOFF immobilization could be almost entirely removed by repolarization to voltages as negative as −170 mV. In these conditions, the voltage‐dependence of QOFF (repolarization to +30 to −170 mV) was shifted by 17 mV (negative component) and 30 mV (positive component) towards negative potentials, suggesting an interconversion into charge 2.
Most of CAF effects were suppressed when the sarcoplasmic reticulum (SR) was not functional or when the cells were loaded with BAPTA‐AM.
We conclude that CAF effects on ICM are likely due to Ca2+ ions released from the SR, and which accumulate in the subsarcolemmal fuzzy spaces in the vicinity of the Ca channels. Because CAF effects were more pronounced on QOFF than on QON the channels have likely to open before Ca2+ ions could affect their gating properties. It is speculated that such an effect on gating charges might contribute to the Ca‐induced inactivation of the Ca current.

British Journal of Pharmacology (2002) 135, 721–734; doi:10.1038/sj.bjp.0704520
A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats
Authors: Springborg Jacob Bertram , Ma XiaoDong , Rochat Per , Knudsen Gitte Moos , Amtorp Ole , Paulson Olaf B , Juhler Marianne , Olsen Niels Vidiendal 
Published: January 2005

Systemic administration of recombinant erythropoietin (EPO) has been demonstrated to mediate neuroprotection. This effect of EPO may in part rely on a beneficial effect on cerebrovascular dysfunction leading to ischaemic neuronal damage. We investigated the in vivo effects of subcutaneously administered recombinant EPO on impaired cerebral blood flow (CBF) autoregulation after experimental subarachnoid haemorrhage (SAH).
Four groups of male Sprague‐Dawley rats were studied: group A, sham operation plus vehicle; group B, sham operation plus EPO; group C, SAH plus vehicle; group D, SAH plus EPO. SAH was induced by injection of 0.07 ml of autologous blood into the cisterna magna. EPO (400 iu kg−1 s.c.) or vehicle was given immediately after the subarachnoid injection of blood or saline. Forty‐eight hours after the induction of SAH, CBF autoregulatory function was evaluated using the intracarotid 133Xe method.
CBF autoregulation was preserved in both sham‐operated groups (lower limits of mean arterial blood pressure: 91±3 and 98±3 mmHg in groups A and B, respectively). In the vehicle treated SAH‐group, autoregulation was abolished and the relationship between CBF and blood pressure was best described by a single linear regression line. A subcutaneous injection of EPO given immediately after the induction of SAH normalized autoregulation of CBF (lower limit in group D: 93±4 mmHg, NS compared with groups A and B).
Early activation of endothelial EPO receptors may represent a potential therapeutic strategy in the treatment of cerebrovascular perturbations after SAH.

British Journal of Pharmacology (2002) 135, 823–829; doi:10.1038/sj.bjp.0704521
P2 receptors: new potential players in atherosclerosis
Authors: Virgilio Francesco Di , Solini Anna 
Published: January 2005

Atherosclerosis is a focal inflammatory disease of the arterial wall. It starts with the formation of fatty streaks on the arterial wall that evolve to form a raised plaque made of smooth muscle cells (SMCs), and infiltrating leukocytes surrounding a necrotic core. The pathogenesis of the atherosclerotic lesion is incompletely understood, but it is clear that a dysfunction of the endothelium, recruitment and activation of inflammatory cells and SMC proliferation have a pivotal role. Over recent years receptors for extracellular nucleotides, the P2 receptors, have been recognized as fundamental modulators of leukocytes, platelets, SMCs and endothelial cells. P2 receptors mediate chemotaxis, cytokine secretion, NO generation, platelet aggregation and cell proliferation in response to accumulation of nucleotides into the extracellular milieu. Clinical trials have shown the benefit of antagonists of the ADP platelet receptor(s) in the prevention of vascular accidents in patients with atherosclerosis. Therefore, we anticipate that a deeper understanding of the involvement of P2 receptors in atheroma formation will open new avenues for drug design and therapeutic intervention.British Journal of Pharmacology (2002) 135, 831–842; doi:10.1038/sj.bjp.0704524
5‐HT1B but not 5‐HT6 or 5‐HT7 receptors mediate depression of spinal nociceptive reflexes in vitro
Authors: Hedo G , Lopez‐Garcia J A 
Published: January 2005

The identity of the serotonin (5‐HT) receptors modulating the transmission of segmental C‐fibre mediated signals was studied using an in vitro preparation of the hemisected spinal cord from rat pups.
Responses to trains of stimuli delivered to a lumbar dorsal root were recorded from the corresponding ventral root. The resulting cumulative depolarization (CD) mediated by unmyelinated fibres was quantified in terms of integrated area. The amplitude of the mono‐synaptic reflex was also measured. Serotonergic agents were superfused at known concentrations and their effects on the reflexes evaluated.
5‐HT had depressant effects on the CD (EC50 34 μM). The rank order of potency of agonists for the depression of the CD was 5‐carboxamidotryptamine (5‐CT)>α‐methylserotonin (α‐met‐5‐HT) ∼5‐HT>42‐methylserotonin (2‐met‐5‐HT)∼8‐OH‐DPAT.
All the agonists including 2‐met‐5‐HT and 8‐OH‐DPAT had strong depressant effects on the mono‐synaptic reflex with the following order of potency: 5‐CT>48‐OH‐DPAT>4α‐met‐5‐HT ∼5‐HT∼2‐met‐5‐HT.
The inhibitory effects of 5‐HT, α‐met‐5‐HT and 5‐CT were attenuated by the non‐specific 5‐HT antagonist methiothepin (1 μM) and by the 5‐HT1A/1B antagonist SDZ 21009 (100 nM) but not by the selective 5‐HT1A antagonist WAY 100135 (1 μM).
Other antagonists known to block 5‐HT2, 5‐HT6 and/or 5‐HT7 receptors (ketanserin, RO 04‐6790, ritanserin and clozapine) did not change the effect of the agonists.
The data suggest an important contribution of 5‐HT1B receptors to the inhibition of spinal C‐fibre mediated nociceptive reflexes but no experimental support was found for the intervention of 5‐HT2, 5‐HT6 or 5‐HT7 receptors in this in vitro model.

British Journal of Pharmacology (2002) 135, 935–942; doi:10.1038/sj.bjp.0704526
Involvement of μ‐ and κ‐, but not δ‐, opioid receptors in the peristaltic motor depression caused by endogenous and exogenous opioids in the guinea‐pig intestine
Authors: Shahbazian Anaid , Heinemann Akos , Schmidhammer Helmut , Beubler Eckhard , Holzer‐Petsche Ulrike , Holzer Peter 
Published: January 2005

Opiates inhibit gastrointestinal propulsion, but it is not clear which opioid receptor types are involved in this action. For this reason, the effect of opioid receptor – selective agonists and antagonists on intestinal peristalsis was studied.
Peristalsis in isolated segments of the guinea‐pig small intestine was triggered by a rise of the intraluminal pressure and recorded via the intraluminal pressure changes associated with the peristaltic waves.
μ‐Opioid receptor agonists (DAMGO, morphine), κ‐opioid receptor agonists (ICI‐204,448 and BRL‐52,537) and a δ‐opioid receptor agonist (SNC‐80) inhibited peristalsis in a concentration‐related manner as deduced from a rise of the peristaltic pressure threshold (PPT) and a diminution of peristaltic effectiveness.
Experiments with the δ‐opioid receptor antagonists naltrindole (30 nM) and HS‐378 (1 μM), the κ‐opioid receptor antagonist nor‐binaltorphimine (30 nM) and the μ‐opioid receptor antagonist cyprodime (10 μM) revealed that the antiperistaltic effect of ICI‐204,448 and BRL‐52,537 was mediated by κ‐opioid receptors and that of morphine and DAMGO by μ‐opioid receptors. In contrast, the peristaltic motor inhibition caused by SNC‐80 was unrelated to δ‐opioid receptor activation.
Cyprodime and nor‐binaltorphimine, but not naltrindole and HS‐378, were per se able to stimulate intestinal peristalsis as deduced from a decrease in PPT.
The results show that the neural circuits controlling peristalsis in the guinea‐pig small intestine are inhibited by endogenous and exogenous opioids acting viaμ‐ and κ‐, but not δ‐, opioid receptors.

British Journal of Pharmacology (2002) 135, 741–750; doi:10.1038/sj.bjp.0704527
Cyclooxygenase‐1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites
Authors: López‐Parra Marta , Clària Joan , Planagumà Anna , Titos Esther , Masferrer Jaime L , Woerner B Mark , Koki Alane T , Jiménez Wladimiro , Altuna Rosario , Arroyo Vicente , Rivera Francisca , Rodés Joan 
Published: January 2005

The maintenance of renal function in decompensated cirrhosis is highly dependent on prostaglandins (PGs). Since PG synthesis is mediated by cyclooxygenase‐1 and −2 (COX‐1 and COX‐2), the present study was designed to examine which COX isoform is involved in this phenomenon.
Renal COX‐1 and COX‐2 protein expression and distribution were analysed by Western blot and immunohistochemistry in nine rats with carbon tetrachloride‐induced cirrhosis and ascites and 10 control animals. The effects of placebo and selective COX‐1 (SC‐560) and COX‐2 (celecoxib) inhibitors on urine flow (V), urinary excretion of sodium (UNaV) and PGE2 (UPGE2V), glomerular filtration rate (GFR), renal plasma flow (RPF), the diuretic and natriuretic responses to furosemide and renal water metabolism were assessed in 88 rats with cirrhosis and ascites.
COX‐1 protein levels were found to be unchanged in kidneys from cirrhotic rats. In contrast, these animals showed enhanced renal COX‐2 protein expression which was focally increased in the corticomedullary region. Although UPGE2V was equally reduced by SC‐560 and celecoxib, only SC‐560 produced a significant decrease in UNaV, GFR and RPF and a pronounced impairment in the diuretic and natriuretic responses to furosemide in rats with cirrhosis and ascites. Neither SC‐560 nor celecoxib affected renal water metabolism in cirrhotic rats.
These results indicate that despite abundant renal COX‐2 protein expression, the maintenance of renal function in cirrhotic rats is mainly dependent on COX‐1‐derived prostaglandins.

British Journal of Pharmacology (2002) 135, 891–900; doi:10.1038/sj.bjp.0704528
Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin‐1 in the control of pulmonary vascular tone
Authors: Deuchar Graeme A , Docherty Andrew , MacLean Margaret R , Hicks Martin N 
Published: January 2005

Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L‐NAME (30 μmol.min−1 i.v.) and the subsequent responses to cumulatively administered endothelin‐1 (ET‐1) (0.001 – 4 nmol.kg−1 i.v.) or big ET‐1 (0.1 – 2.0 nmol.kg−1 i.v.) were studied. Additionally, the effect of the non‐selective ET‐1 receptor antagonist, SB209670, was investigated.
Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy.
Blockade of NOS caused a greater increase in basal PAP (increased by 7.7±1.1 mmHg c.f. 3.8±1.0 mmHg in controls, P<0.05) and uncovered a greater pulmonary pressor response to exogenous ET‐1 in rabbits with PHT (increased by 10.2±2.3 mmHg c.f. 4.9±1.0 mmHg in controls, P<0.05).
Big ET‐1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT.
The non‐selective ET‐1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P<0.05) in rabbits with PHT and blocked the response to ET‐1 in the presence of L‐NAME.
In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET‐1. An increased responsiveness to ET‐1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET‐1 in this model.

British Journal of Pharmacology (2002) 135, 1060–1068; doi:10.1038/sj.bjp.0704529
A flavonoid‐rich diet increases nitric oxide production in rat aorta
Authors: Benito S , Lopez D , Sáiz M P , Buxaderas S , Sánchez J , Puig‐Parellada P , Mitjavila M T 
Published: January 2005

Red wine intake is associated with a low risk of cardiovascular disease. This effect has been partly attributed to the action of polyphenolic compounds, which decrease the oxidation of plasma low density lipoproteins. Moreover, nitric oxide (•NO) is a vasodilator and polyphenolic compounds induce endothelium‐dependent vasorelaxation in vitro.
Here we studied whether a diet rich in dealcoholated red wine (DRW) increases acetylcholine‐induced vasorelaxation and whether ingestion of DRW‐, quercetin‐ or catechin‐rich diets modifies the •NO‐cyclic guanosine‐3′,5′‐monophosphate (cyclic GMP) pathway and superoxide anion (O2.−) release in aorta in a resting state in rats fed semi‐purified diets containing either 35% (v w−1) DRW, 0.3% (w w−1) quercetin or 0.3% (w w−1) catechin for 10 days.
•NO‐mediated vasorelaxation induced by acetylcholine was greater in rats fed the DRW‐rich diet than in those that received the control diet.
Expression of endothelial •NO synthase (eNOS) was similar in the four dietary groups. The aortic rings of rats fed either the DRW‐, quercetin‐, or catechin‐rich diets showed higher NOS activity, •NO production and cyclic GMP content than those of rats fed the control diet. No changes were observed in O2.− production.
In summary, diets rich in either DRW, quercetin or catechin induced endothelium‐dependent vasorelaxation in rat aorta in a resting state through the enhancement of •NO production, without modifying O2.− generation, thus the bioavailability of •NO was increased. The increase in the •NO‐cyclic GMP pathway explains the beneficial effect of flavonoids at vascular level.

British Journal of Pharmacology (2002) 135, 910–916; doi:10.1038/sj.bjp.0704534
Effects of ketanserin and DOI on spontaneous and 5‐HT‐evoked peristalsis of the pig ureter in vivo
Authors: Hauser D S , Mevissen M , Weiss R , Portier C J , Scholtysik G , Studer U E , Danuser H 
Published: January 2005

The influence of 5‐hydroxytryptamine (5‐HT) receptor agonists and antagonists on the ureter motility was investigated in vivo on intact ureters of anaesthetized pigs. Drugs were administered intravenously or topically.
5‐HT induced a dose‐dependent increase in the frequency of ureter contractions in anaesthetized pigs when given intravenously (0.0001 – 1 mg kg−1; ED50 0.066 mg kg−1) or topically (0.001 – 1 mg ml−1; EC50 0.043 mg ml−1). Significant increases in heart rate and blood pressure were observed when the drug was given intravenously but not topically.
The 5‐HT2A agonist, DOI (1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane) increased the frequency of ureteral contractions in a dose‐dependent manner (1 – 300 μg kg−1 i.v.). Calculation of ED50 indicated this compound to be about 1.5 times more potent with an efficacy of 23% compared to 5‐HT.
The 5‐HT2A/2C antagonist, ketanserin (0.5 mg kg−1) and the 5‐HT2C antagonist, methysergide (1 mg kg−1) antagonized the 5‐HT‐induced ureter peristalsis when given intravenously. Contraction amplitude, blood pressure and heart rate were not affected by the antagonists.
Intravenous (0.0001 – 1 mg kg−1) and topical (0.0001 – 1 μg ml−1) ketanserin significantly decreased the frequency of spontaneous ureteral contractions to about 30% of controls, which could be partly reversed by 5‐HT (0.3 mg kg−1 i.v.). The contraction amplitude, contractions of the contralateral, saline perfused ureter, heart rate and mean arterial blood pressure were not affected.
Thus, contractility of porcine ureter is mediated by 5‐HT2 receptors. Their antagonists ketanserin and methysergide seem to be promising drugs for treatment of acute ureteric colic or in preparing the ureter for ureteroscopy.

British Journal of Pharmacology (2002) 135, 1026–1032; doi:10.1038/sj.bjp.0704536