bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physiological antagonism between ventricular β1‐adrenoceptors and α1‐adrenoceptors but no evidence for β2‐ and β3‐adrenoceptor function in murine heart
Authors: Heubach Jürgen F , Rau Thomas , Eschenhagen Thomas , Ravens Ursula , Kaumann Alberto J 
Published: January 2005

Murine left atrium lacks inotropic β2‐adrenoceptor function. We investigated whether β2‐adrenoceptors are involved in the cardiostimulant effects of (−)‐adrenaline on spontaneously beating right atria and paced right ventricular myocardium of C57BL6 mice. We also studied a negative inotropic effect of (−)‐adrenaline.
Sinoatrial tachycardia, evoked by (−)‐adrenaline was resistant to blockade by β2‐selective ICI 118,551 (50 nM) but antagonized by β1‐selective CGP 20712A (300 nM). This pattern was unaffected by pretreatment with pertussis toxin (PTX, 600 μg kg−1 i.p. 24 h) which reversed carbachol‐evoked bradycardia to tachycardia.
Increases of ventricular force by (−)‐adrenaline and (−)‐noradrenaline were not blocked by ICI 118,551 but antagonized by CGP 20712A.
Under blockade of β‐adrenoceptors, (−)‐adrenaline and (−)‐noradrenaline depressed ventricular force (−logIC50M=7.7 and 6.9). The cardiodepressant effects of (−)‐adrenaline were antagonized by phentolamine (1 μM) and prazosin (1 μM) but not by (−)‐bupranolol (1 μM). Prazosin potentiated the positive inotropic effects of (−)‐adrenaline (in the absence of β‐blockers) from −logEC50M=6.2–6.8.
PTX‐treatment reduced carbachol‐evoked depression of ventricular force in the presence of high catecholamine concentrations. Inhibition of ventricular function of Gi protein was verified by 82% reduction of in vitro ADP‐ribosylation. PTX‐treatment tended to increase the positive inotropic potency of (−)‐adrenaline under all conditions investigated, including the presence of ICI 118,551.
(−)‐Adrenaline causes murine cardiostimulation through β1‐adrenoceptors but not through β2‐adrenoceptors. The negative inotropic effects of (−)‐adrenaline are mediated through ventricular α1‐adrenoceptors but not through β3‐adrenoceptors. Both Gi protein and α1‐adrenoceptors restrain (−)‐adrenaline‐evoked increases in right ventricular force mediated through β1‐adrenoceptors.

British Journal of Pharmacology (2002) 136, 217–229; doi:10.1038/sj.bjp.0704700
Intracisternal urocortin inhibits vagally stimulated gastric motility in rats: role of CRF2
Authors: Chen C ‐Y , Million M , Adelson D W , Martínez V , Rivier J , Taché Y 
Published: January 2005

Corticotropin‐releasing factor (CRF) acts in the brain to inhibit thyrotropin‐releasing hormone (TRH) analogue, RX‐77368‐induced vagal stimulation of gastric motility. We investigated CRF receptor‐mediated actions of rat urocortin (rUcn) injected intracisternally (ic) on gastric motor function.
Urethane‐anaesthetized rats with strain gauges on the gastric corpus were injected i.c. with rUcn and 20 min later, with i.c. RX‐77368. CRF antagonists were injected i.c. 10 min before rUcn.
RX‐77368 (1.5, 3, 10, 30 and 100 ng, i.c.) dose‐dependently increased corpus contractions, expressed as total area under the curve (AUC, mV min−1) to 2.6±2.5, 6.1±5.9, 9.8±2.6, 69.7±21.7 and 74.9±28.7 respectively vs 0.2±0.1 after i.c. saline. Ucn (1, 3 or 10 μg) inhibited RX‐77368 (30 ng)‐induced increase in total AUC by 28, 62 and 93% respectively vs i.c. saline+RX‐77368.
The CRF1/CRF2 antagonist, astressin‐B (60 μg, i.c.) completely blocked i.c. rUcn (3 μg, i.c.)‐induced inhibition of gastric motility stimulated by RX‐77368 (30 ng).
The selective CRF2 antagonist, astressin2‐B (30, 60 or 100 μg, i.c.) dose‐dependently prevented i.c. rUCn action while the CRF1 antagonist, NBI‐27914 did not.
In conscious rats, rUcn (0.6 or 1 μg, i.c.) inhibited gastric emptying of an ingested chow meal by 61 and 92% respectively. rUcn action was antagonized by astressin2‐B.
These data show that i.c. rUcn acts through CRF2 receptors to inhibit central vagal gastric contractile response and postoprandial emptying.

British Journal of Pharmacology (2002) 136, 237–247; doi:10.1038/sj.bjp.0704713
Inhibitory effect of aprindine on Na+/Ca2+ exchange current in guinea‐pig cardiac ventricular myocytes
Authors: Watanabe Yasuhide , Iwamoto Takahiro , Shigekawa Munekazu , Kimura Junko 
Published: January 2005

Using the whole‐cell voltage clamp technique, the effect of aprindine on Na+/Ca2+ exchange current (INCX) was examined in guinea‐pig single cardiac ventricular myocytes and CCL39 fibroblasts expressing a dog cardiac Na+/Ca2+ exchanger (NCX1).
INCX was recorded by ramp pulses from the holding potential of −60 mV with the external solution containing 140 mM Na+ and 1 mM Ca2+, and the pipette solution containing 20 mM Na+, 20 mM BAPTA and 13 mM Ca2+ (433 nM free Ca2+).
External application of aprindine suppressed INCX in a concentration‐dependent manner. The IC50 values of outward (measured at 50 mV) and inward (measured at −100 mV) INCX components were 48.8 and 51.8 μM with Hill coefficients of 1.3 and 1, respectively.
Intracellular application of trypsin via the pipette solution did not change the blocking effect of aprindine, suggesting that aprindine does not affect the exchanger from the cytoplasmic side.
Aprindine inhibited INCX of a mutant NCX1 with a deletion of amino acids 247 – 671 in the large intracellular domain between the transmembrane segments 5 and 6 in a similar manner to that of the wild‐type, suggesting that the site of aprindine inhibition is not in the large intracellular domain of NCX1.
A kinetic study indicated that aprindine was cooperatively competitive with KB‐R7943, another inhibitor of NCX and that aprindine was a competitive inhibitor with respect to external Ca2+.
We conclude that aprindine may modestly inhibit INCX in a therapeutic range of concentrations (around 2.5∼6.9 μM) possibly at an external or intra‐membranous site of the exchanger.

British Journal of Pharmacology (2002) 136, 361–366; doi:10.1038/sj.bjp.0704721
Hyper‐reactivity of diacylglycerol kinase is involved in the dysfunction of aortic smooth muscle contractility in streptozotocin‐induced diabetic rats
Authors: Nobe Koji , Sakai Yasushi , Maruyama Yoshiaki , Momose Kazutaka 
Published: January 2005

Dysfunction of vascular contraction in diabetes has been reported; however, the mechanisms are poorly understood. In this study, calcium sensitization involving increases in contraction in streptozotocin‐induced diabetic rat aorta was detected. We hypothesize that an alteration in the intracellular signalling system plays a role in the dysfunction of vascular contractility in diabetes. Therefore, diacylglycerol (DG) kinase as a key enzyme of phosphatidylinositol (PI) turnover was investigated.
Treatment with norepinephrine (NE) caused time‐ and dose‐dependent activation of DG kinase in control rats. This activation required simultaneous increases in intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activation.
In diabetic rats, hyper‐reactivity of DG kinase involving inactivation in the resting state and over‐activation in NE stimulation was observed. During hyper‐reactivity, [Ca2+]i dependency of DG kinase was enhanced. Treatment with 50 mM KCl induced significant escalation in activity; moreover, basal activation of PKC was detected only in diabetes. These results suggested that PKC had been activated in the resting state. In contrast, these conditions were insufficient for DG kinase activation due to the absence of [Ca2+]i elevation.
During NE‐stimulation, PKC activation was maintained and [Ca2+]i increased. Therefore, DG kinase was activated and an elevation in calcium dependency enhanced this activation.
The present study suggested that DG kinase hyper‐reactivity in diabetes involved both an increase in [Ca2+]i and basal activation of PKC. This phenomenon may be associated with increased vascular contraction in diabetes mediated by acceleration of PI‐turnover.

British Journal of Pharmacology (2002) 136, 441–451; doi:10.1038/sj.bjp.0704722
Involvement of NO in the failure of neutrophil migration in sepsis induced by Staphylococcus aureus
Authors: Crosara‐Alberto D P , Darini A L C , Inoue R Y , Silva J S , Ferreira S H , Cunha F Q 
Published: January 2005

Sepsis induced by S. aureus was used to investigate whether neutrophil migration failure to infectious focus correlates with lethality in Gram‐positive bacteria‐induced sepsis in mice.
By contrast with the sub‐lethal (SL‐group), the lethal (L‐group) intraperitoneal inoculum of S. aureus caused failure of neutrophil migration (92% reduction), high CFU in the exudate, bacteremia and impairment of in vitro neutrophil chemotactic activity.
Pre‐treatments of L‐group with adequate doses of aminoguanidine prevented the neutrophil migration failure and improved the survival of the animals (pre‐treated: 43%; untreated: 0% survival). Thus, the impairment of neutrophil migration in the L‐group appears to be mediated by nitric oxide (NO).
The injection of S. aureus SL‐inoculum in iNOS deficient (−/−) or aminoguanidine‐treated wild‐type mice (pre‐ and post‐treatment), which did not present neutrophil migration failure, paradoxically caused severe peritonitis and high mortality. This fact is explainable by the lack of NO dependent microbicidal activity in migrated neutrophils.
In conclusion, although the NO microbicidal mechanism is active in neutrophils, the failure of their migration to the infectious focus may be responsible for the severity and outcome of sepsis.

British Journal of Pharmacology (2002) 136, 645–658; doi:10.1038/sj.bjp.0704734
Cardiac electrophysiologic and antiarrhythmic actions of a pavine alkaloid derivative, O‐methyl‐neocaryachine, in rat heart
Authors: Chang Gwo‐Jyh , Su Ming‐Jai , Hung Li‐Man , Lee Shoei‐Sheng 
Published: January 2005

O‐methyl‐neocaryachine (OMNC) suppressed the ischaemia/reperfusion‐induced ventricular arrhythmias in Langendorff‐perfused rat hearts (EC50=4.3 μM). Its electrophysiological effects on cardiac myocytes and the conduction system in isolated hearts as well as the electromechanical effects on the papillary muscles were examined.
In rat papillary muscles, OMNC prolonged the action potential duration (APD) and decreased the maximal rate of depolarization (Vmax). As compared to quinidine, OMNC exerted less effects on both the Vmax and APD but a positive inotropic effect.
In the voltage clamp study, OMNC decreased Na+ current (INa) (IC50=0.9 μM) with a negative‐shift of the voltage‐dependent inactivation and a slowed rate of recovery from inactivation. The voltage dependence of INa activation was, however, unaffected. With repetitive depolarizations, OMNC blocked INa frequency‐dependently. OMNC blocked ICa with an IC50 of 6.6 μM and a maximum inhibition of 40.7%.
OMNC inhibited the transient outward K+ current (Ito) (IC50=9.5 μM) with an acceleration of its rate of inactivation and a slowed rate of recovery from inactivation. However, it produced little change in the steady‐state inactivation curve. The steady‐state outward K+ current (ISS) was inhibited with an IC50 of 8.7 μM. The inward rectifier K+ current (IK1) was also reduced by OMNC.
In the perfused heart model, OMNC (3 to 30 μM) prolonged the ventricular repolarization time, the spontaneous cycle length and the atrial and ventricular refractory period. The conduction through the AV node and His‐Purkinje system, as well as the AV nodal refractory period and Wenckebach cycle length were also prolonged (30 μM).
In conclusion, OMNC blocks Na+, Ito and ISS channels and in similar concentrations partly blocks Ca2+ channels. These effects lead to a modification of the electromechanical function and may likely contribute to the termination of ventricular arrhythmias. These results provide an opportunity to develop an effective antiarrhythmic agent with modest positive inotropy as well as low proarrhythmic potential.

British Journal of Pharmacology (2002) 136, 459–471; doi:10.1038/sj.bjp.0704736
Multiple effects of trichloroethanol on calcium handling in rat submandibular acinar cells
Authors: Pochet S , Keskiner N , Fernandez M , Marino A , Chaïb N , Dehaye J P , Métioui M 
Published: January 2005

The effect of trichloroethanol (TCEt), the active metabolite of chloral hydrate, on the intracellular concentration of calcium ([Ca2+]i) was investigated in rat submandibular glands (RSMG) acini loaded with fura‐2.
TCEt (1–10 mM) increased the [Ca2+]i independently of the presence of calcium in the extracellular medium. Dichloroethanol (DCEt) and monochloroethanol (MCEt) reproduced the stimulatory effect of TCEt but at much higher concentrations (about 6 fold higher for DCEt and 20 fold higher for MCEt).
TCEt mobilized an intracellular pool of calcium, which was depleted by a pretreatment with thapsigargin, an inhibitor of the sarcoplasmic and endoplasmic reticulum calcium‐dependent ATPases, but not with FCCP, an uncoupler of mitochondria.
TCEt 10 mM inhibited by 50% the thapsigargin‐sensitive microsomal Ca2+‐ATPase. DCEt 10 mM and MCEt 10 mM inhibited the ATPase by 20 and 10%, respectively.
TCEt inhibited the increase of the [Ca2+]i and the production of inositol phosphates in response to carbachol, epinephrine and substance P.
TCEt inhibited the uptake of calcium mediated by the store‐operated calcium channel (SOCC).
ATP and Bz‐ATP increased the [Ca2+]i in RSMG acini and this effect was blocked by extracellular magnesium, by Coomassie blue and by oxydized ATP (oATP).
TCEt potentiated the increase of the [Ca2+]i and of the uptake of extracellular calcium in response to ATP and Bz‐ATP.
TCEt had no effect on the uptake of barium and of ethidium bromide in response to purinergic agonists.
These results suggest that TCEt, at sedative concentrations, exerts various effects on the calcium regulation: (1) it mobilizes a thapsigargin‐sensitive intracellular pool of calcium in RSMG acini; (2) it inhibits the uptake of calcium via the SOCC; (3) it inhibits the activation by G protein‐coupled receptors of a polyphosphoinositide‐specific phospholipase C. It does not interfere with the activation of the ionotropic P2X receptors.
The use of chloral hydrate should be avoided in studies exploring the in vivo responses to sialagogues.

British Journal of Pharmacology (2002) 136, 568–580; doi:10.1038/sj.bjp.0704745
Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5‐HT2A and 5‐HT2C receptors
Authors: Acuña‐Castillo Claudio , Villalobos Claudio , Moya Pablo R , Sáez Patricio , Cassels Bruce K , Huidobro‐Toro J Pablo 
Published: January 2005

The pharmacological profile of a series of (±)‐2,5‐dimethoxy‐4‐(X)‐phenylisopropylamines (X=I, Br, NO2, CH3, or H) and corresponding phenylethylamines, was determined in Xenopus laevis oocytes injected with cRNA coding for rat 5‐HT2A or 5‐HT2C receptors. The efficacy and relative potency of these drugs were determined and compared to classical 5‐HT2 receptor agonists and antagonists.
The rank order of agonist potency at the 5‐HT2A receptor was: α‐methyl‐5‐HT=5‐HT>m‐CPP>MK‐212; at the 5‐HT2C receptor the order was: 5‐HT>α‐methyl‐5‐HT>MK‐212>m‐CPP. All these compounds were full agonists at the 5‐HT2C receptor, but α‐methyl‐5‐HT and m‐CPP showed lower efficacy at the 5‐HT2A receptor.
4‐(4‐Fluorobenzoyl)‐1‐(4‐phenylbutyl)piperidine (4F 4PP) was 200 times more potent as a 5‐HT2A antagonist than at 5‐HT2C receptors. Conversely, RS 102221 was 100 times more potent as a 5‐HT2C antagonist, confirming their relative receptor selectivities.
The phenylisopropylamines were partial agonists at the 5‐HT2A receptor, with Imax relative to 5‐HT in the 22±7 to 58±15% range; the corresponding phenylethylamines had lower or undetectable efficacies. All these drugs had higher efficacies at 5‐HT2C receptors; DOI was a full 5‐HT2C agonist. 2C‐I and the other phenylethylamines examined showed relative efficacies at the 5‐HT2C receptor ranging from 44±10% to 76±16%.
2C‐N was a 5‐HT2 receptor antagonist; the mechanism was competitive at the 5‐HT2A, but non‐competitive at the 5‐HT2C receptor. The antagonism was time‐dependent at the 5‐HT2C receptor but independent of pre‐incubation time at the 5‐HT2A receptor subtype.
The α‐methyl group determines the efficacy of these phenylalkylamines at the 5‐HT2A and 5‐HT2C receptors.

British Journal of Pharmacology (2002) 136, 510–519; doi:10.1038/sj.bjp.0704747
Extracellular ATP and UTP activate the protein kinase B/Akt cascade via the P2Y2 purinoceptor in renal mesangial cells
Authors: Huwiler Andrea , Rölz Waltraud , Dorsch Simone , Ren Shuyu , Pfeilschifter Josef 
Published: January 2005

Extracellular nucleotides can activate a common purinoceptor mediating various cell responses. In this study we report that stimulation of rat mesangial cells with ATP and UTP leads to a rapid activation of the protein kinase B/Akt (PKB) pathway. Time‐course studies reveal a rapid and transient phosphorylation of both Ser473 and Thr308 of PKB with a maximal effect after 5 min of stimulation. The response is concentration‐dependent with a maximal effect at 30 μM of ATP and UTP. Western blot analysis of mesangial cells reveals the expression of the isoenzymes PKB‐α and PKB‐γ, but not the PKB‐β.
ATP and UTP also activate the upstream located PI 3‐kinase‐dependent kinase. Furthermore, the ATP‐ and UTP‐induced PKB phosphorylation is abolished by two inhibitors of the PI 3‐kinase. In addition, suramin, a putative P2Y2 receptor antagonist, and pertussis toxin, an inhibitor of Gi/Go activation, markedly block ATP‐ and UTP‐induced PKB phosphorylation.
A series of ATP and UTP analogues were tested for their ability to stimulate PKB phosphorylation. UTP, ATP and γ‐thio‐ATP are the only compounds capable of activating PKB.
Stress‐induced apoptosis of mesangial cells is reduced by the stable ATP analogue, γ‐thio‐ATP, and this inhibitory effect is reversed in the presence of LY 294002.
In summary, these results demonstrate that extracellular nucleotides are able to activate the PI 3‐kinase/PDK/PKB cascade via the P2Y2‐receptor and a pertussis toxin‐sensitive Gi protein. Moreover, in mesangial cells this cascade may have an important role in the antiapoptotic response but not in the mitogenic or inflammatory response produced by extracellular nucleotides.

British Journal of Pharmacology (2002) 136, 520–529; doi:10.1038/sj.bjp.0704748
Dual effect of nitric oxide in articular inflammatory pain in zymosan‐induced arthritis in rats
Authors: Rocha José C da S , Peixoto Magno E B , Jancar Sônia , Cunha Fernando de Q , Ribeiro Ronaldo de A , Rocha Francisco A C da 
Published: January 2005

The contribution of nitric oxide (NO) to articular pain in arthritis induced by zymosan (1 mg, intra articular) in rats was assessed by measuring articular incapacitation (AI).
Systemic treatment with the non‐selective NO synthase (NOS) inhibitor L‐NAME (10–100 mg kg−1 i.p.) or with the selective iNOS inhibitors aminoguanidine (AG; 10–100 mg kg−1 i.p.) or 1400W (0.5–1 mg kg−1 s.c.) inhibited the AI induced by injection of zymosan 30 min later.
Local (intra articular) treatment with the NOS inhibitors (L‐NAME or AG, 0.1–1 μmol; 1400W, 0.01 (μmol) 30 min before zymosan also inhibited the AI.
Systemic or local treatment with the NOS inhibibitors (L‐NAME; AG, 100 mg kg−1 i.p. or 0.1 μmol joint−1; 1400W, 1 mg kg−1 s.c. or 0.01 μmol joint−1), 2 h after zymosan did not affect the subsequent AI.
Local treatment with the NO donors SNP or SIN‐1, 2 h after zymosan did inhibit AI.
L‐NAME and AG, given i.p. inhibited nitrite but not prostaglandin E2 (PGE2) levels in the joints. L‐NAME (100 mg kg−1) but not AG (100 mg kg−1) increased mean arterial blood pressure. Neither L‐NAME, AG nor the NO donor SIN‐1 altered articular oedema induced by zymosan.
In conclusion, inhibitors of iNOS decrease pain in zymosan arthritis only when given before the zymosan. This was not due to inhibition of articular PGE2 release or oedema. NO donors also promoted antinociception in zymosan arthritis without affecting oedema.

British Journal of Pharmacology (2002) 136, 588–596; doi:10.1038/sj.bjp.0704755
Effect of dopamine receptor agonists on sensory nerve activity: possible therapeutic targets for the treatment of asthma and COPD
Authors: Birrell Mark A , Crispino Natascia , Hele David J , Patel Hema J , Yacoub Magdi H , Barnes Peter J , Belvisi Maria G 
Published: January 2005

Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve‐mediated responses.
In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D2/3 agonist), ropinirole (D2/3/4 agonist), SKF 38393 (D1/5 agonist), AR‐C68397AA (Viozan™) (dual D2/B2 agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR‐C68397AA and quinagolide also inhibited depolarization of the human vagus.
The quinagolide response was blocked by sulpiride (D2/3 antagonist) but not SCH 23390 (D1/5 antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR‐C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus‐specific as it inhibited capsaicin‐induced depolarization of the rat vagus in a spiperone sensitive manner.
In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease.

British Journal of Pharmacology (2002) 136, 620–628; doi:10.1038/sj.bjp.0704758
Role of adrenergic receptors in vascular remodelling of the rat choroid
Authors: Steinle Jena J , Smith Peter G 
Published: January 2005

Choroidal blood vessels, located between the sclera and retina, constitute the principle source of blood flow to ocular structures. The choroid is innervated by vasoconstrictor sympathetic and vasodilator parasympathetic nerves.
We have shown previously that sympathetic denervation for 6 weeks leads to significant increases in choroidal thickness, percentage of choroid occupied by vascular lumina, and numbers of choroidal venules, large arterioles and outer retinal capillaries. Sympathetic deafferentation produces similar increases, indicating that loss of sympathetic nerve activity is responsible for increased vascularity after sympathectomy. Thus, sympathetic neurotransmission normally may be important in suppressing vascular proliferation in the adult rodent eye.
The aim of the present study was to determine whether sympathetic nerves act by way of adrenergic receptors to maintain normal choroidal vascular integrity.
The α‐adrenoceptor antagonist, phentolamine (1 mg kg−1 day−1), the β‐receptor antagonist, propranolol (1 mg kg−1 day−1), or saline vehicle was infused for 3 weeks using subcutaneously implanted osmotic minipumps.
In phentolamine treated rats, no significant changes were noted relative to saline infused controls. However, propranolol treatment resulted in increases in choroidal thickness, vascular luminal area, and numbers of large choroidal venules and both small and large arterioles, approximating the remodelling seen after chronic sympathectomy.
We conclude that sympathetic nerves play a role in maintaining normal choroidal vascular architecture through actions mediated primarily by β‐adrenoceptors.

British Journal of Pharmacology (2002) 136, 730–734; doi:10.1038/sj.bjp.0704771