bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical stretch reveals different components of endothelial‐mediated vascular tone in rat aortic strips
Authors: Franchi‐Micheli Sergio , Failli Paola , Mazzetti Luca , Bani Daniele , Ciuffi Mario , Zilletti Lucilla 
Published: January 2005

Since the role of mechanical stretches in vascular tone regulation is poorly understood, we studied how stretch can influence endothelial tone.
Isometric contractions of isolated rat aortic helical strips were recorded. The resting tension was set at 0.7 g, 1.2 g or 2.5 g. Endothelium‐preserved strips were precontracted with either phenylephrine or prostaglandin F2α (PGF2α).
In control conditions, acetylcholine (ACh) dose‐dependently relaxed phenylephrine‐precontracted strips independently of resting tension.
At 0.7 g resting tension, nitric oxide synthase (NOS) inhibitors did not reduce ACh‐induced relaxation, while either a guanylyl cyclase inhibitor or a NO trapping agent prevented it. At 1.2 g and 2.5 g resting tensions, NOS inhibitors shifted the ACh dose‐response curve to the right.
After preincubation with indomethacin (5 μM) or ibuprofen (10 and 100 μM), at 0.7 g and 1.2 g resting tensions, ACh induced an endothelium‐dependent, dose‐dependent contraction. ACh (10−6 M) increased the contraction up to two times greater the phenylephrine‐induced one. Lipoxygenase inhibitors prevented it. At high stretch, the ACh vasorelaxant effect was marginally influenced by cyclooxygenase (COX) inhibition. Similar results were obtained when aortic strips were precontracted with PGF2α.
Our data indicate that when resting tension is low, ACh mobilizes a stored NO pool that, synergistically with COX‐derived metabolites, can relax precontracted strips. COX inhibition up‐regulates the lipoxygenase metabolic pathway, accounting for the ACh contractile effect. At an intermediate resting tension, NO production is present, but COX inhibition reveals a lipoxygenase‐dependent, ACh‐induced contraction. At high resting tension, NO synthesis predominates and COX metabolites influence ACh‐induced relaxation marginally.

British Journal of Pharmacology (2000) 131, 1355–1362; doi:10.1038/sj.bjp.0703707
Tachykinin‐induced contraction of the guinea‐pig isolated oesophageal mucosa is mediated by NK2 receptors
Authors: Kerr Karen P , Thai Binh , Coupar Ian M 
Published: January 2005

The tachykinin receptor present in the guinea‐pig oesophageal mucosa that mediates contractile responses of the muscularis mucosae has been characterized, using functional in vitro experiments.
The NK1 receptor‐selective agonist, [Sar9(O2)Met11]SP and the NK3 receptor‐selective agonists, [MePhe7]‐NKB and senktide, produced no response at submicromolar concentrations. The NK2 receptor‐selective agonists, [Nle10]‐NKA(4–10), and GR 64,349 produced concentration‐dependent contractile effects with pD2 values of 8.20±0.16 and 8.30±0.15, respectively.
The concentration‐response curve to the non‐selective agonist, NKA (pD2=8.13±0.04) was shifted significantly rightwards only by the NK2 receptor‐selective antagonist, GR 159,897 and was unaffected by the NK1 receptor‐selective antagonist, SR 140,333 and the NK3 receptor‐selective antagonist, SB 222,200.
The NK2 receptor‐selective antagonist, GR 159,897, exhibited an apparent competitive antagonism against the NK2 receptor‐selective agonist, GR 64,349 (apparent pKB value=9.29±0.16) and against the non‐selective agonist, NKA (apparent pKB value=8.71±0.19).
The NK2 receptor‐selective antagonist, SR 48,968 exhibited a non‐competitive antagonism against the NK2 receptor‐selective agonist, [Nle10]‐NKA(4–10). The pKB value was 10.84±0.19.
It is concluded that the guinea‐pig isolated oesophageal mucosa is a useful preparation for studying the effects of NK2 receptor‐selective agonists and antagonists as the contractile responses to various tachykinins are mediated solely by NK2 receptors.

British Journal of Pharmacology (2000) 131, 1461–1467; doi:10.1038/sj.bjp.0703708
Relevance of the C‐terminal Arg‐Phe sequence in γ2‐melanocyte‐stimulating hormone (γ2‐MSH) for inducing cardiovascular effects in conscious rats
Authors: Nijsen M J M A , De Ruiter G J W , Kasbergen C M , Hoogerhout P , De Wildt D J 
Published: January 2005

The cardiovascular effects by γ2‐melanocyte‐stimulating hormone (γ2‐MSH) are probably not due to any of the well‐known melanocortin subtype receptors. We hypothesize that the receptor for Phe‐Met‐Arg‐Phe‐amide (FMRFa) or Phe‐Leu‐Phe‐Gln‐Pro‐Gln‐Arg‐Phe‐amide (neuropeptide FF; NPFFa), other Arg‐Phe containing peptides, is the candidate receptor. Therefore, we studied various Arg‐Phe containing peptides to compare their haemodynamic profile with that of γ2‐MSH(6–12), the most potent fragment of γ2‐MSH.
Mean arterial pressure (MAP) and heart rate (HR) changes were measured in conscious rats after intravenous administration of γ2‐MSH related peptides.
Phe‐Arg‐Trp‐Asp‐Arg‐Phe‐Gly (γ2‐MSH(6–12)), FMRFa, NPFFa, Met‐enkephalin‐Arg‐Phe‐amide (MERFa), Arg‐Phe‐amide (RFa), acetyl‐Phe‐norLeu‐Arg‐Phe‐amide (acFnLRFa) and desamino‐Tyr‐Phe‐norLeu‐Arg‐Phe‐amide (daYFnLRFa) caused a dose‐dependent increase in MAP and HR. γ2‐MSH(6–12) showed the most potent cardiovascular effects (ED50=12 nmol kg−1 for ΔMAP; 7 nmol kg−1 for ΔHR), as compared to the other Arg‐Phe containing peptides (ED50=177–292 nmol kg−1 for ΔMAP; 130–260 nmol kg−1 for ΔHR).
Peptides, which lack the C‐terminal Arg‐Phe sequence (Lys‐Tyr‐Val‐Met‐Gly‐His‐Phe‐Arg‐Trp‐Asp‐Arg‐Pro‐Gly (γ2‐pro11‐MSH), desamino‐Tyr‐Phe‐norLeu‐Arg‐[L‐1,2,3,4 tetrahydroisoquinoline‐3‐carboxylic acid]‐amide (daYFnLR[TIC]a) and Met‐enkephalin (ME)), were devoid of cardiovascular actions.
The results indicate that the baroreceptor reflex‐mediated reduction of tonic sympathetic activity due to pressor effects is inhibited by γ2‐MSH(6–12) and that its cardiovascular effects are dependent on the presence of a C‐terminal Arg‐Phe sequence.
It is suggested that the FMRFa/NPFFa receptor is the likely candidate receptor, involved in these cardiovascular effects.

British Journal of Pharmacology (2000) 131, 1468–1474; doi:10.1038/sj.bjp.0703709
Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts
Authors: Nakaya Haruaki , Furusawa Yoshie , Ogura Takehiko , Tamagawa Masaji , Uemura Hiroko 
Published: January 2005

We investigated the effects of JTV‐519 (4‐[3‐(4‐benzylpiperidin‐1‐yl)propionyl]‐7‐methoxy‐2,3,4,5‐tetrahydro‐1,4‐benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K+ currents in guinea‐pig atrial cells by use of patch‐clamp techniques. We also evaluated the effects of JTV‐519 on experimental atrial fibrillation (AF) in isolated guinea‐pig hearts.
In atrial cells stimulated at 0.2 Hz, JTV‐519 in concentrations of 0.3 and 1 μM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration‐dependent manner.
The muscarinic acetylcholine receptor‐operated K+ current (IK.ACh) was activated by the extracellular application of carbachol (1 μM), adenosine (10 μM) or by the intracellular loading of GTPγS (100 μM). JTV‐519 inhibited the carbachol‐, adenosine‐ and GTPγS‐induced IK.ACh with the IC50 values of 0.12, 2.29 and 2.42 μM, respectively, suggesting that the drug may inhibit IK.ACh mainly by blocking the muscarinic receptors.
JTV‐519 (1 μM) inhibited the delayed rectifier K+ current (IK). Electrophysiological analyses indicated that the drug preferentially inhibits IKr (rapidly activating component) but not IKs (slowly activating component).
In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV‐519 (1 μM) inhibited the induction of AF by prolonging MAP and ERP.
We conclude that JTV‐519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K+ currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease.

British Journal of Pharmacology (2000) 131, 1363–1372; doi:10.1038/sj.bjp.0703713
Rapid activation of basolateral potassium transport in human colon by oestradiol
Authors: McNamara Brian , Winter Desmond C , Cuffe John , Taylor Colm , O'Sullivan Gerald C , Harvey Brian J 
Published: January 2005

We investigated the effect of oestradiol on basolateral potassium channels in human colonic epithelium.
Ion transport was quantified using short circuit current (Isc) measurements of samples mounted in Ussing chambers. Serosal K transport was studied using nystatin permeabilization of the apical membrane. Intracellular pH changes were quantified using spectroflouresence techniques.
Experiments were performed with either 10 nM or 1 μM Ca2+ in the apical bathing solution. With 10 nM Ca2+ in the apical bathing solution addition of oestradiol (1 nM) to the basolateral bath produced a rapid increase in current (ΔIK=11.2±1.2 μA.cm−2, n=6). This response was prevented by treatment of the serosal membrane with tolbutamide (1 μM). With 1 μM Ca2+ in the apical bathing solution addition of oestradiol produced a rapid fall in current (ΔIK=−12.8±1.4μA.cm−2), this response was prevented by treatment of the basolateral membrane with tetra‐pentyl‐ammonium (TPeA). These responses were rapid and occurred independently of protein synthesis.
Inhibition of basolateral Na+/H+ exchange with either amiloride or a low sodium bathing solution prevented this response. These responses were prevented by inhibition of protein kinase C (PKC) with bis‐indolyl‐maleimide.
Oestradiol (1 nM) produced a rapid intracellular alkanization (mean increase=0.11 pH units; n=6; P<0.01).
These results suggest that oestradiol rapidly modulates serosal K transport in human colon. These effects depend upon intact Na+/H+ exchange and protein kinase C. We propose a non‐classical, possibly membrane linked, mechanism for oestradiol action in human colonic epithelium.

British Journal of Pharmacology (2000) 131, 1373–1378; doi:10.1038/sj.bjp.0703714
Essential role of L‐arginine uptake and protein tyrosine kinase activity for NO‐dependent vasorelaxation induced by stretch, isometric tension and cyclic AMP in rat pulmonary arteries
Authors: Hucks David , Khan Nayeem M , Ward Jeremy P T 
Published: January 2005

The NO‐dependent component of cyclic AMP‐induced vasorelaxation in rat pulmonary arteries is critically dependent on extracellular L‐arginine but independent of endothelial cell intracellular [Ca2+]. We examined whether L‐arginine uptake was also essential for NO production induced by passive stretch or isometric tension, processes also reported to be Ca2+‐independent.
The passive length‐tension curve was depressed by physiological concentrations of L‐arginine (400 μM; P<0.05). Inhibition of the y+ transporter with 10 mM L‐lysine, NO synthase with L‐NAME (100 μM), or protein tyrosine kinase with erbstatin A (30 μM) caused identical upward shifts (P<0.001), alone or in combination. Tyrphostin 23 was similar to erbstatin A, whilst the inactive analogue tyrphostin A1 and genistein were without effect.
L‐arginine (400 μM) shifted the PGF2α concentration‐response curve under isometric conditions to the right (P<0.05), whereas L‐NAME or L‐lysine caused a leftward shift (P<0.001). Tyrphostin 23 (30 μM) more than reversed the L‐arginine‐induced suppression of PGF2α‐induced tension; subsequent addition of L‐NAME had no effect. The L‐lysine‐sensitive component of CPT cyclic AMP‐induced vasorelaxation was abolished by erbstatin A.
ACh‐induced vasorelaxation was ∼80% inhibited by L‐NAME, but was not affected by L‐lysine or 400 μM L‐arginine. Erbstatin A reduced the vasorelaxation by only ∼25%.
We conclude that activation of NO production by stretch, isometric tension, or cyclic AMP in rat pulmonary arteries is critically dependent on the presence and uptake of physiological concentrations of extracellular L‐arginine, and protein tyrosine kinase activity. This directly contrasts with ACh‐induced vasorelaxation, which was independent of extracellular L‐arginine, and relatively unaffected by tyrosine kinase inhibition.

British Journal of Pharmacology (2000) 131, 1475–1481; doi:10.1038/sj.bjp.0703718
P2X receptor expression in mouse urinary bladder and the requirement of P2X1 receptors for functional P2X receptor responses in the mouse urinary bladder smooth muscle
Authors: Vial C , Evans R J 
Published: January 2005

We have used subtype selective P2X receptor antibodies to determine the expression of P2X1–7 receptor subunits in the mouse urinary bladder. In addition we have compared P2X receptor mediated responses in normal and P2X1 receptor deficient mice to determine the contribution of the P2X1 receptor to the mouse bladder smooth muscle P2X receptor phenotype.
P2X1 receptor immunoreactivity was restricted to smooth muscle of the bladder and arteries and was predominantly associated with the extracellular membrane. Diffuse P2X2 and P2X4 receptor immunoreactivity not associated with the extracellular membrane was detected in the smooth muscle and epithelial layers. Immunoreactivity for the P2X7 receptor was associated with the innermost epithelial layers and some diffuse staining was seen in the smooth muscle layer. P2X3, P2X5 and P2X6 receptor immunoreactivity was not detected.
P2X receptor mediated inward currents and contractions were abolished in bladder smooth muscle from P2X1 receptor deficient mice. In normal bladder nerve stimulation evoked contractions with P2X and muscarinic acetylcholine (mACh) receptor mediated components. In bladder from the P2X1 receptor deficient mouse the contraction was mediated solely by mACh receptors. Contractions to carbachol were unaffected in P2X1 receptor deficient mice demonstrating that there had been no compensatory effect on mACh receptors.
These results indicate that homomeric P2X1 receptors underlie the bladder smooth muscle P2X receptor phenotype and suggest that mouse bladder from P2X1 receptor deficient and normal animals may be models of human bladder function in normal and diseased states.

British Journal of Pharmacology (2000) 131, 1489–1495; doi:10.1038/sj.bjp.0703720
Block of the lymphocyte K+ channel mKv1.3 by the phenylalkylamine verapamil: Kinetic aspects of block and disruption of accumulation of block by a single point mutation
Authors: Röbe Raphael J , Grissmer Stephan 
Published: January 2005

Phenylalkylamines (PAA) usually known for their action on L‐type Ca2+ channels potently block the C‐type inactivating lymphocyte Kv1.3 channel resulting in inhibition of activation of T lymphocytes. In order to design PAAs blocking Kv1.3 specifically over L‐type Ca2+ channels, we investigated the state‐dependent manner of mKv1.3 block by the PAA verapamil.
Verapamil seems to have access to the open state (OB) and, once bound to the channel, the channel‐verapamil complex is absorbed into a slowly recovering state. This state was proposed to be the inactivated blocked state (IB). Here we present a quantitative description of the transition into this state and provide evidence for the IB state through experiments with an inactivation lacking mutant channel. Since the inactivated state cannot be reached in this case the IB state cannot be reached either.
We show that the transition OB→IB is accelerated by verapamil most likely through a mechanism involving the reduction of [K+] at an inactivation modulating low affinity binding site for K+ at the outer vestibule.
Measurements of the voltage‐dependence of the off‐rate constants for verapamil suggest that verapamil can reach the channel in its neutral form and might get partially protonated while bound. Thus only those verapamil molecules that are protonated can more easily dissociate at hyperpolarizing voltages.
Since open block kinetics were shown to be similar for wild type mKv1.3 and the H404T mutant mKv1.3 channel, and since the block of the H404T mutant channels by verapamil could be described exactly by a simple three‐state open block model, the mutant channel could serve as a screening channel to determine open block affinities of new PAA derivatives in high through‐put experiments.

British Journal of Pharmacology (2000) 131, 1275–1284; doi:10.1038/sj.bjp.0703723
[Nphe1]‐Nociceptin (1‐13)‐NH2, a nociceptin receptor antagonist, reverses nociceptin‐induced spatial memory impairments in the Morris water maze task in rats
Authors: Redrobe J P , Calo G , Guerrini R , Regoli D , Quirion R 
Published: January 2005

The present study was undertaken to investigate the effects of the novel nociceptin receptor antagonist, [Nphe1]‐Nociceptin (1‐13)‐NH2 (bilateral intrahippocampal injection, 50 nmole rat−1) on purported nociceptin‐induced (bilateral intrahippocampal injection, 5 nmole rat−1) deficits in spatial learning in the rat Morris water maze task. In addition, experiments were performed in an ‘open field’ to investigate possible peptide‐induced changes in exploratory behaviour.
Nociceptin significantly impaired the ability of the animal to locate the hidden platform throughout training (P<0.001 versus control group).
Pretreatment with [Nphe1]‐Nociceptin (1‐13)‐NH2 significantly blocked nociceptin‐induced impairment of spatial learning (P<0.001 versus nociceptin group).
A probe trial revealed that vehicle‐treated animals spent more time in the quadrant that had previously contained the hidden platform, whereas nociceptin‐treated animals did not spend more time in any one quadrant.
Learning impairments were not attributable to non‐specific deficits in motor performance or change in exploratory behaviour.
Taken together, our results reveal that [Nphe1]‐Nociceptin (1‐13)‐NH2 represents an effective and useful in vivo antagonist at the nociceptin receptors involved in learning and memory.

British Journal of Pharmacology (2000) 131, 1379–1384; doi:10.1038/sj.bjp.0703724
Partial to complete antagonism by putative antagonists at the wild‐type α2C‐adrenoceptor based on kinetic analyses of agonist : antagonist interactions
Authors: Pauwels Petrus J , Colpaert Francis C 
Published: January 2005

Activation of the recombinant human α2C‐adrenoceptor (α2C AR) by (−)‐adrenaline in CHO‐K1 cells transiently co‐expressing a chimeric Gαq/i1 protein induced a rapid, transient Ca2+ response with a high‐magnitude followed by a low‐magnitude phase which continued throughout the recorded time period (15 min).
Activation of the α2C AR by various α2 AR agonists revealed the following rank order of high‐magnitude Ca2+ response [Emax (%) versus 10 μM (−)‐adrenaline]: UK 14304 (102±4)=talipexole (101±3)=(−)‐adrenaline (100)=d‐medetomidine (98±1)>oxymetazoline (81±4)⋍clonidine (75±5).
The methoxy‐ (RX 821002) and ethoxy‐derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high‐ and the low‐magnitude Ca2+ response. However, though acting as full antagonists of the high‐magnitude response, the further putative α2 AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low‐magnitude response only partially.
In conclusion, kinetic analyses of agonist : antagonist interactions at the α2C AR demonstrate a wide spectrum of partial to complete antagonism of the low‐magnitude Ca2+ response for structurally related α2 AR ligands.

British Journal of Pharmacology (2000) 131, 1385–1390; doi:10.1038/sj.bjp.0703726
Human renal mesangial cells are a target for the anti‐inflammatory action of 9‐cis retinoic acid
Authors: Manzano V Moreno , Muñoz J C Sepúlveda , Jiménez J Rodriguez , Puyol M Rodriguez , Puyol D Rodriguez , Kitamura M , Cazaña F J Lucio 
Published: January 2005

Mesangial cells play an active role in the inflammatory response to glomerular injury. We have studied in cultured human mesangial cells (CHMC) several effects of 9‐cis retinoic acid (9‐cRA), an activator of both retinoic acid receptors (RARs) and retinoid X receptors (RXRs).
9‐cRA inhibited foetal calf serum‐induced CHMC proliferation. It also prevented CHMC death induced by the inflammatory mediator H2O2. This preventive effect was not due to any increase in H2O2 catabolism and it persisted even when both catalase and glutathione synthesis were inhibited. Finally, 9‐cRA diminished monocyte adhesion to FCS‐stimulated CHMC. Interestingly, the retinoid also inhibited in FCS‐stimulated cells the protein expression of two mesangial adhesion molecules, fibronectin and osteopontin, but it did not modify the protein expression of intercellular adhesion molecule‐1 and vascular adhesion molecule‐1.
All major RARs and RXRs isotypes were expressed in CHMC regardless of the presence or absence of 9‐cRA. Transcripts to RAR‐α, RAR‐β and RXR‐α increased after incubation with 9‐cRA whereas RXR‐γ was inhibited, suggesting a major role for RARs and RXRs in 9‐cRA‐anti‐inflammatory effects.
9‐cRA was toxic only at 50 μM (a concentration 50–5000 times higher than required for the effects above). Cell death occurred by apoptosis, whose onset was associated with a pronounced increase in catalase activity and reduced glutathione content, being more effectively induced by all‐trans retinoic acid. Modulation of the oxidant/antioxidant balance failed to inhibit apoptosis.
We conclude that mesangial cells might be a target for the treatment of inflammatory glomerulopathies with 9‐cRA.

British Journal of Pharmacology (2000) 131, 1673–1683; doi:10.1038/sj.bjp.0703728
Enhanced contractile response to thrombin in the pregnant rat myometrium
Authors: Shintani Yoshinobu , Hirano Katsuya , Nishimura Junji , Nakano Hitoo , Kanaide Hideo 
Published: January 2005

Thrombin causes various cellular events by activating protease‐activated receptors (PARs). Here, we showed, for the first time, that thrombin induced myometrial contraction. To determine the mechanism of thrombin‐induced myometrial contraction, we simultaneously measured intracellular Ca2+ concentration ([Ca2+]i) and tension of fura‐PE3‐loaded rat myometrium using front‐surface fluorimetry. The expression of thrombin receptor mRNA in the rat myometrium were determined by reverse transcription‐polymerase chain reaction analysis (RT–PCR analysis).
Thrombin (0.01–3 u ml−1) caused dose‐dependent increase in [Ca2+]i and tension in the rat myometrium, and this effect was greatly enhanced in the pregnant myometrium. PAR1‐activating peptide mimicked the effects of thrombin.
In Ca2+‐free PSS, thrombin induced no increase in [Ca2+]i and tension in the pregnant myometrium. Both diltiazem (10 μM) and SK‐F 96365 (10 μM) significantly inhibited the thrombin‐induced elevations of [Ca2+]i and tension, and their effects were additive.
RT–PCR analysis revealed an approximately 10 fold increase in the level of thrombin receptor mRNA in the pregnant myometrium compared to that obtained in the non‐pregnant myometrium.
In conclusion, the contractile response to thrombin was greatly enhanced in the pregnant myometrium, mainly due to the up‐regulation of thrombin receptor. We propose that initiation of a post‐parturitional myometrial contraction is one of the most important physiological roles of thrombin receptor.

British Journal of Pharmacology (2000) 131, 1619–1628; doi:10.1038/sj.bjp.0703729