bluuebunny/crossref_metadata_2025_split huggingface dataset:
Control of vascular tone in isolated mesenteric arterial segments from hypertensive patients
Authors: Hutri‐Kähönen Nina , Kähönen Mika , Wu Xiumin , Sand Juhani , Nordback Isto , Taurio Jyrki , Pörsti Ilkka 
Published: January 2005

Experimental hypertension is associated with several functional alterations of vascular endothelium and smooth muscle, but relatively few studies have examined the control of arterial tone in isolated vascular preparations from patients with essential hypertension. Therefore, we compared functional characteristics in vitro of distal ring segments of the mesenteric artery from 17 hypertensive and 22 normotensive humans.
Arterial constrictor responses induced by cumulative addition of Ca2+ in the presence of noradrenaline (NA) were more effectively inhibited by the Ca2+ entry blocker nifedipine (0.5 nM) in hypertensive than normotensive subjects (by 55.4±4.9, n=17 and 35.0±5.2%, n=22, respectively). Also the contractions elicited by high concentrations of KCl were more effectively inhibited by nifedipine in arterial rings from hypertensive than normotensive patients (by 38.9±3.7, n=17 and 20.2±4.6%, n=22, respectively). However, the concentration‐response curves of contractions to NA, serotonin and KCl in the absence of nifedipine were similar between the study groups.
The concentration‐response curves of endothelium‐dependent relaxations to acetylcholine and Ca2+ ionophore A23187, as well as of endothelium‐independent relaxations to the nitric oxide donor nitroprusside, β‐adrenoceptor agonist isoprenaline and K+ channel opener cromakalim did not show any differences between the groups. Moreover, the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (0.1 mM) almost abolished the relaxations to acetylcholine and Ca2+ ionophore in both groups, indicating that these responses were largely mediated by nitric oxide. The function of arterial sodium pump was evaluated by relaxations elicited by the return of K+ upon contractions induced by K+‐free solution. The rate of K+‐relaxation was similar in hypertensive and normotensive arteries (for all these responses n=20–22 in the normotensive and 15–17 in the hypertensive group).
These results suggest abnormal function of voltage‐dependent Ca2+ channels in arterial smooth muscle of hypertensive patients, whereas vascular responses to endothelium‐dependent and ‐independent vasodilators and classical contractile agents were similar between hypertensive and normotensive subjects. The present findings support the view that blockade of voltage‐dependent Ca2+ channels is an effective means of reducing arterial tone in essential hypertension.

British Journal of Pharmacology (1999) 127, 1735–1743; doi:10.1038/sj.bjp.0702716
Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d‐amphetamine: modulation by α2‐adrenoceptors
Authors: Wortley K E , Hughes Z A , Heal D J , Stanford S C 
Published: January 2005

The effects of sibutramine (0.25–10 mg kg−1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane‐anaesthetized rats were compared with those of d‐amphetamine (1–3 mg kg−1, i.p.) using in vivo microdialysis. The role of presynaptic α2‐adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective α2‐adrenoceptor antagonist, RX821002.
Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose‐response relationship was described by a bell‐shaped curve with a maximum effect at 0.5 mg kg−1. In contrast, d‐amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose.
Pretreatment with the α2‐adrenoceptor antagonist, RX821002 (dose 3 mg kg−1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg−1) and reduced the latency of sibutramine to reach its maximum effect from 144–56 min.
RX821002‐pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d‐amphetamine alone (10 mg kg−1) and had no effect on the latency to reach maximum.
These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic α2‐adreno‐ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d‐amphetamine is consistent with this being mainly due to an increase in Ca2+‐independent release of noradrenaline.

British Journal of Pharmacology (1999) 127, 1860–1866; doi:10.1038/sj.bjp.0702720
Calcium channels involved in the inhibition of acetylcholine release by presynaptic muscarinic receptors in rat striatum
Authors: Doležal Vladimír , Tuček Stanislav 
Published: January 2005

The mechanism of the inhibitory action of presynaptic muscarinic receptors on the release of acetylcholine from striatal cholinergic neurons is not known. We investigated how the electrically stimulated release of [3H]‐acetylcholine from superfused rat striatal slices and its inhibition by carbachol are affected by specific inhibitors of voltage‐operated calcium channels of the L‐type (nifedipine), N‐type (ω‐conotoxin GVIA) and P/Q‐type (ω‐agatoxin IVA).
The evoked release of [3H]‐acetylcholine was not diminished by nifedipine but was lowered by ω‐conotoxin GVIA and by ω‐agatoxin IVA, indicating that both the N‐ and the P/Q‐type (but not the L‐type) channels are involved in the release. The N‐type channels were responsible for approximately two thirds of the release. The release was >97% blocked when both ω‐toxins acted together.
The inhibition of [3H]‐acetylcholine release by carbachol was not substantially affected by the blockade of the L‐ or P/Q‐type channels. It was diminished but not eliminated by the blockade of the N‐type channels.
In experiments on slices in which cholinesterases had been inhibited by paraoxon, inhibition of [3H]‐acetylcholine release by endogenous acetylcholine accumulating in the tissue could be demonstrated by the enhancement of the release after the addition of atropine. The inhibition was higher in slices with functional N‐type than with functional P/Q‐type channels.
We conclude that both the N‐ and the P/Q‐type calcium channels contribute to the stimulation‐evoked release of acetylcholine in rat striatum, that the quantitative contribution of the N‐type channels is higher, and that the inhibitory muscarinic receptors are more closely coupled with the N‐type than with the P/Q‐type calcium channels.

British Journal of Pharmacology (1999) 127, 1627–1632; doi:10.1038/sj.bjp.0702721
The recombinant 5‐HT1A receptor: G protein coupling and signalling pathways
Authors: Raymond John R , Mukhin Yurii V , Gettys Thomas W , Garnovskaya Maria N 
Published: January 2005

The 5‐hydroxytryptamine 5‐HT1A receptor was one of the first G protein coupled receptors whose cDNA and gene were isolated by molecular cloning methods. Transfection of the cDNA of this receptor into cells previously bearing no 5‐HT receptors has resulted in the acquisition of large amounts of information regarding potential signal transduction pathways linked to the receptor, correlations of receptor structure to its various functions, and pharmacological properties of the receptor. Transfection studies with the 5‐HT1A receptor have generated critical new information that might otherwise have been elusive. This information notably includes the discovery of unsuspected novel signalling linkages, the elucidation of the mechanisms of receptor desensitization, the refinement of models of the receptor pharmacophore, and the development of silent receptor antagonists, among others. The current review summarizes the most important studies of the recombinant 5‐HT1A receptor in the decade since the identificiation of its cDNA.British Journal of Pharmacology (1999) 127, 1751–1764; doi:10.1038/sj.bjp.0702723
Glucocorticoids potently block tumour necrosis factor‐α‐ and lipopolysaccharide‐induced apoptotic cell death in bovine glomerular endothelial cells upstream of caspase 3 activation
Authors: Meßmer Udo K , Winkel Gundula , Briner Verena A , Pfeilschifter Josef 
Published: January 2005

Endothelial cell damage in glomeruli and kidney arterioles appears to play a pivotal role in glomerular inflammatory diseases. Glomerular endothelial cells, a specialized microvascular cell type involved in the regulation of glomerular ultrafiltration, die by apoptosis in response to tumour necrosis factor‐α (TNF‐α), TNF‐α/basic fibroblast growth factor (bFGF), TNF‐α/cycloheximide, and bacterial lipopolysaccharide (LPS). Apoptotic cell death is characterized by extensive DNA cleavage, DNA ladder formation, and characteristic morphological alterations.
In search for apoptosis‐preventing signals, we identified glucocorticoids as potent death preventing factors. Co‐treatment of cells with 10 nM dexamethasone and TNF‐α, TNF‐α/bFGF, TNF‐α/cycloheximide, or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells.
Similarly to dexamethasone (TNF‐α‐ and LPS‐induced apoptosis are prevented with IC50 values of 0.8 and 0.9 nM, respectively), other synthetic and natural forms of glucocorticoids, such as fluocinolone, prednisolone, hydrocortisone, and corticosterone potently inhibited cell death with IC50 values of 0.2, 6, 50 and 1000 nM, for TNF‐α and 0.7, 8, 100 and 500 nM for LPS, respectively.
Apart from glucocorticoids, mineralocorticoids such as aldosterone also blocked TNF‐α/LPS‐induced apoptosis (IC50 ∼500 nM for TNF‐α and ∼500 nM for LPS), whereas sex hormones, i.e. β‐estradiol and testosterone remained without effect.
The protective effect of glucocorticoids (and mineralocorticoids) required glucocorticoid receptor binding as it could be antagonized by the glucocorticoid receptor antagonist RU‐486. Concerning TNF‐α and LPS signal transduction, we found that dexamethasone efficiently prevented TNF‐α‐ and LPS‐induced activation of caspase‐3‐like proteases. Therefore, we postulate inhibitory mechanisms upstream of terminal death pathways.

British Journal of Pharmacology (1999) 127, 1633–1640; doi:10.1038/sj.bjp.0702726
Effects of anion channel antagonists in canine colonic myocytes: comparative pharmacology of Cl−, Ca2+ and K+ currents
Authors: Dick Gregory M , Kong In Deok , Sanders Kenton M 
Published: January 2005

Volume‐Sensitive, Outwardly Rectifying (VSOR) Cl− currents were measured in canine colonic myocytes by whole‐cell patch clamp. Decreasing extracellular osmolarity 50 milliosmoles l−1 activated current that was carried by Cl− and 5–7 times greater in the outward direction.
Niflumic acid, an inhibitor of Ca2+‐activated Cl− channels, did not inhibit VSOR Cl− current. Glibenclamide, an antagonist of CFTR, and anthracene‐9‐carboxylate (9‐AC) inhibited current less than 25% at 100 μM.
DIDS (4,4‐diisothiocyanato‐stilbene‐2,2′disulphonate) inhibited VSOR Cl− current more potently than SITS (4‐acetamido‐4′‐isothiocyanato‐stilbene‐2,2′‐disulphonate). IC50s were 0.84 and 226 μM, respectively.
VSOR Cl− current was strongly inhibited by tamoxifen ([Z]‐1‐[p‐dimethylaminoethoxy‐phenyl]‐1,2‐diphenyl‐1‐butene), an anti‐oestrogen compound (IC50=0.57 μM).
Gd3+ antagonized VSOR Cl− current more potently than La3+. The IC50 for Gd3+ was 23 μM. In contrast, 100 μM La3+ inhibited current only 35±7%.
Antagonists of VSOR Cl− current had non‐specific effects. These compounds blocked voltage‐dependent K+ and Ca2+ currents in colonic myocytes. Tamoxifen (10 μM) and DIDS (10 μM) inhibited L‐type Ca2+ current 87±7 and 31±5%, respectively. Additionally, in the presence of 300 nM charybdotoxin, tamoxifen (1 μM) and DIDS (10 μM) inhibited delayed rectifier K+ current 38±8 and 10±2%, respectively.
The pharmacology of VSOR Cl− channels overlaps with voltage‐dependent cation channels. DIDS and tamoxifen inhibited VSOR Cl− equally. However, because DIDS had much less effect on L‐type Ca2+ and delayed rectifier K+ channels than did tamoxifen, it might be useful in experiments to investigate the physiological and pathophysiological role of this conductance in whole tissues.

British Journal of Pharmacology (1999) 127, 1819–1831; doi:10.1038/sj.bjp.0702730
UTP‐preferring P2 receptor mediates inhibition of sodium transport in porcine thyroid epithelial cells
Authors: Bourke John , Abel Keith , Huxham Graham , Cooper Vanessa , Manley Simon 
Published: January 2005

The effects of adenosine 5′‐triphosphate (ATP), uridine 5′‐triphosphate (UTP) and analogues on forskolin‐stimulated absorption of Na+ by porcine thyroid epithelial cells were analysed in cultures grown as confluent monolayers on permeable supports in Transwell Ussing chambers.
85% of the forskolin (10 μM)‐stimulated short‐circuit current was inhibited by phenamil (1 μM), which is a selective antagonist for epithelial type Na+ channels.
Phenamil‐sensitive current was inhibited in a dose dependent manner by nucleotides added to the apical compartment of Ussing chambers. In contrast, the phenamil‐resistant current, previously shown to represent anion secretion, was unaffected by nucleotides.
The order of potency (with EC50 values given in μM) was UTP (0.08)>>ATP (6.3)=uridine 5′‐diphosphate (UDP) (6.6)>2methyl‐thio‐adenosine‐5′‐triphosphate (2MeSATP) (84.5)>adenosine 5′‐diphosphate (ADP) (147.8)>α,β‐methylene ATP (>150)>>adenosine (>1000).
P2 receptors mediating inhibition of sodium absorption were present on the apical membrane of the cells since addition of UTP (1–1000 μM) to the basal compartment of the Ussing chambers had little effect while subsequent addition to the apical compartment produced a normal response.
Cibachron blue (Reactive blue 2) (1–100 μM), an antagonist at some P2 receptor subtypes, inhibited phenamil sensitive current in a dose dependent manner with half maximal inhibition occurring at 14.25 μM.
Suramin (100 μM), pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (100 μM) and pyridoxal 5′‐phosphate (P5P) (100 μM) showed only slight competitive antagonism against the response to UTP.
These results indicate that a UTP‐preferring P2 receptor located on the apical membrane of thyroid epithelial cells mediates inhibition of Na+ absorption.

British Journal of Pharmacology (1999) 127, 1787–1792; doi:10.1038/sj.bjp.0702733
L‐NAME inhibits Mg2+‐induced rat aortic relaxation in the absence of endothelium
Authors: Das Rapti , Kravtsov Gennadi M , Ballard Heather J , Kwan Chiu‐Yin 
Published: January 2005

L‐NG‐nitro‐arginine methyl ester (L‐NAME; 100 μM), a nitric oxide synthase (NOS) inhibitor, reversed the relaxation induced by 3 μM acetylcholine (ACh) and 2–10 mM Mg2+ in endothelium‐intact (+E) rat aortic rings precontracted with 1 μM phenylephrine (PE). In PE‐precontracted endothelium‐denuded (−E) rat aorta, 3 μM ACh did not, but Mg2+ caused relaxation which was reversed by L‐NAME, but not by D‐NAME.
The concentration response profiles of L‐NAME in reversing the equipotent relaxation induced by 5 mM Mg2+ and 0.2 μM ACh were not significantly different.
L‐NAME (100 μM) also reversed Mg2+‐relaxation of −E aorta pre‐contracted with 20 mM KCl or 10 μM prostaglandin F2α (PGF2α). L‐NG‐monomethyl‐arginine (L‐NMMA; 100 μM) was also effective in reversing the Mg2+‐relaxation.
Addition of 0.2 mM Ni2+, like Mg2+, caused relaxation of PE‐pre‐contracted −E aorta, which was subsequently reversed by 100 μM L‐NAME.
Reversal of the Mg2+‐relaxation by 100 μM L‐NAME in PE‐precontracted −E aorta persisted following pre‐incubation with 1 μM dexamethasone or 300 μM aminoguanidine (to inhibit the inducible form of NOS, iNOS).
Pretreatment of either +E or −E aortic rings with 100 μM L‐NAME caused elevation of contractile responses to Ca2+ in the presence of 1 μM PE.
Our results suggest that L‐NAME exerts a direct action on, as yet, unidentified vascular smooth muscle plasma membrane protein(s), thus affecting its reactivity to divalent cations leading to the reversal of relaxation. Such an effect of L‐NAME is unrelated to the inhibition of endothelial NOS or the inducible NOS.

British Journal of Pharmacology (1999) 128, 493–499; doi:10.1038/sj.bjp.0702737
Effect of Na+/Ca2+ exchange inhibitor, KB‐R7943 on ouabain‐induced arrhythmias in guinea‐pigs
Authors: Watano Tomokazu , Harada Yoshimitsu , Harada Kengo , Nishimura Noriyasu 
Published: January 2005

We investigated protective effects of KB‐R7943, a Na+/Ca2+ exchange (NCX) inhibitor, on ouabain‐induced tonotropy and arrhythmias in isolated whole atria and ouabain‐induced changes in electrocardiogram (ECG) in the guinea‐pig.
KB‐R7943 (10 and 30 μM) suppressed the tonotropic effect of ouabain, and prolonged the onset time of extra‐systole induced by ouabain in isolated atria.
The intravenous injection of KB‐R7943 (1 and 3 mg kg−1) significantly increased the doses of ouabain required to induce ventricular premature beats (VPB), ventricular tachycardia (VT), ventricular fibrillation (VF) and cardiac arrest (CA) in anaesthetized guinea‐pigs.
Lidocaine (Na+channel inhibitor) and R56865 (Na+ and Ca2+ overload inhibitor) also suppressed the ouabain‐induced tonotropic effect and extra‐systole in isolated atria, but Hoe‐694 (Na+/H+ exchange inhibitor) or diltiazem (Ca2+ channel inhibitor) did not affect them.
Lidocaine also increased the doses of ouabain required to induce VPB, VT, VF and CA in anaesthetized guinea‐pigs.
From these results, we conclude that KB‐R7943 suppresses ouabain‐induced arrhythmias through inhibition of the reverse‐mode NCX.

British Journal of Pharmacology (1999) 127, 1846–1850; doi:10.1038/sj.bjp.0702740
Inactivation block of the HERG human cardiac K+ channels by RP58866
Authors: Wang Huizhen , Shi Hong , Wang Zhiguo 
Published: January 2005

RP58866 possesses a unique electrophysiological property: highly effective against various types of arrhythmias including ventricular fibrillation in animal models, noticeably those occurring during ischaemia with depolarized membrane due to elevated extracellular K+ concentrations. To understand the potential ionic mechanisms, we performed detailed studies on the effects of RP58866 on the HERG channels expressed in Xenopus oocytes, which are believed to be important compositions of the rapid component of delayed rectifier K+ current in the hearts.
RP58866 significantly inhibited the HERG channels in a concentration‐dependent manner, with ∼50% decrease in the current amplitude at a concentration of 1 μM.
RP58866 produced more pronounced inhibition with voltage protocols which favoured inactivation of the HERG channels. It caused substantial negative shift of the inactivation curves but did not alter the activation properties. The inhibition was considerably relieved by elevating [K+]o from 5–20 mM, which weakened the channel inactivation. More importantly, the potency was reduced by ∼100 fold on the mutated HERG channels (S631A) in which the C‐type inactivation was substantially weakened.
We conclude that blockade of the HERG channels by RP58866 is mainly associated with the binding of the drugs to the inactivated channels. This unique property of HERG blockade might explain some previously reported but unexplained observations: RP58866 maintains its efficacy in APD prolongation with depolarized membrane potential and in arrhythmias during ischaemia with manifested membrane depolarization.

British Journal of Pharmacology (1999) 127, 1899–1907; doi:10.1038/sj.bjp.0702741
Inducible expression of the kinin B1 receptor in the endotoxemic heart: mechanisms of des‐Arg9bradykinin‐induced coronary vasodilation
Authors: McLean Peter G , Perretti Mauro , Ahluwalia Amrita 
Published: January 2005

We have investigated the role of kinin B1 receptor induction in the endotoxemic rat heart and elucidated the mechanisms underlying B1 receptor‐mediated coronary vasodilation. We also investigated the role of these receptors in endotoxin‐induced hypotension.
Endotoxin treatment induced cardiac B1 receptor mRNA expression and promoted a coronary vasodilation response to des‐Arg9bradykinin (DABK; ED50=149.4 pmol, n=9) ex vivo peaking at 6 h. The B1 receptor antagonist des‐Arg9‐[Leu8]‐BK (DALBK, 30 nM) significantly (P<0.05) inhibited the DABK‐induced response (pA2=8.4, n=5) whilst HOE140 (B2 receptor antagonist, 10 nM) was inactive (n=4).
Removal of the endothelium or infusion with indomethacin (5 μM), but not L‐NAME (300 μM) or ODQ (1 μM), inhibited (>85%, P<0.05, n=5) the DABK‐induced response. DABK caused a dose‐dependent release of the prostacyclin metabolite, 6‐keto‐PGF1a (Emax=0.3 ng ml−1, n=6).
In vitro perfusion of hearts with endotoxin (1 μg ml−1, n=6) or interleukin‐1β (5 ng ml−1, n=6) induced B1 receptor mRNA expression and promoted a time‐dependent vasodilation response to DABK.
Endotoxin treatment (6 h) in vivo promoted a hypotensive response to DABK (ED50=29.7 nmol kg−1, n=10) which was antagonised by DALBK (3–6 nmol kg−1 min−1, P<0.05, n=7). DALBK (3 nmol kg−1 min−1) and des‐Arg10HOE140 (B1 receptor antagonist, 30 nmol kg−1 min−1) produced a 5.3% (n=6, P<0.05) and 8.8% (n=5, P<0.05) reversal, respectively, of endotoxin‐induced hypotension.
In summary, we have shown that in endotoxemia activation of B1 receptors causes coronary vasodilation via endothelial prostacyclin release. Additionally, B1 receptor antagonists partially reversed endotoxin‐induced hypotension. Therefore activation of B1 receptors may have a role to play in the vascular changes associated with endotoxemia.

British Journal of Pharmacology (1999) 128, 275–282; doi:10.1038/sj.bjp.0702743
Inhibition of heterologously expressed cystic fibrosis transmembrane conductance regulator Cl− channels by non‐sulphonylurea hypoglycaemic agents
Authors: Cai Z , Lansdell K A , Sheppard D N 
Published: January 2005

Hypoglycaemia‐inducing sulphonylureas, such as glibenclamide, inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channels. In search of modulators of CFTR, we investigated the effects of the non‐sulphonylurea hypoglycaemic agents meglitinide, repaglinide, and mitiglinide (KAD‐1229) on CFTR Cl− channels in excised inside‐out membrane patches from C127 cells expressing wild‐type human CFTR.
When added to the intracellular solution, meglitinide and mitiglinide inhibited CFTR Cl− currents with half‐maximal concentrations of 164±19 μM and 148±36 μM, respectively. However, repaglinide only weakly inhibited CFTR Cl− currents.
To understand better how non‐sulphonylurea hypoglycaemic agents inhibit CFTR, we studied single channels. Channel blockade by both meglitinide and mitiglinide was characterized by flickery closures and a significant decrease in open probability (Po). In contrast, repaglinide was without effect on either channel gating or Po, but caused a small decrease in single‐channel current amplitude.
Analysis of the dwell time distributions of single channels indicated that both meglitinide and mitiglinide greatly decreased the open time of CFTR. Mitiglinide‐induced channel closures were about 3‐fold longer than those of meglitinide.
Inhibition of CFTR by meglitinide and mitiglinide was voltage‐dependent: at positive voltages channel blockade was relieved.
The data demonstrate that non‐sulphonylurea hypoglycaemic agents inhibit CFTR. This indicates that these agents have a wider specificity of action than previously recognized. Like glibenclamide, non‐sulphonylurea hypoglycaemic agents may inhibit CFTR by occluding the channel pore and preventing Cl− permeation.

British Journal of Pharmacology (1999) 128, 108–118; doi:10.1038/sj.bjp.0702748