bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in the actions of some blockers of the calcium‐activated potassium permeability in mammalian red cells
Authors: Benton D C H , Roxburgh C J , Ganellin C R , Shiner M A R , Jenkinson D H 
Published: January 2005

The actions of some inhibitors of the Ca2+‐activated K+ permeability in mammalian red cells have been compared.
Block of the permeability was assessed from the reduction in the net loss of K+ that followed the application of the Ca2+ ionophore A23187 (2 μM) to rabbit red cells suspended at a haematocrit of 1% in a low potassium solution ([K]0 0.12–0.17 mM) at 37°C. Net movement of K+ was measured using a K+‐sensitive electrode placed in the suspension.
The concentrations (μM±s.d.) of the compounds tested causing 50% inhibition of K+ loss were: quinine, 37±3; cetiedil, 26±1; the cetiedil congeners UCL 1269, UCL 1274 and UCL 1495, ∼150, 8.2±0.1, 0.92±0.03 respectively; clotrimazole, 1.2±0.1; nitrendipine, 3.6±0.5 and charybdotoxin, 0.015±0.002.
The characteristics of the block suggested that compounds could be placed in two groups. For one set (quinine, cetiedil, and the UCL congeners), the concentration‐inhibition curves were steeper (Hill coefficient, nH, 2.7) than for the other (clotrimazole, nitrendipine, charybdotoxin) for which nH∼amp;1.
Compounds in the first set alone became less active on raising the concentration of K+ in the external solution to 5.4 mM.
The rate of K+ loss induced by A23187 slowed in the presence of high concentrations of cetiedil and its analogues, suggesting a use‐dependent component to the inhibitory action. This was not seen with clotrimazole.
The blocking action of the cetiedil analogue UCL 1274 could not be overcome by an increase in external Ca2+ and its potency was unaltered when K+ loss was induced by the application of Pb2+ (10 μM) rather than by A23187.
These results, taken with the findings of others, suggest that agents that block the red cell Ca2+‐activated K+ permeability can be placed in two groups with different mechanisms of action. The differences can be explained by supposing that clotrimazole and charybdotoxin act at the outer face of the channel whereas cetiedil and its congeners may block within it, either at or near the K+ binding site that determines the flow of K+.

British Journal of Pharmacology (1999) 126, 169–178; doi:10.1038/sj.bjp.0702292
Antagonist activity of α‐substituted 4‐carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells
Authors: Doherty A J , Collingridge G L , Jane D E 
Published: January 2005

We have investigated the antagonist properties of 6 α‐substituted phenylglycine analogues based on the structure of 4‐carboxyphenylglycine (4‐CPG) for group I metabotropic glutamate receptors (mGlu1α and mGlu5a) permanently expressed in CHO cells.
(S)‐4‐CPG and (S)‐MCPG were the most selective mGlu1α receptor antagonists. Longer chain α‐carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1α receptors but not at mGlu5a receptors. Thus mGlu1α receptor antagonists require small aliphatic groups at the α‐position. α‐cyclopropyl‐4‐CPG showed a tendency towards mGlu5a selectivity, suggesting that bulky groups at this position may favour mGlu5a receptor antagonism.
We demonstrate that the mGlu5a receptor displays agonist‐dependent antagonism. L‐glutamate‐induced Ca2+ release in mGlu5a receptor expressing cells was more susceptible to antagonism by cyclic α‐carbon derivatives than (S)‐3,5‐dihydroxyphenylglycine (DHPG)‐induced Ca2+ release in the same cell line.
The data presented suggests that mGlu1α and mGlu5a receptors have different steric and/or conformational requirements for the binding of antagonists and different amino acids which could interact with agonists.
These phenylglycine analogues could provide leads for the development of subtype selective antagonists.

British Journal of Pharmacology (1999) 126, 205–210; doi:10.1038/sj.bjp.0702297
Acetylcholine‐induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice
Authors: Chataigneau Thierry , Félétou Michel , Huang Paul L , Fishman Mark C , Duhault Jacques , Vanhoutte Paul M 
Published: January 2005

Isometric tension was recorded in isolated rings of aorta, carotid, coronary and mesenteric arteries taken from endothelial nitric oxide synthase knockout mice (eNOS(−/−) mice) and the corresponding wild‐type strain (eNOS(+/+) mice). The membrane potential of smooth muscle cells was measured in coronary arteries with intracellular microelectrodes.
In the isolated aorta, carotid and coronary arteries from the eNOS(+/+) mice, acetylcholine induced an endothelium‐dependent relaxation which was inhibited by Nω‐L‐nitro‐arginine. In contrast, in the mesenteric arteries, the inhibition of the cholinergic relaxation required the combination of Nω‐L‐nitro‐arginine and indomethacin.
The isolated aorta, carotid and coronary arteries from the eNOS(−/−) mice did not relax in response to acetylcholine. However, acetylcholine produced an indomethacin‐sensitive relaxation in the mesenteric artery from eNOS(−/−) mice.
The resting membrane potential of smooth muscle cells from isolated coronary arteries was significantly less negative in the eNOS(−/−) mice (−64.8±1.8 mV, n=20 and −58.4±1.9 mV, n=17, for eNOS(+/+) and eNOS(−/−) mice, respectively). In both strains, acetylcholine, bradykinin and substance P did not induce endothelium‐dependent hyperpolarizations whereas cromakalim consistently produced hyperpolarizations (−7.9±1.1 mV, n=8 and −13.8±2.6 mV, n=4, for eNOS(+/+) and eNOS(−/−) mice, respectively).
These findings demonstrate that in the blood vessels studied: (1) in the eNOS(+/+) mice, the endothelium‐dependent relaxations to acetylcholine involve either NO or the combination of NO plus a product of cyclo‐oxygenase but not EDHF; (2) in the eNOS(−/−) mice, NO‐dependent responses and EDHF‐like responses were not observed. In the mesenteric arteries acetylcholine releases a cyclo‐oxygenase derivative.

British Journal of Pharmacology (1999) 126, 219–226; doi:10.1038/sj.bjp.0702300
Roles of threonine 192 and asparagine 382 in agonist and antagonist interactions with M1 muscarinic receptors
Authors: Huang Xi‐Ping , Nagy Peter I , Williams Frederick E , Peseckis Steven M , Messer William S 
Published: January 2005

Conserved amino acids, such as Thr in transmembrane domains (TM) V and Asn in TM VI of muscarinic receptors, may be important in agonist binding and/or receptor activation. In order to determine the functional roles of Thr192 and Asn382 in human M1 receptors in ligand binding and receptor activation processes, we created and characterized mutant receptors with Thr192 or Asn382 substituted by Ala.
HM1 wild‐type (WT) and mutant receptors [HM1(Thr192Ala) and HM1(Asn382Ala)] were stably expressed in A9 L cells. The Kd values for 3H‐(R)‐QNB and Ki values for other classical muscarinic antagonists were similar at HM1(WT) and HM1(Thr192Ala) mutant receptors, yet higher at HM1(Asn382Ala) mutant receptors. Carbachol exhibited lower potency and efficacy in stimulating PI hydrolysis via HM1(Thr192Ala) mutant receptors, and intermediate agonist activity at the HM1(Asn382Ala) mutant receptors.
The Asn382 residue in TM VI but not the Thr192 residue in TM V of the human M1 receptor appears to participate directly in antagonist binding. Both Thr192 and Asn382 residues are involved differentially in agonist binding and/or receptor activation processes, yet the Asn382 residue is less important than Thr192 in agonist activation of M1 receptors.
Molecular modelling studies indicate that substitution of Thr192 or Asn382 results in the loss of hydrogen‐bond interactions and changes in the agonist binding mode associated with an increase in hydrophobic interactions between ligand and receptor.

British Journal of Pharmacology (1999) 126, 735–745; doi:10.1038/sj.bjp.0702301
Trigeminal nerve ganglion stimulation‐induced neurovascular reflexes in the anaesthetized cat: Role of endothelinB receptors in carotid vasodilatation
Authors: Raval Pravin , Bingham Sharon , Aiyar Nambi , Elliott John D , Hunter A Jackie , Ohlstein Eliot H , Parsons Andrew A 
Published: January 2005

The effects of intravenous administration of endothelin (ET) receptor antagonists SB‐209670 (0.001–10.0 mg kg−1), SB‐217242, SB‐234551 (0.01–10.0 mg kg−1) and BQ‐788 (0.001–1.0 mg kg−1) were investigated on trigeminal nerve ganglion stimulation‐induced neurovascular reflexes in the carotid vasculature of the anaesthetized cat. Comparisons were made with sumatriptan (0.003–3.0 mg kg−1) and α‐CGRP8–37 (0.001–0.1 mg kg−1).
Trigeminal nerve ganglion stimulation produced frequency related increases in carotid blood flow, reductions in carotid vascular resistance and non‐frequency related increases in blood pressure. Guanethidine (3 mg kg−1, i.v.) blocked trigeminal nerve ganglion‐induced increases in blood pressure but had no effect on changes in carotid flow or resistance. Maximal reductions in carotid vascular resistance was observed at 10 Hz, and this frequency was selected to investigate the effects of drugs on trigeminal nerve ganglion stimulation‐induced responses in guanethidine treated cats.
Saline, α‐CGRP8–37 SB‐209670 and BQ‐788 had little or no effect on resting haemodynamic parameters. SB‐217242 (10 mg kg−1, n=3) produced a 56% reduction in arterial blood pressure whereas SB‐233451 (10 mg kg−1, n=3) produced a 30% reduction in carotid vascular resistance. Sumatriptan produced dose‐related reductions in resting carotid flow and increases (max. 104% at 0.3 mg kg−1, n=5) in vascular resistance.
SB‐209670 (n=6–7), SB‐217242 (n=3) and BQ‐788 (n=3) produced inhibition of trigeminal nerve ganglion stimulation‐induced reductions in carotid vascular resistance. Saline, SB‐234551, α‐CGRP8–37 and sumatriptan had no effect.
These data demonstrate ETB receptor blockade attenuates the vasodilator effects of trigeminal nerve ganglion stimulation in the carotid vascular bed of guanethidine pretreated anaesthetized cats.

British Journal of Pharmacology (1999) 126, 485–493; doi:10.1038/sj.bjp.0702306
Effects of vanadium complexes with organic ligands on glucose metabolism: a comparison study in diabetic rats
Authors: Reul Bénédicte A , Amin Sean S , Buchet Jean‐Pierre , Ongemba Lumbe N , Crans Debbie C , Brichard Sonia M 
Published: January 2005

Vanadium compounds can mimic actions of insulin through alternative signalling pathways. The effects of three organic vanadium compounds were studied in non‐ketotic, streptozotocin‐diabetic rats: vanadyl acetylacetonate (VAc), vanadyl 3‐ethylacetylacetonate (VEt), and bis(maltolato)oxovanadium (VM). A simple inorganic vanadium salt, vanadyl sulphate (VS) was also studied.
Oral administration of the three organic vanadium compounds (125 mg vanadium element l−1 in drinking fluids) for up to 3 months induced a faster and larger fall in glycemia (VAc being the most potent) than VS. Glucosuria and tolerance to a glucose load were improved accordingly.
Activities and mRNA levels of key glycolytic enzymes (glucokinase and L‐type pyruvate kinase) which are suppressed in the diabetic liver, were restored by vanadium treatment. The organic forms showed greater efficacy than VS, especially VAc.
VAc rats exhibited the highest levels of plasma or tissue vanadium, most likely due to a greater intestinal absorption. However, VAc retained its potency when given as a single i.p. injection to diabetic rats. Moreover, there was no relationship between plasma or tissue vanadium levels and any parameters of glucose homeostasis and hepatic glucose metabolism. Thus, these data suggest that differences in potency between compounds are due to differences in their insulin‐like properties.
There was no marked toxicity observed on hepatic or renal function. However, diarrhoea occurred in 50% of rats chronically treated with VS, but not in those receiving the organic compounds.
In conclusion, organic vanadium compounds, in particular VAc, correct the hyperglycemia and impaired hepatic glycolysis of diabetic rats more safely and potently than VS. This is not simply due to improved intestinal absorption, indicating more potent insulin‐like properties.

British Journal of Pharmacology (1999) 126, 467–477; doi:10.1038/sj.bjp.0702311
Modification of left ventricular hypertrophy by chronic etomoxir treatment
Authors: Turcani Marian , Rupp Heinz 
Published: January 2005

Etomoxir (2[6(4‐chlorophenoxy)hexyl]oxirane‐2‐carboxylate), an irreversible carnitine palmitoyltransferase 1 inhibitor, reduces the expression of the myocardial foetal gene programme and the functional deterioration during heart adaption to a pressure‐overload. Etomoxir may, however, also improve the depressed myocardial function of hypertrophied ventricles after a prolonged pressure overload.
To test this hypothesis, we administered racemic etomoxir (15 mg kg−1 day−1 for 6 weeks) to rats with ascending aortic constriction beginning 6 weeks after imposing the pressure overload.
The right ventricular/body weight ratio increased (P<0.05) by 20% in etomoxir treated rats (n=10) versus untreated rats with ascending aortic constriction (n=10). Left ventricular weight was increased (P<0.05) by 8%. Etomoxir blunted the increase in left ventricular chamber volume. Etomoxir raised the proportion of V1 isomyosin (35±4% versus 24±2%; P<0.05) and decreased the percentage of V3 isomyosin (36±4% versus 48±3%; P<0.05).
Maximum isovolumically developed pressure was higher in etomoxir treated rats than in untreated pressure overloaded rats (371±22 versus 315±23 mmHg; P<0.05). Maximum rates of ventricular pressure development (14,800±1310 versus 12,340±1030 mmHg s−1; P<0.05) and decline (6440±750 versus 5040±710 mmHg s−1; P<0.05) were increased as well. Transformation of pressure values to ventricular wall stress data revealed an improved myocardial function which could partially account for the enhanced function of the whole left ventricle.
The co‐ordinated action of etomoxir on ventricular mass, geometry and myocardial phenotype enhanced thus the pressure generating capacity of hypertrophied pressure‐overloaded left ventricles and delayed the deleterious dilative remodelling.

British Journal of Pharmacology (1999) 126, 501–507; doi:10.1038/sj.bjp.0702312
Characterization of α1‐adrenoceptor subtypes mediating vasoconstriction in human umbilical vein
Authors: Errasti Andrea Emilse , Velo María Pía Rogines , Torres Rodrigo Martín , Sardi Sergio Pablo , Rothlin Rodolfo Pedro 
Published: January 2005

The present study attempted to characterize pharmacologically the subtypes of α‐adrenoceptors mediating contractions in human umbilical vein (HUV).
HUV rings were mounted in isolated organ baths and cumulative concentration‐response curves were constructed for the α‐adrenoceptor agonists phenylephrine and adrenaline. Adrenaline was more potent than phenylephrine (pD2=7.29 and 6.04 respectively).
Isoproterenol exhibited no agonism on KCl pre‐contracted HUV rings. Propranolol (1 μM) and rauwolscine (0.1 μM) did not affect the concentration‐response curves to adrenaline. These results demonstrate the lack of involvement of functional β‐ or α2‐adrenoceptors in adrenaline‐induced vasoconstriction.
The non subtype selective α1‐adrenoceptor antagonist prazosin was evaluated on phenylephrine and adrenaline concentration‐response curves. The effects of the competitive α1A and α1D‐adrenoceptor antagonists, 5‐methyl urapidil and BMY 7378 and the irreversible α1B selective compound chloroethylclonidine (CEC) were also evaluated on adrenaline concentration‐response curves.
The potencies of prazosin against responses mediated by adrenaline (pA2=10.87) and phenylephrine (pA2=10.70) indicate the involvement of prazosin‐sensitive functional α1‐adrenoceptor subtype in vasoconstriction of the HUV.
The potencies of 5‐methyl urapidil (pA2=6.70) and BMY 7378 (pA2=7.34) were not consistent with the activation of an α1A‐ or α1D‐adrenoceptor population.
Exposure to a relatively low CEC concentration (3 μM) abolished the maximum response to adrenaline suggesting that this response was mediated by an α1B‐adrenoceptor subtype.
We conclude that HUV express a prazosin‐sensitive functional α1‐adrenoceptor resembling the α1B‐subtype according with the low pA2 values for both 5‐methyl urapidil and BMY 7378 and the high sensitivity to CEC.

British Journal of Pharmacology (1999) 126, 437–442; doi:10.1038/sj.bjp.0702320
Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: role of 5‐HT1B/1D receptors and α2‐adrenoceptors
Authors: Villalón Carlos M , De Vries Peter , Rabelo Gonzalo , Centurión David , Sánchez‐López Araceli , Saxena Pramod 
Published: January 2005

The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and artificially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display affinity for several binding sites, including α‐adrenoceptors and several 5‐HT1 and 5‐HT2 receptor subtypes, this study has analysed the mechanisms involved in the above responses.
Intracarotid (i.c.) infusions during 1 min of methysergide (31–310 μg min−1), ergotamine (0.56–5.6 μg min−1) or DHE (5.6–31 μg min−1) dose‐dependently reduced external carotid blood flow (ECBF) by up to 46±4, 37±4 and 49±5%, respectively. Blood pressure and heart rate remained unchanged.
The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre‐treated with GR127935 (10 μg kg−1, i.v.).
The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre‐treated (i.v.) with prazosin (300 μg kg−1), but were partly antagonized in animals pre‐treated with either GR127935 (10 or 30 μg kg−1) or yohimbine (1000 μg kg−1). Pre‐treatment with a combination of GR127935 (30 μg kg−1) and yohimbine (1000 μg kg−1) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors.
These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5‐HT1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5‐HT1B/1D receptors as well as α2‐adrenoceptors.

British Journal of Pharmacology (1999) 126, 585–594; doi:10.1038/sj.bjp.0702324
Cyclo‐oxygenase‐2 mediates P2Y receptor‐induced reactive astrogliosis
Authors: Brambilla Roberta , Burnstock Geoffrey , Bonazzi Albino , Ceruti Stefania , Cattabeni Flaminio , Abbracchio Maria P 
Published: January 2005

Excessive cyclo‐oxygenase‐2 (COX‐2) induction may play a role in chronic neurological diseases characterized by inflammation and astrogliosis. We have previously identified an astroglial receptor for extracellular nucleotides, a P2Y receptor, whose stimulation leads to arachidonic acid (AA) release, followed, 3 days later, by morphological changes resembling reactive astrogliosis. Since COX‐2 may be upregulated by AA metabolites, we assessed a possible role for COX‐2 in P2Y receptor‐mediated astrogliosis. A brief challenge of rat astrocytes with the ATP analogue α,β‐methylene ATP (α,βmeATP) resulted, 24 h later, in significantly increased COX‐2 expression. The selective COX‐2 inhibitor NS‐398 completely abolished α,βmeATP‐induced astrocytic activation. Constitutive astroglial COX‐1 or COX‐2 did not play any role in purine‐induced reactive astrogliosis. PGE2, a main metabolite of COX‐2, also induced astrocytic activation. These data suggest that a P2Y receptor mediates reactive astrogliosis via induction of COX‐2. Antagonists selective for this receptor may counteract excessive COX‐2 activation in both acute and chronic neurological diseases.British Journal of Pharmacology (1999) 126, 563–567; doi:10.1038/sj.bjp.0702333
Effect of the cannabinoid receptor agonist WIN55212‐2 on sympathetic cardiovascular regulation
Authors: Niederhoffer Nathalie , Szabo Bela 
Published: January 2005

The aim of the present study was to analyse the cardiovascular actions of the synthetic CB1/CB2 cannabinoid receptor agonist WIN55212‐2, and specifically to determine its sites of action on sympathetic cardiovascular regulation.
Pithed rabbits in which the sympathetic outflow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular effects, respectively. For studying effects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular effects of the cannabinoid were studied in conscious rabbits with intravenous drug administration.
In pithed rabbits in which the sympathetic outflow was continuously electrically stimulated, intravenous injection of WIN55212‐2 (5, 50 and 500 μg kg−1) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these effects were antagonized by the CB1 cannabinoid receptor‐selective antagonist SR141716A. The hypotensive and the sympathoinhibitory effect of WIN55212‐2 was shared by CP55940, another mixed CB1/CB2 cannabinoid receptor agonist, but not by WIN55212‐3, the enantiomer of WIN55212‐2, which lacks affinity for cannabinoid binding sites. WIN55212‐2 had no effect on vascular tone established by infusion of noradrenaline in pithed rabbits.
Intracisternal application of WIN55212‐2 (0.1, 1 and 10 μg kg−1) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter effect was antagonized by atropine.
In conscious animals, intravenous injection of WIN55212‐2 (5 and 50 μg kg−1) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve firing. The highest dose of WIN55212‐2 (500 μg kg−1) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined.
The results obtained in pithed rabbits indicate that activation of CB1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212‐2 uncovered two effects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal fibres. The highest dose of systemically administered WIN55212‐2 produced central sympathoinhibition; the primary site of this action is not known.

British Journal of Pharmacology (1999) 126, 457–466; doi:10.1038/sj.bjp.0702337