bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective antagonism of calcium channel activators by fluspirilene
Authors: Kenny Barry A. , Fraser Stuart , Kilpatrick Andrew T. , Spedding Michael 
Published: July 2012

Fluspirilene has been claimed to bind to a high affinity site in the calcium channel in skeletal muscle. We have investigated its calcium‐antagonistic effects in smooth muscle and affinity for the channel in radioligand binding assays.
Fluspirilene was weakly active as an antagonist of Ca2+‐induced contractions in K+‐depolarized taenia preparations from the guinea‐pig caecum, with threshold antagonism starting from concentrations of 30 nm. Nitrendipine, nicardipine and nimodipine were very potent antagonists in this model (threshold antagonism, > 1 nm).
In contrast, fluspirilene (10–1000 nm) was a potent non‐competitive antagonist of the effects of Bay K 8644 (1–3000 nm) on Ca2+‐induced contractions and, at 10 nm, selectively antagonised the effects of Bay K 8644, abolished the Ca2+‐channel activator effects of CGP 28392, without changing the calcium antagonist effects of nitrendipine, or modifying the sensitivity of the tissues to Ca2+. In contrast, the dihydropyridines were more effective as antagonists of Ca2+ than of Bay K 8644. Fluspirilene therefore selectively antagonised the effects of dihydropyridine Ca2+ channel activators without affecting the antagonist potency.
In radioligand binding experiments, fluspirilene was a potent displacer of [3H]‐PN‐200‐110 binding to rat cerebral cortical membranes (EC50 30 nm), albeit with a low Hill slope (0.66), and was more potent than other lipophilic diphenylalkylamines such as flunarizine and lidoflazine. Fluspirilene interacted non‐competitively with [3H]‐PN‐200‐110 and increased dissociation of the radioligand.
Co‐release of PHI and VIP in dog stomach by peripheral and central vagal stimulation
Authors: Ohta Toshio , Ito Shigeo , Ohga Akira 
Published: July 2012

The purpose of this investigation was to examine the outputs of peptide histidine isoleucine (PHI) and vasoactive intestinal peptide (VIP) from the gastric corpus in response to stimulation of the peripheral (PVS) and central (CVS) ends of the vagus nerve and to compare the effects of PHI on gastric motility and blood flow with those of VIP in atropine‐treated dogs.
PVS and CVS caused parallel increases in gastric venous plasma concentrations of VIP and PHI. The molar ratios of the peptides (VIP/PHI) appearing in the gastric venous plasma were about 1.5 for PVS at 10 Hz, 0.65 for PVS at 40 Hz and about 0.7 for CVS at 10 Hz.
The molar ratio of peptide concentration extracted from the gastric corpus was about 1.5 in the muscle layer and 2.7 in the mucosal layer.
Intra‐arterially‐injected PHI was about 5 fold and 50 fold less effective in producing gastric relaxation and vasodilatation, respectively, than VIP.
These results indicate that PHI is co‐released with VIP by peripheral vagal stimulation and by initiation of the vago‐vagal reflex, and that PHI seems to have an important role in the regulation of gastric motility but not gastric blood flow in the dog.
Interactions of palmitoyl carnitine with the endothelium in rat aorta
Authors: Dainty I.A. , Bigaud M. , McGrath J.C. , Spedding M. 
Published: July 2012

Palmitoyl carnitine (10–1000 μm) resembled Bay K 8644 (10–1000 nm) in that it directly contracted rat aortic rings which were partially depolarized with K+ (12 mm). However, the effects of Bay K 8644 were reduced in the presence of endothelium whereas the presence of the endothelium hardly affected the palmitoyl carnitine‐induced contractions, which occurred at high concentrations (< 10 μm).
Lower concentrations of palmitoyl carnitine (0.3–30 μm; EC50 1.1 μm), but not Bay K 8644, carnitine or palmitic acid, antagonized the relaxant effects of acetylcholine in rat aorta. The antagonism was specific for endothelium‐dependent relaxations, in that the relaxations to ATP and the calcium ionophore A23187 were also non‐competitively antagonized, albeit at slightly higher concentrations, whereas the direct relaxant effects of sodium nitroprusside were unaffected. Palmitoyl carnitine therefore antagonizes the effects or the release of endothelial‐derived relaxant factor (EDRF). The inhibitory effects were reversed on prolonged washout, indicating that the effects were not due to destruction of the endothelial cells.
In superfusion experiments, palmitoyl carnitine inhibited the release of EDRF from rat aorta but did not affect the responsiveness to exogenous EDRF, indicating a site of action at the endothelial cell. In superfusion experiments, palmitoyl carnitine, and lysophosphatidyl choline, caused direct relaxations of the aorta, indicating EDRF release, prior to inhibition of release evoked by receptor stimulation. These substances may modulate vascular responsiveness under certain conditions.
Responses of rat substantia nigra compacta neurones to L‐DOPA
Authors: Mercuri Nicola B. , Calabresi Paolo , Bernardi Giorgio 
Published: July 2012

The electrophysiological actions of l‐DOPA were studied on substantia nigra dopamine‐containing neurones by use of intracellular recordings, current and voltage clamp, in vitro.
l‐DOPA (3–300 μm), applied by superfusion, decreased the spontaneous firing activity of the neurones, hyperpolarized the membrane potential and produced an outward current.
These effects of l‐DOPA were graded and were antagonized by sulpiride, a D2‐receptor antagonist.
The l‐DOPA activated membrane hyperpolarization persisted in slices exposed to tetrodotoxin while it was markedly reduced or abolished in solutions with no calcium plus cobalt (2 mm).
In slices treated with carbidopa, an inhibitor of the aromatic amino acid decarboxylase enzyme, the actions of l‐DOPA were greatly reduced.
We propose that l‐DOPA inhibits the firing of substantia nigra zona compacta neurones by being converted to dopamine which is then released by these cells.
The actions of adenosine 5′‐triphosphate on guinea‐pig intracardiac neurones in culture
Authors: Allen T.G.J. , Burnstock G. 
Published: July 2012

The actions of adenosine 5′‐triphosphate (ATP) and related nucleotides and nucleosides on the membrane ion conductances of m and AH type intracardiac neurones cultured from ganglia within the atria and interatrial septum of newborn guinea‐pig heart were studied with intracellular current‐ and voltage‐clamp techniques.
Approximately 74% (120 out of 161) of AH type cells and 41% (5 out of 12) m cells responded to direct application of ATP (500 μm) onto their soma.
In 41% of m and 43% of AH type cells, focal application of ATP (500 μm) evoked rapid depolarization with an increase in conductance which frequently elicited action potential discharge. The underlying inward current had a null potential of −11.2 mV and was reduced in solutions containing low extracellular sodium and calcium but unaffected by reduced chloride‐containing solutions.
In a further 31% of AH type cells, ATP evoked a multi‐component response consisting of an initial depolarization followed by a hyperpolarization and a slow prolonged depolarization. The current underlying the initial depolarization resulted from an increase in conductance and had a null potential of −19.1 mV. The current was increased in low chloride‐containing solutions and was only slightly reduced in low sodium‐ and calcium‐containing solutions. The subsequent hyperpolarization and outward current resulted from an increase in membrane conductance and had a null potential of −88.5 mV, which was close to the potassium equilibrium potential in these cells. The slow depolarization and inward current was not associated with change in membrane conductance.
In less than 2% of AH cells, ATP evoked a second type of slow depolarization. This was associated with a fall in conductance and had a null potential of −90.7 mV.
In 40% of AH cells, adenosine (10–100 μ m) inhibited the calcium‐sensitive potassium current responsible for the after‐hyperpolarization. The action of adenosine was antagonized by the P1‐purinoceptor antagonist 8‐phenyltheophylline (1–10 μm).
The potency order of agonists for all of the ATP‐evoked responses, except the slow depolarization associated with a fall in conductance was ATP > ADP with AMP and adenosine being ineffective.
Responses to ATP were only weakly desensitized by α,β‐methylene ATP (3 × 10−6 m) and the potency order of analogues was 2‐methylthio ATP ≤ ATP > α,β‐methylene ATP, indicating the involvement of receptors similar to P2Y purinoceptors.
Refractoriness of the gravid rat uterus to tocolytic and biochemical effects of atrial natriuretic peptide
Authors: Potvin W. , Varma D.R. 
Published: July 2012

Effects of atrial natriuretic peptide (ANP) on tension development, particulate guanylate cyclase activity and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) concentrations of uteri from oestrogen‐treated, progesterone‐treated, ovariectomized and pregnant rats were determined in vitro.
ANP inhibited the tension development by myometrial tissues from oestrogen‐treated virgin rats and the sterile horn of 10 to 14 day pregnant rats but not of the uterus from pregnant and progesterone‐treated rats.
Inhibition of cyclo‐oxygenase and lipoxygenase activities did not restore the tocolytic activity of ANP on gravid uterus. ANP exerted a tocolytic effect on nongravid uterus submaximally stimulated by prostaglandin F2α (PGF2α), oxytocin, vasopressin, angiotensin II or 5‐hydryoxtryptamine (5‐HT).
Ovariectomy decreased the tocolytic effects of ANP, which could be restored by oestrogen treatment.
The refractoriness to the tocolytic effect of ANP in pregnant rats was not accompanied by a decrease in its relaxant effects on isolated aortic strips.
Tocolytic effects of isoprenaline, isobutylmethyl xanthine and hydroxylamine were not influenced by pregnancy or progesterone treatment. Up to a concentration of 3 mm, sodium nitroprusside did not affect myometrial tension development.
Pregnancy and progesterone treatment markedly inhibited ANP‐induced increases in myometrial particulate guanylate cyclase activity and cyclic GMP concentrations but did not influence the effects of ANP on aortic cyclic GMP concentrations.
It is concluded that exposure of the myometrium to circulating and placentally‐produced progesterone is responsible for the pregnancy‐induced decrease in the effects of ANP on myometrial particulate guanylate cyclase activity and cyclic GMP concentrations and in turn on myometrial tension development.
Cyclic AMP counteracts mitogen‐induced inositol phosphate generation and increases in intracellular Ca2+ concentrations in human lymphocytes
Authors: van Tits Lambertus J.H. , Michel Martin C. , Motulsky Harvey J. , Maisel Alan S. , Brodde Otto‐Erich 
Published: July 2012

The effects of increases in intracellular adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) on mitogen‐induced generation of inositol phosphates and increases in intracellular Ca2+ concentration were investigated in human peripheral blood mononuclear leukocytes (MNL).
The mitogens concanavalin A (Con A), pokeweed mitogen (PWM) and phytohaemagglutinin (PHA) concentration‐dependently stimulated generation of inositol phosphates. Catecholamines inhibited this process with an order of potency: isoprenaline > adrenaline > noradrenaline indicating involvement of β2‐adrenoceptors. This order of potency was also consistent with the catecholamine potencies for stimulating the generation of cyclic AMP.
In addition to catecholamines, the cyclic AMP formation‐stimulating agents prostaglandin E1 (PGE1) and forskolin concentration‐dependently inhibited mitogen‐induced inositol phosphate generation, too. Moreover, the inhibitory effect of isoprenaline was potentiated by co‐incubation with the phosphodiesterase inhibitor isobutylmethylxanthine demonstrating that these inhibitory effects were mediated by cyclic AMP.
Con A and PHA concentration‐dependently increased the intracellular Ca2+ concentration in human MNL (assessed by the fluorescent indicator dye Fura‐2). This increase was almost completely blocked by chelation of extracellular Ca2+, demonstrating influx rather than mobilization from intracellular stores.
The elevation of intracellular Ca2+ was not blocked by pretreatment with pertussis toxin, 100 ng ml−1, for 16 h.
Isoprenaline, PGE1, and forskolin, however, inhibited the mitogen‐stimulated elevation of intracellular Ca2+. This inhibition was enhanced by the phosphodiesterase inhibitors isobutylmethylxanthine and Ro 20–1724, demonstrating mediation by cyclic AMP.
We conclude that catecholamines and other cyclic AMP increasing agents can inhibit mitogen‐stimulated generation of inositol phosphates and elevation of intracellular Ca2+ in resting human MNL. Since generation of inositol phosphates and increases in intracellular Ca2+ are very early events in activation of MNL, attenuation of these events might well contribute to the inhibitory effect of cyclic AMP on MNL function.
Alkaline buffers release EDRF from bovine cultured aortic endothelial cells
Authors: Mitchell Jane A. , de Nucci Gilberto , Warner Timothy D. , Vane John R. 
Published: July 2012

Release of endothelium‐derived relaxing factor (EDRF) and prostacyclin (PGI2) from bovine cultured aortic endothelial cells (EC) was measured by bioassay and radioimmunoassay, respectively.
Bradykinin (BK, 3–30 pmol), adenosine diphosphate (ADP, 2–6 nmol) or the sodium ionophore monensin (40–100 nmol) injected through a column of EC released EDRF. l‐Arginine free base (FB; 10–20 μmol) or d‐arginine FB (10–20 μmol) injected through the column of EC released similar amounts of EDRF and also caused an increase in pH of the Krebs solution perfusing the EC from 7.5–8.0 to 8.6–9.5. Sodium carbonate (Na2CO3) an alkaline buffer which caused the same changes in the pH of the Krebs solution also induced the same release of EDRF. The hydrochloride salts of l‐ or d‐arginine did not cause either release of EDRF when injected through the column of EC or increases in the pH of the Krebs solution.
Inhibitors of either diacylglycerol lipase (RHC 80267) or kinase (R59022) inhibited the release of EDRF induced by BK or ADP but potentiated the release induced by l‐arginine FB, monensin (40–100 nmol) or alkaline buffer (Na2CO3). R59022 and RHC 80267 infused through the EC increased the basal release of EDRF.
When calcium chloride was omitted from the Krebs solution the release of EDRF induced by alkaline buffer (Na2CO3; pH 8.6–9.5) or l‐arginine FB (10–20 μmol) was selectively inhibited when compared to that induced by BK (3–30 pmol) or ADP (2–6 nmol). This inhibition was reversed when calcium (2.5 mm) was restored.
NG‐monomethyl‐l‐arginine (NMMA; 30 μm) inhibited release of EDRF induced by BK (10–30 pmol) or alkaline buffers (Na2CO3 or d‐arginine FB; pH 8.6–9.5). This inhibition was partially reversed by l‐but not d‐arginine FB or HCl (30–100 μm).
Prostacyclin was released when BK (10 pmol), ADP (2 nmol) or arachidonic acid (30 nmol) were injected through the column of EC. However, monensin (40 nmol) or alkaline buffers (pH 8.6–9.5) did not release detectable amounts of PGI2 as measured by radioimmunoassay for 6‐oxo‐prostaglandin F1α.
Thus alkalinisation of the external bathing solution can release EDRF from cultured EC by a mechanism which does not involve receptor activation and which depends on the presence of extracellular calcium.
A novel anti‐inflammatory peptide from human lipocortin 5
Authors: Perretti Mauro , Becherucci Cristina , Mugridge Kenneth G. , Solito Egle , Silvestri Sergio , Parente Luca 
Published: July 2012

A novel anti‐inflammatory peptide (residues 204–212) of human recombinant lipocortin 5 (hrLC5) found on the high similarity region with uteroglobin is described.
Peptide 204–212 dose‐dependently inhibited the contractions of rat isolated stomach strips elicited by porcine pancreatic phospholipase A2 (PLA2). Contractions caused by arachidonic acid (AA), prostaglandin E2 (PGE2) and 5‐hydroxytryptamine were not affected. No direct enzyme inhibition was observed in a radiochemical assay.
PGE2 release by both human fibroblasts and rat macrophages was reduced by peptide 204–212 in a dose‐dependent manner.
The development of carrageenin‐induced oedema in rats was significantly inhibited by the local administration of peptide 204–212.
The pattern and potency of the biological effects of peptide 204–212 are similar to those of antiflammin 2, a lipocortin 1‐derived peptide.
It is suggested that peptide 204–212 may represent the active site responsible for the anti‐inflammatory properties of lipocortin 5.
Blockade by the local anaesthetic, tetracaine, of desensitization of Ca‐induced Ca release after muscarinic stimulation in smooth muscle
Authors: Hishinuma Shigeru , Uchida Masaatsu K. 
Published: July 2012

Desensitization of contractile responses dependent on release of intracellularly stored Ca elicited by carbachol, histamine or caffeine was measured after desensitizing treatment with carbachol or histamine in the presence or absence of local anaesthetics in Ca‐free solution containing 2 mm EGTA in the smooth muscle of guinea‐pig taenia caecum.
Histamine‐induced homologous desensitization was inhibited by tetracaine and procainamide. Dibucaine did not exert an inhibitory effect on the desensitization. This is consistent with our previous findings concerning the effects of local anaesthetics on the densitization of histamine H1‐receptors measured under normal physiological conditions.
Carbachol induced a functional change of intracellular Ca stores which resulted in heterologous desensitization. Tetracaine completely blocked carbachol‐induced desensitization of the caffeine‐elicited contraction, but in the case of carbachol‐induced desensitization of carbachol‐ and histamine‐elicited contractions, this blocking effect of tetracaine was very weak and absent, respectively. The other local anaesthetics used did not affect the desensitization. These results suggest that the Ca‐induced and inositol trisphosphate‐induced Ca release mechanisms were both desensitized by carbachol and that the desensitization of the Ca‐induced Ca release mechanism was selectively blocked by tetracaine.
Negative chronotropic effect of a novel class III antiarrhythmic drug, UK‐68,798, devoid of β‐blocking action on isolated guinea‐pig atria
Authors: Yang Tao , Tande Pål M. , Refsum Helge 
Published: July 2012

The chronotropic effects of a novel class III antiarrhythmic drug, UK‐68,798, and the β‐adrenoceptor blocker, propranolol, for comparison, were studied on spontaneously beating right atria isolated from guinea‐pigs in the absence and presence of increasing concentrations of isoprenaline (10−10–10−4 m).
UK‐68,798 (10−9–10−5 m) decreased spontaneous atrial rate by 6–21%. Propranolol (10−8–10−6 m) also had a negative but significantly smaller chronotropic effect.
UK‐68,798 dose‐dependently reduced the maximal positive chronotropic effect induced by isoprenaline, but without significantly shifting the concentration‐response curve for isoprenaline in a parallel fashion. A pD'2 value of 5.88 was obtained. As expected, propranolol displayed a competitive inhibition with a pA2 value of 8.21.
The results demonstrate a negative chronotropic effect of UK‐68,798, which is not associated with a β‐adrenoceptor blocking action. We suggest that the negative chronotropic effect is linked with potassium channel blockade and thereby the class III antiarrhythmic action of UK‐68,798.
Effects of propafenone on 45Ca movements and contractile responses in vascular smooth muscle
Authors: Carrón Rosalia , Pérez‐Vizcaino Francisco , Delpón Eva , Tamargo Juan 
Published: July 2012

In rat isolated aorta the class Ic antiarrhythmic drug, propafenone, dose‐dependently inhibited the contractile responses induced by high K (80 mm) and noradrenaline (NA, 10−5 m), the IC50s being 2.5 ± 0.7 × 10−6 m and 8.7 ± 0.8 × 10−6 m, respectively. These inhibitory actions were also observed with propafenone added after the induced contractions.
Contractile responses induced by addition of Ca to 0 Ca high‐K solution were also inhibited by propafenone (IC50 = 2.5 ± 0.8 × 10−6 m). Moreover, propafenone inhibited the contractile responses elicited by NA in strips incubated in 0 Ca (IC50 = 1.9 ± 0.9 × 10−6 m).
Propafenone also inhibited (IC50 = 1.2 ± 0.4 × 10−5 m) the development of spontaneous mechanical activity in portal vein segments.
Propafenone, 5 × 10−6 m and 10−5 m, inhibited 45Ca uptake stimulated by high K or NA without altering 45Ca uptake in resting strips.
These results indicated that in rat isolated aortae and portal veins propafenone inhibited Ca entry through voltage‐operated channels and NA‐induced Ca uptake as well as Ca release from intracellular stores. As a consequence it would reduce the concentration of intracellular free Ca available at the contractile apparatus for vascular smooth muscle contraction.
IgE‐dependent activation of alveolar macrophages augments neurally mediated contraction of small airways
Authors: Tamaoki J. , Sakai N. , Kanemura T. , Yamawaki I. , Takizawa T. 
Published: July 2012

We studied the effect of immunologically activated pulmonary alveolar macrophages (PAM) on functions of canine bronchiolar smooth muscle under isometric conditions in vitro.
PAM, stimulated with monoclonal anti‐dinitrophenyl (DNP) IgE antibody and DNP‐human serum albumin (DNP‐HSA), augmented the contractile responses of bronchioles to electrical field stimulation, whereas PAM treated with IgE antibody alone had no effect.
In contrast, the contractile responses to exogenously administered acetylcholine were not influenced by immunologically activated PAM.
The PAM‐induced increase in the contractile responses to field stimulation was inhibited by pretreatment of PAM with indomethacin and by addition of the thromboxane A2 (TxA2) receptor antagonist SQ 29548.
The release of TxA2 from PAM was increased by anti‐DNP IgE and DNP‐HSA, an effect that was prevented by indomethacin.
These results suggest that PAM may play a role in the development of antigen‐induced hyperreactivity of small airways through an IgE‐dependent release of TxA2 which potentiates prejunctionally the parasympathetic component of bronchiolar smooth muscle tone.
Receptors mediating tachykinin‐induced contractile responses in guinea‐pig trachea
Authors: Ireland S.J. , Bailey F. , Cook A. , Hagan R.M. , Jordan C.C. , Stephens‐Smith M.L. 
Published: July 2012

The classification of tachykinin receptors in the guinea‐pig trachea has been investigated. This was of interest because, from previous studies, it was not clear whether the guinea‐pig trachea contains either a mixture of NK1 and NK2 receptors or, alternatively, a single type of novel tachykinin receptor.
In the present study, the guinea‐pig trachea was contracted by tachykinin agonists selective for NK1 receptors (substance P methylester (SPOMe) and GR73632) or NK2 receptors (GR64349) but not NK3 receptors (senktide).
Against SPOMe and GR73632, the NK1 antagonist, GR71251, behaved as a reversible competitive antagonist having apparent affinity (pKB 7.05 vs SPOMe) consistent with action at NK1 receptors. GR71251 (3 μm) did not antagonize responses to GR64349.
The NK2 antagonists L‐659,877 and Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH2 (R396) antagonized GR64349 although only R396 appeared to behave competitively (pKB 5.73). Neither L‐659,877 (30 μm) nor R396 (30 μm) blocked responses to SPOMe.
For L‐659,877 and R396, comparison was made between activity in guinea‐pig trachea and in preparations known to contain tachykinin receptors predominantly of the NK2 type. In the rabbit trachea, both L‐659,877 and R396 had effects similar to those in guinea‐pig trachea. In contrast, in the rat colon muscularis mucosae, both L‐659,877 and R396 appeared to behave competitively with pKB values against GR64349 of 7.83 and 6.90 respectively.
It is concluded that in guinea‐pig trachea, contractile responses can be induced by activation of both NK1 and NK2 receptors. The present data are discussed with reference to the proposed existence of subtypes of the NK2 receptor.