bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelin‐1 does not mediate hypoxic vasoconstriction in canine isolated blood vessels: effect of BQ‐123
Authors: Douglas Stephen A. , Vickery‐Clark Lynne M. , Ohlstein Eliot H. 
Published: July 2012

The role of endothelin‐1 in mediating the phenomenon of hypoxic vasoconstriction was examined in canine, isolated pulmonary, circumflex coronary and femoral arterial rings.
In tissues with an intact endothelium, the exogenous application of endothelin‐1 (0.1–300 nm) caused concentration‐dependent increases in canine, isolated pulmonary artery tone. Endothelin‐3 (1–300 nm) was approximately 30 fold less potent than endothelin‐1 as a vasoconstrictor in this tissue. In contrast, the selective ETB‐receptor agonist, sarafotoxin S6c (0.01–1 μm), failed to elicit vasoconstriction in this tissue. Thus, endothelin isopeptide‐induced vasoconstriction of the canine isolated pulmonary artery is mediated exclusively by the ETA‐receptor subtype.
The concentration‐dependent increases in isometric tension induced by endothelin‐1 (0.1–300 nm) were antagonized by the ETA‐selective antagonist, BQ‐123 (10 μm); this concentration of antagonist caused a shift to the right in the concentration‐response curve for endothelin‐1 of approximately two orders of magnitude. This concentration of BQ‐123 did not unmask any ETB‐receptor‐mediated vasoconstriction since sarafotoxin S6c (0.01–1 μm) still failed to elicit contraction in the presence of this concentration of BQ‐123.
The hypoxia‐induced vasoconstriction of canine, isolated pulmonary, circumflex coronary and femoral arterial rings was unaffected by pretreatment with the endothelin receptor antagonist, BQ‐123 (10 μm), a concentration shown previously to antagonize the contractile actions of exogenously applied endothelin‐1 in the isolated pulmonary artery.
These results are the first to provide direct evidence showing that the endothelium‐dependent vasoconstriction observed during acute periods of hypoxia in vitro is not mediated by an endothelin‐related isopeptide.
Two distinct cytosolic calcium responses to extracellular ATP in rat parotid acinar cells
Authors: McMillian Michael K. , Soltoff Stephen P. , Cantley Lewis C. , Rudel RuthAnn , Talamo Barbara R. 
Published: July 2012

Increasing concentrations of ATP (0.5 μm‐300 μm) produced a biphasic increase in intracellular calcium concentration [Ca]i in rat parotid acinar cells, reflecting two distinct Cai responses to extracellular ATP.
In the absence of Mg2+ (with 3 mm CaCl2 in the buffer solution), the more sensitive response was maximal at 3–5 μm and was not further increased by 30 μm ATP. This response to ATP was not well maintained and was blocked by ADP (0.5 mm). A second, much larger increase in Cai was observed on addition of 300 μm ATP. This larger effect, which we have described previously, appears to be mediated by ATP4–, and was selectively reversed by 4,4′‐di‐isothiocyanato‐dihydrostilbene‐2,2′‐disulphonate as well as by high concentrations of α,β‐methylene ATP.
Among ATP analogues, only the putative P2Z agonist, 3′‐0‐(4‐benzoyl)benzoyl‐ATP distinguished between the two responses. This analogue was at least 10 fold more potent than ATP in stimulating the ATP4–‐response, but did not evoke the more sensitive response. The agonist potency series for both responses to ATP was identical for other analogues examined (ATP>ATP‐γS = 2‐methylthio ATP (a P2y‐selective agonist) 72>ADP, ITP and α,β‐methylene ATP (a P2X‐selective agonist)).
Although the effect of ATP4– could best be characterized as a P2Z‐type purinoceptor response, this effect was strongly and selectively blocked by reactive blue 2, a putative P2y‐purinoceptor antagonist. Reactive blue 2 may bind to and block P2Z purinoceptors since [γ32P]‐ATP binding to parotid cells was inhibited by this compound.
In contrast to the response to ATP4–, the more sensitive response to ATP was potentiated by reactive blue 2 and was less affected by increases in external Mg2+ and Ca2+.
Parasympathetic denervation selectively increased the more sensitive response, suggesting that it may be physiologically regulated.
Cyclic AMP and Ca2+ interactions affecting epithelial chloride secretion in human cultured colonic epithelia
Authors: MacVinish L.J. , Pickles R.J. , Cuthbert A.W. 
Published: July 2012

Chloride secretion in three types of cultured epithelial monolayers derived from a single human colonic adenocarcinoma was measured in terms of short circuit current. The three cell types were designated HCA‐7, Colony 3 and Colony 29.
Responses of HCA‐7 monolayers to basolaterally applied lysylbradykinin (LBK) (10–1000 nm) or carbachol (1–100 μm) were potentiated by pre‐exposure to forskolin (10 μm) for 5 min. Forskolin itself increased short circuit current (SCC), so that the total response to forskolin and LBK or carbachol were non‐additive.
Colony 3 cells did not respond to LBK on either face but did to carbachol on the basolateral side, while Colony 29 epithelia responded to LBK on both sides and to carbachol and histamine basolaterally. Unlike HCA‐7 epithelia, responses in Colony 3 and Colony 29 epithelia were not potentiated by forskolin, but were attenuated by piroxicam.
In the presence of piroxicam, both forskolin and prostaglandin E2 were able to potentiate the action of both LBK and carbachol in Colony 29 epithelia.
LBK receptor activation in Colony 29 epithelia is transduced into an increase in intracellular Ca2+ and cyclic AMP, while in HCA‐7 epithelia there is only an increase in intracellular Ca2+ (Cai). These conclusions are considered to apply to both apical and basolateral kinin receptors.
It is shown that forskolin has no effect on the elevation of Ca2+ by LBK in either HCA‐7 or Colony 29 cells.
It is concluded that potentiation of agonist responses occurs when cyclic AMP is raised at the time that intracellular Ca2+ increases. No potentiation of LBK or carbachol by forskolin occurs in Colony 29 monolayers as these agonists increase cyclic AMP via eicosanoid production.
Electropharmacological effects of berberine on canine cardiac Purkinje fibres and ventricular muscle and atrial muscle of the rabbit
Authors: Neto Francisco Riccioppo 
Published: July 2012

Conventional microelectrode techniques were used for intracellular recordings of the transmembrane electrical potentials, the effects of berberine were studied on canine cardiac Purkinje and ventricular muscle fibres and on rabbit atrial fibres.
Berberine (3–30 μm) increased in a concentration‐dependent manner, the action potential duration (APD) in canine Purkinje and ventricular muscle without affecting other parameters of the action potential.
The berberine‐induced enlargement of the APD showed reverse use‐dependence, so that the effect was greater at lower rates of stimulation.
Preparations perfused with berberine (30 μm) and driven at rates below 0.5 Hz exhibited early after depolarizations which persisted 3–4 h after washing.
The early afterdepolarizations were reversibly abolished by perfusion with lignocaine (3 μm) or by the increase in the rate of stimulation.
The effective refractory period (ERP) of Purkinje fibres was greatly increased by berberine (30 μm); however, the ratio ERP/APD was not significantly affected.
Berberine (10–100 μm) decreased in a concentration‐dependent manner the spontaneous frequency of rabbit sinoatrial cells. The decrease in frequency was accompanied by a depression of the phase 4 depolarization, without significant changes in other parameters of the nodal action potential.
Atropine (2.5 μm) did not affect the bradycardic effect of berberine. On the other hand, berberine (30 μm) did not alter the chronotropic effect of isoprenaline.
Berberine (30 μm) also increased the duration of slow responses in K‐depolarized rabbit atrial muscle fibres, other parameters being unaffected.
It is suggested that berberine exerts Class III antiarrhythimic and proarrhythmic actions in cardiac muscle of the dog in vitro.
Investigations into the mechanism of vasoconstrictor action of the topical steroid betamethasone‐17‐valerate in the rat
Authors: Ahluwalia A. , Flower R.J. 
Published: July 2012

The effect of topical betamethasone upon skin blood flow was investigated in the rat. Two types of vasodilator stimuli were used; local heating to the surface of the skin and intradermal application of inflammatory agents. Blood flow was measured by laser doppler velocimetry.
Topical betamethasone‐17‐valerate (1 g with an 18 h pretreatment) significantly inhibited the heat‐induced vasodilatation in the rat skin, as also did systemically administered betamethasone (1 mg kg−1, 3 h pretreatment).
Angiotensin converting enzyme (ACE) inhibitors (captopril, 5 mg kg−1 and enalapril, 1 mg kg−1, 30 min pretreatments) were the only drugs out of several different types of systemically administered inhibitors and antagonists that were tested which also inhibited the heat‐induced vasodilatation. Aprotinin (100,000 KIU kg−1, 5 min pretreatment) a serine protease inhibitor, significantly potentiated the heat‐induced response.
Bradykinin (50 nmol per site), des‐Arg9‐bradykinin (5 nmol per site), substance P (0.1 nmol per site) and capsaicin (1 μmol per site) induced an increase in skin blood flow.
Topical betamethasone treatment resulted in a significant inhibition of the vasodilator response to des‐Arg9‐bradykinin, whereas captopril treatment inhibited the responses to substance P, capsaicin, bradykinin and des‐Arg9‐bradykinin.
Intradermal application of captopril (10–100 μg) also caused a dose‐dependent inhibition of the heat‐induced vasodilatation.
These results suggest that topical betamethasone may be acting in a manner similar to that of the ACE inhibitors to produce an inhibition of the flow responses in the skin and that this effect may be brought about by interfering with the action of vasodilator peptide(s) or protein(s).
Incomplete inhibition of the pressor effects of endothelin‐1 and related peptides in the anaesthetized rat with BQ‐123 provides evidence for more than one vasoconstrictor receptor
Authors: McMurdo Lorraine , Corder Roger , Thiemermann Christoph , Vane John R. 
Published: July 2012

The effects of the ETA receptor antagonist, BQ‐123 on blood pressure changes induced by various members of the endothelin (ET)/sarafotoxin (SX) peptide superfamily were investigated in the anaesthetized rat.
ET‐1 (1 nmol kg−1, i.v. bolus) induced a sustained increase in mean arterial pressure (MAP, maximum increase 44 ± 3 mmHg). Intravenous injection of BQ‐123 at 0.2, 1.0 or 5.0 mg kg−1 5 min before ET‐1 inhibited the pressor response by 18, 50 and 61%, respectively. The ET‐1 pressor response was inhibited by 75% when the peptide was given 60 min after the start of a 120 min i.v. infusion of BQ‐123 (0.2 mg kg−1 min−1).
In addition to ET‐1, BQ‐123 (1 mg kg−1, i.v. bolus) attenuated the pressor responses to big ET‐1 (1 nmol kg−1, i.v., bolus, maximum increase in MAP: 68 ± 7 mmHg), ET‐3 (3 nmol kg−1, i.v., bolus, maximum response: 30 ± 3 mmHg), SX6b (1 nmol kg−1, i.v., bolus, maximum response: 41 ± 5 mmHg) and SX6c (1 nmol kg−1, i.v., bolus, maximum response: 24 ± 4 mmHg) by 65, 60, 88 and 50%, respectively.
With the exception of big ET‐1, all the peptides used in this study induced an initial transient depressor response (–32 ±3 mmHg, n = 18). Although BQ‐123 (1 mg kg−1, i.v., bolus) did not affect the absolute magnitude of the fall in MAP, the ETA receptor antagonist significantly prolonged the depressor responses induced by ET‐3 and SX6b.
Thus, BQ‐123 attenuates the pressor, but not the depressor effects of ET‐1, big ET‐1, ET‐3, SX6b and SX6c. Complete inhibition of the pressor responses could not be achieved, suggesting that a component of the pressor response is not mediated via the ETA receptor.
[Leu8]des‐Arg9‐bradykinin inhibits the angiogenic effect of bradykinin and interleukin‐1 in rats
Authors: Hu De‐En , Fan Tai‐Ping D. 
Published: July 2012

Subcutaneous implantation of sterile polyether sponges in rats elicited a reproducible neovascular response over 14 days, as determined by measurements of relative sponge blood flow by a 133Xe clearance technique. The angiogenic response was verified by quantitation of haemoglobin contents and histological evaluation of vascularized sponges.
Daily administration of 1 nmol of bradykinin (BK) into the implants significantly enhanced the basal sponge‐induced neovascularization, leading to higher 133Xe clearance values, increased haemoglobin contents, cellularity and vascularity.
When given alone, lower doses of BK (10 pmol) or recombinant human interleukin‐1 α (IL‐1α, 0.3 pmol) produced no apparent effects on the basal sponge‐induced angiogenesis. However, co‐administration of these two peptides produced an angiogenic response similar to that elicited by 1 nmol of BK.
The BK/IL‐1α‐induced neovascularization was abolished by the bradykinin B1 receptor antagonist, [Leu8]des‐Arg9‐BK (1 nmol day−1), but not by the B2 receptor antagonist Ac‐d‐Arg‐[Hyp3,d‐Phe7,Leu8]‐BK (1 nmol day−1).
Thus, if such interaction between BK and IL‐1α contributes to the excessive neovascularization in chronic inflammatory diseases, the blockade of B1 receptors may provide an effective treatment.
Role of cyclic AMP in promoting the thromboresistance of human endothelial cells by enhancing thrombomodulin and decreasing tissue factor activities
Authors: Archipoff Gisèle , Beretz Alain , Bartha Katalin , Brisson Christine , de la Salle Corinne , Froget‐Léon Catherine , Klein‐Soyer Claudine , Cazenave Jean‐Pierre 
Published: July 2012

The effects of forskolin, prostaglandin E1 (PGE1), dibutyryl cyclic AMP (db cyclic AMP), dibutyryl cyclic GMP (db cyclic GMP) and 3‐isobutyl‐1‐methyl‐xanthine (IBMX) were investigated on the expression of tissue factor and thrombomodulin activities on the surface of human saphenous vein endothelial cells (HSVEC) in culture.
Forskolin (10−6 to 10−4 m), PGE1 (10−7 to 10−5 m) and db cyclic AMP (10−4 to 10−3 m) caused a concentration‐dependent decrease of cytokine‐induced tissue factor activity.
Similar concentrations of forskolin, PGE1 and db cyclic AMP enhanced significantly constitutive thrombomodulin activity and reversed the decrease of this activity caused by interleukin‐1 (IL‐1).
IBMX (10−4 m) decreased tissue factor activity and enhanced the effect of forskolin on tissue factor and thrombomodulin activities.
Forskolin (10−4 m) decreased the IL‐1‐induced tissue factor mRNA and increased the thrombomodulin mRNA level. IL‐1 did not change the thrombomodulin mRNA level after 2 h of incubation with HSVEC in culture.
Dibutyryl cyclic GMP (10−4 m to 10−3 m) did not influence tissue factor or thrombomodulin activity.
Our data suggest that elevation of intracellular cyclic AMP levels may participate in the regulation of tissue factor and thrombomodulin expression, thus contributing to promote or restore antithrombotic properties of the endothelium.
Investigation of the subtypes of α1‐adrenoceptor mediating contractions of rat aorta, vas deferens and spleen
Authors: Aboud R. , Shafii M. , Docherty J.R. 
Published: July 2012

The subtypes of α1‐adrenoceptor mediating contractions to exogenous noradrenaline (NA) or phenylephrine in rat vas deferens, spleen and aorta, and mediating contractions to endogenous NA in rat vas deferens have been examined.
In rat vas deferens, the competitive antagonists prazosin, WB 4101, benoxathian and 5‐methyl‐urapidil inhibited contractions to NA with pA2 values of 9.26, 9.54, 9.02 and 8.43, respectively. The irreversible antagonist chloroethylclonidine (CEC) (100 μm) failed to affect contractions to NA.
In rat vas deferens in the presence of nifedipine (10 μm), contractions to NA were significantly attenuated and under these conditions, CEC (100 μm) significantly reduced the maximum response to NA.
In rat spleen, the competitive antagonists prazosin, WB 4101 and benoxathian inhibited contractions to phenylephrine with pA2 values of 9.56, 8.85 and 7.60, respectively, and 5‐methyl‐urapidil had a KB of 6.62. CEC (100 μm) significantly reduced the maximum contraction to phenylephrine.
In rat aorta, the competitive antagonists, prazosin, WB 4101, benoxathian and 5‐methyl‐urapidil inhibited contractions to NA with pA2 values of 9.45, 9.21, 8.55 and 8.12, respectively. CEC (100 μm) produced an approximately parallel shift in the potency of NA, without significantly reducing the maximum response.
In epididymal portions of rat vas deferens in the presence of nifedipine (10 μm), the isometric contraction to a single electrical pulse was significantly reduced by CEC (100 μm), and by the competitive antagonists prazosin, WB 4101, benoxathian and 5‐methyl‐urapidil at concentrations of 1 nm.
In prostatic portions of rat vas deferens, the α1‐adrenoceptor agonist, amidephrine, produced concentration‐dependent increases in the isometric contraction to a single electrical stimulus and the maximum increase in the evoked response produced by amidephrine was unaffected by CEC (100 μm).
Contractions of rat vas deferens produced by NA (and amidephrine) are mediated predominantly by α1A‐adrenoceptors as shown by the high potency of α1A‐adrenoceptor selective antagonists and the lack of effect of CEC. A small CEC‐sensitive response, particularly in epididymal portions, was revealed in the presence of nifedipine. Contractions of rat spleen are mediated by α1B‐adrenoceptors since α1A‐selective antagonists showed low potency and CEC significantly reduced the maximum contraction to phenylephrine. Contractions of rat aorta to NA are mediated by non‐α1A, non‐α1B‐adrenoceptors, due to the high potency of the α1A‐selective antagonists and sensitivity to CEC.
The noradrenergic contraction of epididymal portions of rat vas deferens in the presence of nifedipine is CEC‐sensitive, but the α1A‐selective antagonists showed high potency, suggesting that this response is mediated by non‐α1A, non‐α1B‐adrenoceptors.
In conclusion, at least three subtypes of functional α1‐adrenoceptors have been demonstrated in these studies.
Effects of pyrogenic immunomodulators on the release of corticotrophin‐releasing factor‐41 and prostaglandin E2 from the intact rat hypothalamus in vitro
Authors: Milton N.G.N. , Self C.H. , Hillhouse E.W. 
Published: July 2012

The actions of the following pyrogens: lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (Poly‐I:C), human interleukin (IL)‐1α and IL‐1β, human IL‐6 and rat interferon (INF) on corticotrophin‐releasing factor‐41 (CRF‐41) and prostanglandin E2 (PGE2) release from the intact rat hypothalamus in vitro have been studied.
Rat hypothalami were incubated in vitro in an artificial cerebrospinal fluid. Immunoreactive (ir)‐CFR‐41 and PGE2 released into the medium were measured by two‐site enzyme amplified immunometric assay (EAIA) and radioimmunoassay (RIA) respectively.
Human IL‐6 (1 to 10,000 iu ml−1) caused a dose‐dependent release of irCRF‐41, rising to a maximal 3–4 fold increase over basal at the highest dose tested. Human IL‐1α (1 to 1000 iu ml−1), human IL‐1β (1 to 1000 iu ml−1), poly‐I:C (10 pg ml−1 to 100 μg ml−1) and rat INF (1 to 10,000 IRu ml−1) all failed to alter irCRF‐41 release.
LPS (1 mg ml−1) caused a 35% decrease in irCRF‐41 release; however, over the dose‐range of 0.1 μg ml−1 to 100 μg ml−1, LPS failed to alter irCRF‐41 release. The decreased irCRF‐41 release in response to LPS (1 mg ml−1) was accompanied by a decrease in the subsequent 56 mm KCl stimulation of irCRF‐41.
Human IL‐1α and IL‐1β (1000 iu ml−1) were able to stimulate the release of irPGE2 from intact hypothalami, causing a 2 fold increase over basal release. Poly‐I:C (100 μg ml−1), LPS (0.1 μg ml−1 to 1 mg ml−1), rat INF (10,000 IRu ml−1) and human IL‐6 (1 to 10,000 iu ml−1) all failed to alter irPGE2 release.
In conclusion, these results suggest that the in vitro release of CRF‐41 and PGE2, in response to pyrogens, are mediated via different cytokines. In view of this it is possible that different cytokines may mediate the temperature, prostaglandin and hypothalamo‐pituitary‐adrenocortical axis activation seen during pyrogenic stimulation in vivo.
Effects of pH on the actions of dizocilpine at the N‐methyl‐D‐aspartate receptor complex
Authors: Rajdev Sunita , Reynolds Ian J. 
Published: July 2012

The effects of varying pH from 6.5 to 7.4 and 8.0 on the actions of dizocilpine (MK801) on the N‐methyl‐d‐aspartate (NMDA) receptor were investigated by use of a [3H]‐dizocilpine binding assay and NMDA‐induced intracellular free Ca2+ ([Ca2+]i) increases in cultured forebrain neurones.
Increasing pH from 6.5 to 8.0 significantly increased the rate of association and dissociation of [3H]‐dizocilpine. The association process was better described by two rate constants under each condition, while only dissociation of [3H]‐dizocilpine at pH 8.0 required two rate constants adequately to describe the curve. Equilibrium affinity of [3H]‐dizocilpine was not altered by changing pH from 6.5 to 8.0.
NMDA and glycine together increased [Ca2+]i measured by fura‐2 microspectrofluorimetry in single cultured neurones from rat forebrain. Compared to control response measured at pH 7.4, the combined effects of NMDA and glycine were reduced to 38.9% of control values by lowering pH to 6.5 and increased to 148.9% by raising pH to 8.0.
Dizocilpine (200 nm) effectively reversed increases in [Ca2+]i produced by NMDA together with glycine. The rate of reversal produced by this concentration of dizocilpine was considerably slower than that required for cells to recover to baseline following agonist removal. The rate at which dizocilpine reversed NMDA‐ and glycine‐induced [Ca2+]i increases was not altered by raising pH from 6.5 to 8.0.
These data support the hypothesis that the rates associated with [3H]‐dizocilpine binding are controlled by the level of activation of the receptor. In addition, these data confirm previous findings that NMDA responses are sensitive to small changes in pH. However, the lack of sensitivity to pH changes of dizocilpine inhibition of NMDA responses show that other factors are also important in controlling the action of channel‐blocking NMDA receptor antagonists.
The action of amlodipine on voltage‐operated calcium channels in vascular smooth muscle
Authors: Hughes A.D. , Wijetunge S. 
Published: July 2012

Amlodipine, a dihydropyridine derivative largely ionized at physiological pH, inhibited calcium channel currents in single vascular smooth muscle cells isolated from rabbit ear artery in a concentration‐dependent manner.
Amlodipine inhibited the current‐voltage relationship for calcium channel currents across the range of test potentials used. However, the effect of amlodipine was more marked on more depolarized test potentials. Amlodipine also shifted the steady‐state inactivation curve for calcium channel currents in a hyperpolarized direction.
The potency of amlodipine as determined from the steady‐state inhibition of calcium channel current induced by the drug was dependent on the holding potential of the cells. Use of a more depolarized holding potential increased the potency of amlodipine.
Onset of amlodipine‐induced inhibition was relatively rapid at both −60 mV and −40 mV holding potential. The use of a more depolarized holding potential increased the rate of association of amlodipine. No recovery from amlodipine‐induced inhibition was seen over a 20 min period following washout of the drug.
In addition to voltage‐dependence, the action of amlodipine showed use‐dependence, in that the effect of amlodipine was more marked when calcium channel currents were evoked frequently. Increasing the frequency of activation of calcium channel currents did not alter the apparent onset rate of amlodipine‐induced inhibition, but increased the degree of inhibition achieved by the drug.
The electrophysiological properties of amlodipine, particularly its voltage‐dependence are probably important determinants of its action in vivo.