bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of the Na+/K+‐pump in rat peritoneal mast cells following histamine release: a possible role in cell recovery
Authors: Knudsen T. , Ferjan I. , Johansen T. 
Published: July 2012

The activity of the Na+/K+‐pump in rat peritoneal mast cells was measured at various time intervals after induction of cellular histamine release by compound 48/80 or by the antigen‐antibody reaction. The Na+/K+‐pump activity was assessed as the ouabain‐sensitive potassium uptake of the cells using 86Rb+ as a tracer for potassium (K+(86Rb+)‐uptake).
Stimulation of the cells with compound 48/80 induced a time and concentration dependent increase of the Na+/K+‐pump activity. The pump activity was maximal 2 min after stimulation of the cells. Then, the activity gradually decreased and reached a level not significantly different from the controls after 2 h of incubation.
When the cells were stimulated by the antigen‐antibody reaction, there was also a rapid (within 5 min) stimulation of the Na+/K+‐pump. In contrast to the stimulation with compound 48/80, the pump activity returned to the control level after 60 min of incubation with antigen.
The ouabain‐resistant potassium uptake of the cells was increased after stimulation of the cells, regardless of the secretagogue used. This probably reflects the increased surface area of the cells present after the histamine release.
On the basis of the present results, we suggest a role for the Na+/K+‐pump in the recovery process of the mast cell following histamine release.
Influences of the endothelium and hypoxia on α1‐ and α2‐adrenoceptor‐mediated responses in the rabbit isolated pulmonary artery
Authors: MacLean Margaret R. , McCulloch K.M. , McGrath J.C. 
Published: July 2012

The effects of the inhibitor of nitric oxide synthase, Nω‐nitro‐l‐arginine methylester (l‐NAME, 10−4 m), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (α1‐ and α2‐adrenoceptor agonist), phenylephrine (α1‐adrenoceptor agonist) and UK 14304 (α2‐adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10−6 m, α2‐adrenoceptors) and prazosin (10−7 m, α1‐adrenoceptors) on the contractions to noradrenaline before and after exposure to l‐NAME were also assessed.
Noradrenaline, phenylephrine and UK 14304 all produced concentration‐dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). l‐NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After l‐NAME, contractions to noradrenaline, although still sensitivie to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine.
Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304.
Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304.
In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by l‐NAME involves a potentiation of α2‐adrenoceptor‐mediated contraction probably through an effect on the synthesis of endothelium‐derived nitric oxide. Experimental hypoxia had differential effects on all three agonists and did not mimic the effect of nitric oxide synthase inhibition.
Lack of effect of sumatriptan and UK‐14,304 on capsaicin‐induced relaxation of guinea‐pig isolated basilar artery
Authors: O'Shaughnessy C.T. , Waldron G.J. , Connor H.E. 
Published: July 2012

The objectives of this study were to assess the effects of sensory neuropeptide antagonists and presynaptically acting receptor agonists on capsaicin‐induced relaxations of guinea‐pig isolated basilar artery (GPBA).
Capsaicin, human α‐calcitonin gene‐related peptide (CGRP) and substance P (SP) caused concentration‐related relaxations of GPBA which had been pre‐contracted with prostaglandin F2α (PGF2α). Responses to capsaicin were not modified by the peptidase inhibitors, phosphoramidon (1 μm) and bestatin (100 μm).
The relaxant responses to capsaicin were blocked in a selective manner by ruthenium red (3 μm) and by the CGRP antagonist, CGRP8_37 (1 μm). CGRP8_37 also selectively inhibited the relaxant effects of CGRP.
The selective NK1 receptor antagonist, GR82334 (10 μm), inhibited SP‐induced relaxations but had little effect on capsaicin‐induced relaxations.
The 5‐HT1 receptor agonist, sumatriptan, produced small contractions of GPBA under conditions of resting tone. In the presence of PGF2α, sumatriptan had no further contractile effect. Sumatriptan (0.3 and 3 μm) did not modify capsaicin‐induced relaxations of GPBA.
The α2‐adrenoceptor agonist, UK‐14,304 (0.1 μm), had no effect on basal or PGF2α‐induced tone. UK‐14,304 did not modify capsaicin‐induced relaxations.
These results suggest that capsaicin causes relaxation of GPBA via a release of CGRP. This process is amenable to blockade by CGRP8–37 and ruthenium red, but not to modulation by either sumatriptan or UK‐14,304.
Effects of hyperkalaemia on the depression of maximum rate of depolarization by class I antiarrhythmic agents in guinea‐pig myocardium
Authors: Wyse Kenneth R. , Ye Victor , Campbell Terence J. 
Published: July 2012

Standard microeletrode methods were used to record intracellular action potentials from strips of guinea‐pig right ventricular myocardium superfused with either standard physiological saline ([K+] = 5.6 mm) or the same solution modified to contain [K+] = 11.2 mm.
The effects on action potential parameters of three therapeutic concentrations of mexiletine, quinidine and disopyramide were studied under both conditions at four different drive rates (interstimulus intervals = 2400, 1200, 600 and 300 ms).
Hyperkalaemia in the absence of drugs produced reductions in resting potential (−86.7 ± 2.5 mV to −71.8 ± 3.7 mV; n = 30; P < 0.001), maximum rate of depolarization (300 ± 46.5 Vs−1 to 205.6 ± 37.6 Vs−1; P < 0.0001), and action potential duration (205 ± 26 ms to 188 ± 32 ms; P < 0.05).
All three drugs produced increased depression of maximum rate of depolarization in hyperkalaemia compared to control conditions, but at all three concentrations this enhancement of effect was greater for mexiletine than for quinidine, with disopyramide exhibiting intermediate behaviour.
Mexiletine behaved very similarly to therapeutic concentrations of lignocaine as described in previous reports from this laboratory.
Quinidine behaved very similarly to Class Ic agents.
It is concluded that mexiletine demonstrated significantly greater selectivity for depolarized myocardium than quinidine and that this may have implications in terms of proarrhythmic potential.
Disopyramide exhibited intermediate selectivity for depolarized myocardium between mexiletine and quinidine.
Evidence for an external location of the dihydropyridine agonist receptor site on smooth muscle and skeletal muscle calcium channels
Authors: Strübing C. , Hering S. , Glossmann H. 
Published: July 2012

The location of the binding domain for agonist dihydropyridines (DHP) has been studied by comparing the action of (+)‐202 791 and (−)‐Bay K 8644 on Ba2+ currents (IBa) in whole cell patch clamp experiments. Drug effects were examined upon internal and external (extracellular) application in A7r5 smooth muscle cells and BC3H1 cells, a cell line expressing Ca channels of the skeletal muscle type.
Efficiency of internal drug application in the whole cell studies was demonstrated by inhibition of potassium currents and barium currents (IBa) upon internal perfusion with tetraethylammonium (TEA+) (10 mm) and the permanently charged phenylalkylamine, D 890 (100 μm) respectively. The uncharged DHP, (−)‐STBODIPY‐DHP (2 μm) was used to estimate the time course of internal perfusion by monitoring its fluorescence.
Intracellular application of (+)‐202 791 and (−)‐Bay K 8644 (5 μm) in patch clamp experiments was ineffective in stimulating Ca2+ channel currents in both cell lines. In contrast a 50 fold lower agonist concentration (0.1 μm (−)‐Bay K8644) applied to the external face of the membrane induced typical changes in tail currents and a current increase under conditions when up to 10 μm of the agonist was present in the intracellular perfusion solution.
In cell‐attached patches in A7r5 cells, (−)‐Bay K 8644 increased and (+)‐PN 200 110 inhibited single channel activity when applied via the bath solution. This suggests partitioning and lateral diffusion of the DHPs in the lipid of the plasma membrane.
We conclude that the binding site for agonist DHPs on Ca2+ channels in A7r5 and BC3H1 cells is located close to the external surface of the membrane. The DHP binding domain can be reached by agonists and antagonists from the extracellular but not from the intracellular face of the membrane.
The effects of Nω‐nitro‐L‐arginine methyl ester, sodium nitroprusside and noradrenaline on venous return in the anaesthetized cat
Authors: Bower E.A. , Law A.C.K. 
Published: July 2012

The vascular actions of Nω‐nitro‐l‐arginine methyl ester (l‐NAME), sodium nitroprusside and noradrenaline were investigated in cats under chloralose anaesthesia with controlled vascular tone and ventilation. Cardiac output, heart rate, vascular pressures and mean circulatory filling pressure (MCFP) were measured. Total peripheral resistance (TPR) and resistance to venous return (Rvr) were calculated from steady‐state readings.
l‐NAME (37 μmol kg−1, i.v.) administered to ten cats receiving noradrenaline (6 nmol kg−1 min−1, i.v.) increased aortic pressure by 47.5 ± 7.1 mmHg from 106 mmHg, and MCFP by 1.56 ± 0.36 mmHg from 10.0 mmHg (means ± s.e.means). Mean changes in portal venous pressure, RAP and heart rate were not significant. Cardiac output fell by 29.7 ± 3.3% from 130 ml min−1 kg−1. TPR rose by 108 ± 7.2% from 796 mmHg l−1 min kg and Rvr by 58.4 ± 4.5% from 64 mmHg l−1 min kg.
Infusion of sodium nitroprusside into cats receiving noradrenaline evoked dose‐related falls in aortic pressure, MCFP, TPR and Rvr. Changes in portal venous pressure, RAP and heart rate were not significant, and cardiac output fell slightly. After l‐NAME, sensitivity to nitroprusside was increased by 139 ± 34% for MCFP, 176 ± 19% for TPR and 351 ± 39% for Rvr, and cardiac output rose slightly. The nitroprusside infusion required to restore TPR after l‐NAME was estimated to be 5.8 × 10±0.41 nmol kg−1 min−1, which was approximately three times more than that required to restore MCFP.
Infusion of noradrenaline evoked dose‐related increases in aortic and portal venous pressures, heart rate, cardiac output, MCFP, TPR and Rvr. After l‐NAME and nitroprusside (4.4 nmol kg−1 min−1, i.v.), TPR and Rvr were not significantly different, but MCFP was reduced by 1.76 ± 0.24 mmHg, and cardiac output by 22 ± 1.9%. After subsequent expansion of the circulating blood volume (5–7.5 ml kg−1 dextran‐saline), mean values for all parameters were restored to their previous levels. Sensitivity to noradrenaline was not significantly altered for heart rate, TPR and Rvr, but was reduced by 31.8 ± 12% for MCFP and by 66.5 ± 18% for cardiac output.
The depression of cardiac output by l‐NAME is attributed to the increase in Rvr, partly compensated by the rise in MCFP. For a given rise in MCFP, the increase in Rvr was seven times greater after l‐NAME than after noradrenaline, and the difference in the relative actions of the two drugs on resistance and capacitance vessels largely accounts for their contrasting effects on venous return. A procedure is suggested for replacement of vascular nitric oxide by nitroprusside infusion and blood volume expansion.
Relaxing actions of corticotropin‐releasing factor on rat resistance arteries
Authors: Lei S. , Richter R. , Bienert M. , Mulvany M.J. 
Published: July 2012

Although it well established that corticotropin‐releasing factor (CRF) injected i.v. can cause hypotension and vasodilatation, there is no in vitro evidence that CRF acts as a vasodilator. We have therefore tested the hypothesis that the hypotensive effect of i.v. CRF is due to a direct vasodilator action by carrying out experiments in vitro on rat resistance arteries (i.d. 150–300 μm).
Initial in vivo experiments confirmed that CRF (1.5 nmol kg−1) injected i.v. caused hypotension in rats, this being partially antagonized by the CRF analogue CRF9–41.
For the in vitro experiments, vessels were taken from the mesenteric, cerebral and femoral vascular beds, and mounted as ring preparations in an isometric myograph. The vessels were pre‐contracted with one of 3 agonists (prostaglandin F2α, arginine vasopressin or noradrenaline) or with a high‐potassium solution (K+).
With maximal concentrations of the agonists, CRF caused relaxation of mesenteric and cerebral vessels with 10 nm, and near complete relaxation with 100 nm. Femoral vessels preconstricted with agonists and all vessels preconstricted with K+ were less affected by CRF. In the mesenteric vessels, with sub‐maximal levels of pre‐constriction, CRF caused substantial relaxation at 1 nm and could cause complete relaxation at 10 nm.
The relaxant effect of CRF on contractions of mesenteric vessels was antagonized by 100 nm CRF9–41. Neither tetraethyl ammonium (30 mm) nor glibenclamide (3 μm) antagonized the relaxant effect of CRF.
The relaxant effect of CRF on mesenteric small arteries was found to be unaffected by removal of the endothelium.
The results indicate that CRF causes an endothelial‐independent vasodilatation of rat resistance arteries under in vitro conditions at concentrations which are consistent with this being an important cause of the hypotension observed with i.v. injection of CRF.
Characterization of the inhibitory prostanoid receptors on human neutrophils
Authors: Wheeldon Alan , Vardey Christopher J. 
Published: July 2012

We have evaluated the effects of various prostanoid agonists on the release of leukotriene B4 (LTB4) and superoxide anions (O2−) from human neutrophils stimulated with opsonized zymosan (OZ) and formyl‐methionyl‐leucyl‐phenylalanine (FMLP), respectively.
Prostaglandin E2 (PGE2) and PGD2 inhibited both OZ‐induced LTB4 release (EC50 0.72 μm and 0.91 μm respectively), and FMLP‐induced O2− release (EC50 0.42 μm and 0.50 μm respectively). PGF2α, the TP‐receptor agonist, U46619, and the IP‐receptor agonist, iloprost, were also active, but were all at least an order of magnitude less potent than PGE2 and PGD2.
The EP2/EP3‐receptor agonist, misoprostol, and the selective EP2‐agonist, AH13205, were both effective inhibitors of LTB4 release, being approximately equipotent with and 16‐times less potent than PGE2, respectively. In contrast, the EP1/EP3‐receptor agonist, sulprostone, had no inhibitory activity at concentrations of up to 10 μm.
The selective DP‐receptor agonist, BW245C, inhibited LTB4 release, (EC50 0.006 μm) being approximately 50 times more potent than PGD2. BW245C also inhibited O2− release, and this inhibition was antagonized competitively by the DP‐receptor blocking drug, AH6809 (pA2 6.6).
These data indicate the presence of both inhibitory EP‐ and DP‐receptors on the human neutrophil. The rank order of potency of EP‐receptor agonists suggest that the EP‐receptors are of the EP2‐subtype.;
Single channel and whole‐cell K‐currents evoked by levcromakalim in smooth muscle cells from the rabbit portal vein
Authors: Beech D.J. , Zhang H. , Nakao K. , Bolton T.B. 
Published: July 2012

Single channel and whole‐cell current recordings were made from single smooth muscle cells isolated from the rabbit portal vein.
Application of 10 μm levcromakalim ((−)‐Ckm) to single cells held with pipettes containing 1 mm GDP induced a K‐current (IK(Ckm)) which occurred in addition to the current caused by GDP alone (IK(GDP)) and averaged 135 pA at − 37 mV. We have investigated whether the same K channels underlie the GDP‐ and Ckm‐induced K‐currents.
If 1 mm GDP was in the pipette but Mg ions were omitted the effect of GDP was absent and IK(Ckm) averaged only 10 pA, suggesting that the action of (−)‐Ckm was Mg‐dependent.
Intracellular ATP was not observed to have much effect on IK(‐Ckm). Loading of cells with 10 mm ATP from the recording pipette had no significant effect and flash photolysis of caged‐ATP loaded into cells from the pipette, estimated to release about 1 mm free ATP, also had no effect on IK(‐Ckm).
Bath‐applied glibenclamide inhibited IK(‐Ckm) with an IC50 of 200 nm, a value 8 times higher than that found for inhibition of IK(GDP). The delayed rectifier K‐current (IK(DR)) was also inhibited by glibenclamide but at higher concentrations (IC50 100 μm). Bath‐applied tetraethylammonium ions (TEA) inhibited IK(‐Ckm) and IK(GDP) to the same extent (IC50 about 7 mm).
In inside‐out patch recordings (−)‐Ckm (10 μm) applied to the intracellular surface of the membrane potentiated the opening of K channels already stimulated by 1 mm GDP and all of the channel activity was abolished by 10 μm glibenclamide. The unitary conductance of the channels was 24 pS in a 60 mm: 130 mm K‐gradient.
We suggest that (−)‐Ckm may hyperpolarize and relax smooth muscle cells by opening KNDP, a class of small conductance K channels that are related to the ATP‐sensitive K channels seen in other tissues.
Effect of capsazepine on the release of calcitonin gene‐related peptide‐like immunoreactivity (CGRP‐LI) induced by low pH, capsaicin and potassium in rat soleus muscle
Authors: Santicioli Paolo , Del Bianco Elena , Figini Michela , Bevan Stuart , Maggi Carlo Alberto 
Published: July 2012

We have determined the effect of the competitive antagonist capsazepine at the capsaicin receptor on the release of calcitonin gene‐related peptide‐like immunoreactivity (CGRP‐LI) from rat isolated soleus muscle induced by capsaicin (1 μm), by superfusion with low pH medium (pH 5) or by KCl (80 mm).
Each one of the three stimuli tested produced a marked CGRP‐LI release. Total evoked release (fmol g−1) was 482 ± 69, 169 ± 20 and 253 ± 43 for capsaicin, low pH medium and KCl, respectively.
Prior application of capsaicin (10 μm for 30 min followed by 30 min of washout) to produce capsaicin desensitization in vitro abolished CGRP‐LI release induced by the three stimuli.
Capsazepine (1–100 μm, 45 min preincubation) inhibited the evoked CGRP‐LI release. Capsaicin‐induced release was significantly inhibited by 77, 92 and 96% with 10, 30 and 100 μm capsazepine, respectively. Low pH‐induced release was inhibited by 78, 84, 88 and 93% with 3, 10, 30 and 100 μm capsazepine, respectively. KCl‐induced release was significantly inhibited by 55 and 93% with 30 and 100 μm (but not with 10 μm) capsazepine, respectively.
These findings demonstrate that capsazepine prevents low pH‐ and capsaicin‐induced CGRP‐LI release from rat soleus muscle at concentrations which do not affect the release evoked by KCl. These findings imply a relationship between the action of low pH and activation of the capsaicin receptor. At high concentrations, capsazepine produces a nonspecific inhibitory effect on CGRP‐LI release from peripheral endings of the capsaicin‐sensitive primary afferent neurone.
Comparison of the anti‐inflammatory properties of formoterol, salbutamol and salmeterol in guinea‐pig skin and lung
Authors: Whelan C.J. , Johnson M. , Vardey C.J. 
Published: July 2012

We have compared some anti‐inflammatory properties of formoterol, salbutamol and salmeterol in guinea‐pig skin and lung.
Intradermal formoterol (1 × 10−10 to 1 × 10−8 mol/site), salbutamol (1 × 10−8 and 1 × 10−7 mol/site) and salmeterol (1 × 10−8 and 1 × 10−7 mol/site) inhibited bradykinin‐induced plasma protein extravasation (PPE) in guinea‐pig skin. A maximally effective dose of formoterol (1 × 10−9 mol/site) and salbutamol (1 × 10−8 mol/site) inhibited PPE in guinea‐pig skin for 2–4 h and 1–2 h respectively, whereas salmeterol (1 × 10−8 mol/site) was effective for >6 h.
Inhaled formoterol (nebuliser concentration 0.1 to 100 μg ml−1) inhibited histamine‐induced plasma protein extravasation (PPE) in guinea‐pig lung, with significant inhibition being observed at 10 and 100 μg ml−1. Formoterol (100 μg ml−1) inhibited PPE in guinea‐pig lung for 2–4 h, a duration of action intermediate between that previously obtained for salbutamol (1 h) and salmeterol (>6 h).
Formoterol, like salbutamol, had no effect on neutrophil accumulation or granulocyte‐dependent PPE (zymosan‐induced) in guinea‐pig skin. Formoterol inhibited neutrophil accumulation (lipopolysaccharide‐induced) in guinea‐pig lung but at doses greater than those required to inhibit granulocyte‐independent PPE (histamine‐induced). In contrast, salmeterol inhibited neutrophil accumulation and granulocyte‐dependent PPE in guinea‐pig skin and inhibited neutrophil accumulation in guinea‐pig lung at doses which inhibit granulocyte‐independent PPE.
Inhaled formoterol (nebuliser concentration 100 μg ml−1) and salmeterol (100 μg ml−1) both inhibited PAF‐induced eosinophil accumulation in guinea‐pig lung. However, unlike salmeterol, this effect of formoterol was observed only at suprabronchodilator doses.
We conclude that to inhibit neutrophil accumulation, at doses which inhibit granulocyte‐independent PPE, agonists acting at β‐adrenoceptors on vascular endothelium require a duration of action greater than that of salbutamol and formoterol. However, we speculate that the mechanism of inhibition of eosinophil accumulation in guinea‐pig lung by β2‐adrenoceptor agonists may involve an action on β2‐adrenoceptors on a cell type other than the endothelial cell.
Partial agonist effect of the platelet‐activating factor receptor antagonists, WEB 2086 and WEB 2170, in the rat perfused heart
Authors: Hu Weimin , McNicholl Ila K. , Choy Patrick C. , Man Ricky Y.K. 
Published: July 2012

WEB 2086 and WEB 2170 are potent platelet‐activating factor (PAF) receptor antagonists and have been used widely as pharmacological tools to investigate the actions of PAF in a variety of biological systems.
Low concentrations of WEB 2086 and WEB 2170 blocked the vasoconstrictor action of PAF in the rat perfused heart. In this study, we observed that moderate concentrations of WEB 2086 and WEB 2170 increased the perfusion pressure in rat isolated hearts under constant flow perfusion. The vasoconstrictor actions of WEB 2086 and WEB 2170 were not observed with a structurally different PAF receptor antagonist, FR‐900452.
To determine whether this vasoconstrictor action of WEB 2086 involved non‐specific effects or was via the activation of PAF receptors, hearts were pretreated with 1000 pmol PAF or 50 μm FR‐900452. These pretreatments attenuated the vasoconstrictor action of 1 μm WEB 2086, suggesting that the action of WEB 2086 may be mediated via PAF receptors. Pretreatment with the leukotriene receptor antagonist (L‐649,923, 5 μm) and the leukotriene synthesis inhibitor (MK‐886, 10 μm) that are known to block the vasoconstrictor action of PAF receptor activation also attenuated the vasoconstrictor action of WEB 2086. Pretreatment with PAF or MK‐886 attenuated the vasoconstrictor action of 0.5 μm WEB 2170.
When PAF receptors were activated by PAF in the perfused heart, significant amounts of leukotriene C4 and leukotriene C4/D4/E4 were detected in the coronary effluent. However, no significant amount of these leukotrienes was detected in the coronary effluent when hearts were perfused with 1 μm WEB 2086 or 0.5 μm WEB 2170.
In summary, our results indicate that WEB 2086 and WEB 2170 possess partial agonist effects in the rat perfused heart where they produced vasoconstriction via the activation of PAF receptor. This action could be attenuated by PAF pretreatment or a PAF receptor antagonist. The vasoconstrictor action of WEB 2086 and WEB 2170 involved the production of leukotrienes. But unlike the vasoconstrictor action of PAF, no significant amount of leukotrienes was detected in the effluent suggesting that the vasoconstrictor action of WEB 2086 and WEB 2170 may be explained on the basis of intracellularly or locally produced leukotrienes.