bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dibromosulphophthalein: its pharmacokinetics and binding to hepatic cytosol proteins in rats with acute renal failure
Authors: Silberstein D.J. , Bowmer C.J. , Yates M.S. 
Published: July 2012

The pharmacokinetics, biliary excretion and binding of dibromosulphophthalein (DBSP) to plasma proteins and hepatic cytosol proteins have been studied in male rats with glycerol‐induced acute renal failure (ARF).
The rate constants for hepatic uptake, efflux from liver to plasma and excretion into bile were all significantly decreased in rats with ARF. Furthermore, the plasma clearance of DBSP was also reduced.
The initial (0–10 min) and maximum biliary excretion rates of DBSP were both diminished in animals with ARF. The maximum excretion rate occurred between 5–10 min in control rats and 10–15 min in rats with ARF. However, there was no statistically significant change in the percentage dose recovered from bile after 30 min.
The plasma‐protein binding of DBSP was decreased in rats with ARF and this change was due to a significant reduction in the association constant for the primary binding sites.
The binding of DBSP to ligandin (Y protein) was reduced by about 38% in rats with ARF but no change was noted in binding to Z protein. Reduced binding to ligandin was accompanied by decreased total liver glutathione S‐transferase (GST) activity and a 36% reduction in the GST activity of ligandin.
The results support the contention that altered hepatic handling of cholephilic dyes in rats with ARF may be due to reduced binding to ligandin.
Vasodilator actions of acetylcholine, A23187 and bradykinin in the guinea‐pig isolated perfused heart are independent of prostacyclin
Authors: Stewart Alastair G. , Piper Priscilla J. 
Published: July 2012

The involvement of prostacyclin (PGI2) in the vasodilator responses to acetylcholine (ACh), A23187 and bradykinin (Bk) has been investigated in guinea‐pig, isolated, Krebs‐perfused hearts.
ACh (0.01–10 nmol), A23187 (0.1–1.0 nmol) and Bk (0.3–10 pmol) each elicited dose‐related and shortlasting (∼2 min) reductions in perfusion pressure. Larger maximal responses were obtained in preparations with coronary vascular tone elevated by platelet‐activating factor (100 pmol) than in preparations at basal perfusion pressure.
Bk and A23187 elicited dose‐related increases in the generation of PGI2 as measured by its chemically‐stable breakdown product, 6‐oxo‐PGF1α. Indomethacin (2.8 μm) prevented both basal and the stimulated generation of 6‐oxo‐PGF1α, whereas the magnitudes of the vasodilator responses were unaffected.
Attempts to identify the release of vasodilator materials by on‐line superfusion bioassay of cardiac effluent were unsuccessful, indicating a possible role for a labile vasodilator such as endothelium‐dependent relaxing factor (EDRF). In addition, the inhibitors of EDRF action/production, mepacrine (3 μm) or diethylcarbamazine (300 μm), attenuated vasodilator responses to ACh without altering those to the endothelium‐independent vasodilator, verapamil (1 nmol).
Haemoglobin (10 μm) reduced vasodilator responses to ACh, Bk and verapamil and abolished those induced by A23187. Inhibition of the endothelium‐independent vasodilator, verapamil, was significantly less than that for the other compounds.
The present data indicate the existence of an indomethacin‐resistant vasodilator mechanism in the coronary microcirculation in response to ACh, A23187 and Bk. EDRF is a candidate for mediating these responses; however, a direct vasodilator action of these substances cannot be excluded.
Opioid modulation of non‐cholinergic neural bronchoconstriction in guinea‐pig in vivo
Authors: Belvisi M.G. , Chung K.F. , Jackson D.M. , Barnes P.J. 
Published: July 2012

Opioid receptors have been demonstrated on sensory fibres in the vagus nerve. Non‐cholinergic (NC) neural bronchoconstriction in guinea‐pig is due to release of neuropeptides from sensory nerve endings. We have therefore studied the effect of opioids on this NC bronchoconstriction in the anaesthetized guinea‐pig.
Bilateral vagal stimulation (5 V, 5 ms, 10 Hz) caused reproducible bronchoconstriction in guinea‐pigs which was reduced by atropine (1 mg kg−1), but the NC component was unaffected by hexamethonium (10 mg kg−1).
NC bronchoconstriction was reduced by morphine in a dose‐dependent manner (ED50 = 132 μg kg−1 with a maximal inhibition of 79 ± 2.1% at 1 mg kg−1). Yohimbine (0.5 mg kg−1) did not alter the inhibitory effect of morphine (1 mg kg−1).
The inhibitory effect of morphine was completely reversed by naloxone (1 mg kg−1) which had no effect on NC bronchoconstriction. Propranolol (1 mg kg−1) significantly increased the NC bronchoconstrictor response but did not significantly alter the inhibition by morphine.
The selective μ‐opioid receptor agonist Tyr‐(d‐Ala)‐Gly‐(N‐Me‐Phe)‐Glyol (DAGOL) was significantly more potent than morphine with an ED50 of 5.4 μg kg−1 and complete inhibition at 100 μg kg−1. The δ‐agonist Tyr‐(d‐Pen)‐Gly‐Phe‐(d‐Pen) (DPDPE) was less potent than DAGOL with an ED50 of 28 μg kg−1 and a maximal inhibition of only 50 ± 5% at 100 μg kg−1. The κ‐receptor agonist, U‐50,488H had no inhibitory effect on the NC bronchoconstrictor response.
The bronchoconstrictor responses to exogenous substance P (25 μg kg−1) or acetylcholine (25 μg kg−1) were unaffected by morphine (500 μg kg−1).
We conclude that opioids inhibit the NC bronchoconstrictor response to vagal stimulation via an action on μ‐opioid receptors localized to sensory nerve endings in the airway.
Inhibition of field stimulation‐evoked relaxations in rat oesophageal smooth muscle by the calcium antagonist PN 200–110
Authors: Akbarali H.I. , Bieger D. , Triggle C.R. 
Published: July 2012

The inhibitory effects of the 1,4‐dihydropyridine calcium channel antagonist, PN 200–110 (isradipine), on field stimulation‐evoked tetrodotoxin (TTX)‐sensitive and‐insensitive relaxations were studied in rat oesophageal smooth muscle of the tunica muscularis mucosae.
The TTX‐insensitive relaxation was inhibited by PN 200–110 in a stereoselective manner with the (+)−(S)‐isomer displaying a 1000 fold greater inhibitory potency than the (—)−(R) isomer. A similar potency was noted for inhibition of high K+‐evoked contractions.
TTX‐sensitive relaxations evoked by field stimulation and contractions elicited by the muscarinic cholinoceptor agonist, cis‐2‐methyl‐4‐dimethylamino‐methyl‐1,3‐dioxolane methiodide (cis‐dioxolane) were considerably less sensitive to inhibition by PN 200–110, although, again, stereoselectivity for PN 200–110 was apparent.
Pretreatment with (+)−(S)‐PN 200–110 resulted in a non‐competitive displacement of the Ca2+ concentration‐response curves obtained in the presence of either isotonic 50 mm KCl or cis‐dioxolane. The effect of K+ was 10 fold more sensitive than that of cis‐dioxolane.
The potency rank orders for inhibition of TTX‐insensitive field stimulation‐evoked relaxations and K+‐mediated contractions in a series of calcium channel antagonists were closely correlated; (+)−(S)‐PN 200–110 showing highest potency followed by nifedipine, verapamil, diltiazem, (—)−(R)‐PN 200–110.
It is concluded that TTX‐insensitive relaxations are dependent upon an influx of extracellular Ca2+ through potential‐operated calcium channels.
Similarity of relaxations evoked by BRL 34915, pinacidil and field‐stimulation in rat oesophageal tunica muscularis mucosae
Authors: Akbarali H.I. , Bieger D. , Ohia S.E. , Triggle C.R. 
Published: July 2012

In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 and pinacidil, raised the threshold for concentration‐dependent K+ contractions, suppressed contractions evoked by field stimulation of the TMM in the presence of tetrodotoxin (TTX) and tetraethylammonium (TEA), and relaxed tonic contractions resulting from muscarinic cholinoceptor stimulation.
BRL 34915 and both (+)− and (−)‐pinacidil increased 86Rb efflux from tracer‐loaded tissues; nifedipine abolished this effect.
Relaxations produced by potassium channel openers were inhibited by a temperature drop from 37°C to 26.5°C, an increase in extracellular K+ concentration to 64 mm, and treatment with the calcium channel antagonist, nifedipine. The same treatments also blocked field stimulation‐evoked TTX‐insensitive relaxations.
It is concluded that field stimulation of rat oesophageal smooth muscle in the presence of cholinoceptor‐induced tone results in an increase in K+ permeability that is directly or indirectly coupled to Ca2+ influx through potential‐operated channels.
Effects of Ca2+ on the transient outward current of single isolated Helix central neurones
Authors: Tsuda Y. , Oyama Y. , Carpenter D.O. , Akaike N. 
Published: July 2012

Single Helix neurones were studied under voltage‐clamp conditions with internal perfusion in order to examine the contribution of internal and external Ca2+ and the effects of 4‐aminopyridine (4‐AP) on the transient outward current (IA).
In Na+‐free snail Ringer, replacement of external Ca2+ ([Ca2+]o) with equimolar Co2+ reduced the maximum amplitude of IA and induced a shift of the steady‐state part of the IA inactivation curve (I‐V curve), in a positive direction along the voltage axis when the neurone was internally perfused with K‐aspartate.
In Ca2+‐free solutions, precipitation or chelation of internal Ca2+ ([Ca2+]i) by internal perfusion with KF or EGTA shifted the curve in a more negative direction without affecting the maximum amplitude of IA. Thus, the kinetics of IA are dependent not only upon [Ca2+]o, as previously suggested, but also upon [Ca2+]i.
In the presence of 4‐AP the I‐V curve for IA shifted in a hyperpolarizing direction and the maximal amplitude was reduced when the neurone was internally perfused with K‐aspartate. However, 4‐AP had little or no effect on the I‐V relationship of IA when the neurone was internally perfused with the Ca2+ precipitating or chelating agent, KF or EGTA. These results suggest that the actions of 4‐AP on IA are at least partly dependent upon [Ca2+]i.
Modulatory role of the vascular endothelium in the contractility of human isolated internal mammary artery
Authors: Schoeffter Philippe , Dion Robert , Godfraind Théophile 
Published: July 2012

Endothelium‐dependent relaxant responses and modulation of contractile responses were investigated in human isolated internal mammary artery (HIMA), a vessel widely used for coronary bypass surgery.
Acetylcholine and ionophore A23187 (both 10 nm‐1 μm) elicited concentration‐dependent relaxations of precontracted HIMA. These relaxations were abolished after rubbing of the endothelium, they were inhibited by methylene blue and were insensitive to indomethacin.
Histamine at concentrations lower than 10 μm elicited an endothelium‐dependent, methylene blue‐sensitive relaxation of precontracted HIMA. This effect of histamine was inhibited by the H1‐receptor antagonist mepyramine. Bradykinin, noradrenaline and α2‐adrenoceptor agonists (in the presence of prazosin) did not relax unrubbed HIMA in which acetylcholine or A23187 were shown to be efficient.
Tissue levels of guanosine‐3′:5′‐monophosphate (cyclic GMP) were found to be significantly higher in unrubbed HIMA rings than in matched rubbed rings.
Methylene blue evoked a slow contraction in resting HIMA, and this contraction was significantly greater in unrubbed than in rubbed preparations. Also, methylene blue enhanced the contractile response of HIMA to noradrenaline and this potentiating effect was significantly greater in unrubbed than in rubbed preparations. Indomethacin induced a slow contraction, of similar magnitude in unrubbed and rubbed HIMA rings.
In resting HIMA, the concentration‐effect curve of noradrenaline‐induced contraction was significantly shifted to the left after rubbing of the endothelium, without change in the maximal responses. In unrubbed rings the EC50 value of noradrenaline was about 2 fold that in rubbed rings.
Histamine also contracted resting HIMA in a concentration‐dependent manner and in addition, it triggered rhythmic activity. This rhythmic activity was more prominent in unrubbed preparations and could be partially inhibited by indomethacin. The concentration‐effect curve of histamine‐induced contractions was displaced to the left after rubbing the endothelium, without changes in the maximal responses. The EC50 value of histamine in unrubbed rings was 4 to 9 fold that found in rubbed rings, depending on the level of tension taken into account for the concentration‐effect curve during rhythmic contractions.
In the presence of nifedipine (3 μm), noradrenaline‐induced contractions were not significantly altered, whereas histamine‐induced contractions were found to be inhibited by about 70%.
It is concluded that in HIMA, both spontaneous and stimulated endothelium‐dependent relaxing factor (EDRF) release may occur, and that basal EDRF can itself be responsible for the modulatory effect of endothelium on contractile responses.
Quinoxalinediones selectively block quisqualate and kainate receptors and synaptic events in rat neocortex and hippocampus and frog spinal cord in vitro
Authors: Fletcher E.J. , Martin D. , Aram J.A. , Lodge D. , Honoré T. 
Published: July 2012

Two quinoxalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N‐methyl‐d‐aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least.
The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and about 4 in rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5.
At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically‐evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium‐containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type.
By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium‐free medium. These burst discharges were, however, abolished by NMDA antagonists.
In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components.
Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non‐NMDA receptors in the vertebrate central nervous system.
Effects of ryanodine on tension development in rat aorta and mesenteric resistance vessels
Authors: Julou‐Schaeffer G. , Freslon J.L. 
Published: July 2012

The effects of ryanodine on contractile responses dependent either on intracellular Ca2+ release or on extracellular Ca2+ influx were studied in aorta and mesenteric resistance vessels of the rat.
In aorta, in the presence of extracellular Ca2+, pretreatment with ryanodine (10−5 m) did not modify contractile responses to noradrenaline (NA) (10−6 m) whereas in the absence of Ca2+, pretreatment with ryanodine reduced to about 25% the contractile response to NA (10−6 m) and totally abolished the transient contraction elicited by caffeine (5 × 10−2 m).
In mesenteric resistance vessels, ryanodine (10−5 m) had no effects on NA (10−5 m)‐induced tension in the presence of extracellular Ca2+ but totally abolished contractile responses to caffeine (10−2 m) in the absence of Ca2+.
In K+‐depolarized mesenteric resistance vessels, pretreatment with ryanodine (10−5 m) significantly enhanced contractile responses to Ca2+ concentrations higher than 10−4 m and 10−3 m for arteries depolarized with 30 mm and 40 mm K+ respectively. Concentrations of either diltiazem (6 × 10−7 m) or nifedipine (10−8 m) that abolished contractile responses to Ca2+ in depolarized arteries (K+, 40 mm) did not totally inhibit the enhancement of Ca2+‐induced contractions obtained in the presence of ryanodine.
Ryanodine did not modify the Ca2+ concentration‐effect relationships in mesenteric resistance vessels exposed to NA or arginine vasopressin.
These data are consistent with the hypothesis that ryanodine induces a release of Ca2+ from intracellular stores, resulting in a subsequent reduction of the amplitude of contractions dependent upon intracellular Ca2+ liberation. Furthermore, the ability of sarcoplasmic reticulum to buffer rises in cytoplasmic Ca2+ may be reduced in the presence of ryanodine, thereby accounting for the potentiation of contractile responses to Ca2+ in K+‐depolarized mesenteric resistance vessels.
A comparison of the differential effects of vasoactive intestinal peptide and peptide histidine isoleucine on the vascular and capsular smooth muscle of the dog spleen
Authors: Corder R. , Withrington P.G. 
Published: July 2012

The actions of the two peptides, vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) have been compared to that of isoprenaline on the smooth muscle systems of the isolated blood‐perfused dog spleen.
Intra‐arterial injections of VIP and PHI caused graded increases in splenic arterial blood flow at constant perfusion pressure indicative of splenic arterial vasodilatation.
VIP was significantly more potent than PHI, with their respective molar ED50 values being 9.9 ± 3.7 and 830 ± 141 pmol (P < 0.002). VIP was approximately 10 and 200 times more potent than isoprenaline and PHI respectively.
The maximum reduction in splenic arterial vascular resistance was the same (P > 0.5) in response to intra‐arterial VIP and PHI, although both peptide maxima were significantly less (P < 0.05, 0.01 respectively) than that obtained with isoprenaline.
Small increases in spleen volume accompanied the splenic vasodilator responses to both peptides. They were probably passive in origin, secondary to splenic arterial vasodilatation.
The selective β2‐adrenoceptor antagonist, ICI 118,551, did not antagonize the splenic arterial vasodilator response to VIP or PHI but markedly attenuated the effect of isoprenaline.
These observations indicate that VIP and PHI, when either co‐released locally or present together in the systemic circulation, may exert a differential action on different components of the circulation.
Selective blockade by nifedipine of ‘purinergic’ rather than adrenergic nerve‐mediated vasopressor responses in the pithed rat
Authors: Bulloch J.M. , McGrath J.C. 
Published: July 2012

Nifedipine can attenuate pressor responses to sympathetic nerve stimulation both in the presence and in the absence of α‐adrenoceptor blocking agents.
In the presence of α,β‐methylene ATP, nifedipine produces only a small attenuation of the vasopressor response.
Nifedipine attenuates the vasopressor response produced by intravenous bolus administration of α,β‐methylene ATP.
The results suggest that the purinergic component of the vasopressor response to stimulation of the sympathetic outflow in the rat is subject to blockade by nifedipine, whereas the α‐adrenoceptor‐mediated response to co‐transmitter noradrenaline is relatively resistant.
The action of GABA receptor agonists and antagonists on muscle membrane conductance in Schistocerca gregaria
Authors: Murphy V.F. , Wann K.T. 
Published: July 2012

The properties of postsynaptic γ‐aminobutyric acid (GABA) receptors in the extensor tibiae muscle of Schistocerca gregaria were studied by conventional electrophysiological recording techniques.
GABA and other active GABA receptor agonists produced rapid, dose‐dependent, reversible increases in membrane conductance.
In two microelectrode experiments the ED50 for GABA was approximately 1 mM. In three microelectrode experiments (assuming short cable theory conditions) the ED50 for GABA was 2.3 mM. The Hill coefficient for GABA estimated from the latter experiments was 1.4
The relative potency of muscimol/GABA at the ED50 for GABA was 1.36. 3‐Aminopropane sulphonic acid (3‐APS) and isonipecotic acid were weakly active, baclofen and piperidine‐4‐sulphonic acid (P4S) were inactive. Isoguvacine produced depolarizations and increases in conductance in preparations which hyperpolarized in response to GABA. These depolarizations were enhanced by both picrotoxin and pitrazepin although the increases in input conductance were depressed.
Picrotoxin (20 μm), (+)‐bicuculline (20–100 μm) and pitrazepin (1–10 μm) all reversibly antagonized GABA‐induced responses. Such antagonism was not competitive in the case of picrotoxin and (+)‐bicuculline but was competitive for pitrazepin. Schild plot analysis gave an average pA2 value of 5.5 for pitrazepin.
The significance of these results is briefly discussed.
Anti‐vasoconstrictor effects of the K+ channel opener cromakalim on the rabbit aorta—comparison with the calcium antagonist isradipine
Authors: Cook Nigel S. , Weir Sheila W. , Danzeisen Max C. 
Published: July 2012

Contractile responses of rabbit aortic rings elicited by KCl‐depolarization, angiotensin II (AII), 5‐hydroxytryptamine (5‐HT) and noradrenaline (NA) have been investigated in the presence of cromakalim (BRL 34915) and isradipine (PN 200–110).
Above 10−6m, cromakalim inhibited contractile responses to low (≤32 mm) but not to higher KCl concentrations. The 5‐HT and AII concentration‐response curves were antagonized non‐competitively by cromakalim (10−7‐10−5m) and the maximal responses were inhibited by 40 and 55%, respectively.
Isradipine caused less inhibition of AII and 5‐HT contractile responses than cromakalim, and in the presence of isradipine (10−7 m), cromakalim was still able to antagonize further the contractions to AII in this vessel.
NA‐induced contractions were relatively insensitive to inhibition by cromakalim and isradipine, both drugs causing a small rightward shift of the NA concentration‐response curve. This result suggests that NA utilizes different Ca2+ pools from those involved in AII‐ and 5‐HT‐induced contractions of this vessel.
The sustained (tonic) part of the NA response was inhibited in a concentration‐dependent manner by cromakalim (10−7‐10−5 m), but not by isradipine.
In aortic rings partially depolarized with 3.5 × 10−2 m KCl, the ability of cromakalim, but not of sodium nitroprusside, atriopeptin III or hydralazine, to inhibit AII‐ and tonic NA‐induced contractions was abolished.
Antivasoconstrictor activity of cromakalim on the rabbit aorta appears to involve factors in addition to an indirect inhibition of Ca2+ entry through dihydropyridine‐sensitive Ca2+ channels.
The ability of cromakalim to open K+ channels and thereby modify the membrane potential would appear to underlie these antivasoconstrictor effects. This mechanism of action of cromakalim clearly differs from that of other vasodilators such as sodium nitroprusside and hydralazine.