bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the contractile effects and binding kinetics of endothelin‐1 and sarafotoxin S6b in rat isolated renal artery
Authors: Devadason Peter S S , Henry Peter J 
Published: August 2006

To date, only two mammalian endothelin (ET) receptors, termed ETA and ETB, have been cloned, sequenced and characterized. However, several functional studies of isolated blood vessels suggest that ET‐1‐induced contractions may be mediated by multiple ETA receptors. In this study, the ETA receptors in renal arteries isolated from Wistar rats were characterized by isometric tension recording and radioligand binding techniques.
ET‐1, sarafotoxin S6b (StxS6b) and ET‐3 produced concentration‐dependent contraction with similar response maxima in endothelium‐denuded arteries, whereas the ETB receptor‐selective agonist StxS6c was inactive. ET‐1 and StxS6b were equipotent and 30 times more potent than ET‐3. This agonist profile, together with the findings that the ETA receptor‐selective antagonists, BQ‐123 and FR‐139317 caused concentration‐dependent, rightward shifts of the concentration‐effect curves to each agonist indicated that ET‐1‐induced contractions in rat renal artery were mediated via ETA receptors.
BQ‐123 and FR‐139317 were both significantly more potent inhibitors of contractions induced by StxS6b or ET‐3 than of responses to ET‐1, raising the possibility that a component of ET‐1‐induced contraction was mediated through atypical, BQ‐123 (or FR‐139317)‐insensitive ETA receptors. However, in competition binding studies, specific [125I]‐ET‐1 and [125I]‐StxS6b binding to rat renal artery sections was completely abolished by BQ‐123 in a manner consistent with an action at a single site. Thus, competition binding studies did not provide any supportive evidence of the existence of a BQ‐123‐insensitive ETA receptor.
Additional studies revealed marked differences in the kinetics of [125I]‐ET‐1 and [125I]‐StxS6b binding. Following a 3 h period of association of [125I]‐ET‐1 with its receptors, no significant dissociation of receptor‐bound [125I]‐ET‐1 was observed during a 4 h washout period. In stark contrast, dissociation studies revealed that specific [125I]‐StxS6b binding to ETA receptors was reversible (t0.5diss, 100 min). A series of association binding studies were also consistent with the specific binding of [125I]‐ET‐1 and [125I]‐StxS6b being irreversible and reversible processes, respectively.
Thus, differences in BQ‐123 potency against ET‐1 and StxS6b‐induced contractions in rat renal arteries might be due to differences in the kinetics of agonist binding, rather than due to the existence of atypical ETA receptors.

British Journal of Pharmacology (1997) 121, 253–263; doi:10.1038/sj.bjp.0701126
Actions of the anaesthetic Saffan on rat sympathetic preganglionic neurones in vitro
Authors: Nolan M F , Gibson I C , Logan S D 
Published: August 2006

Whole‐cell patch‐clamp recordings were used to investigate the effects of the anaesthetic Saffan on the electrophysiological properties of sympathetic preganglionic neurones (SPNs) in rat spinal cord slices.
Saffan (1–54 μM) abolished or reduced the frequency of spontaneous action potential firing and abolished spontaneous, sub‐threshold membrane potential oscillations. Saffan caused dose‐dependent decreases in input resistance and depending upon the initial resting membrane potential, either a depolarization, a hyperpolarization or no change in membrane potential.
Responses to Saffan were blocked by the GABAA receptor antagonists bicuculline (5–20 μM) and picrotoxin (20 μM), but not by the glycine receptor antagonist strychnine (20 μM) indicating that they were mediated by GABAA receptors.
Changes in the properties of SPN action potentials were also observed. In the presence of Saffan the amplitude and duration of the action potential after‐hyperpolarization were reduced and larger depolarizations were required in order to evoke trains of action potentials.
To examine the effects of Saffan on electrotonic coupling between SPNs, experiments were performed with the Na+ channel blocker QX‐314 in the intracellular solution and antidromic oscillations were evoked by ventral root stimulation. Saffan failed to abolish antidromic oscillations, but reduced their amplitude and duration. This indicates that the abolition of spontaneous membrane potential oscillations was not a direct effect on the coupling between SPNs, but was a result of the abolition of spontaneous activity by Saffan.
The responses to Saffan occurred within the plasma concentration range of Saffan during anaesthesia, suggesting that the electrophysiological properties of SPNs may be altered during anaesthesia with Saffan. This would be expected to lead to changes in sympathetic tone and in the integration of sympathetic output.

British Journal of Pharmacology (1997) 121, 324–330; doi:10.1038/sj.bjp.0701127
Comparative direct electrophysiological effects of propofol on the conduction system and ionic channels of rabbit hearts
Authors: Wu Mei‐Hwan , Su Ming‐Jai , Siu‐Mun Sun Selma 
Published: August 2006

Propofol, an intravenous anaesthetic agent, can affect cardiac conduction but the ionic mechanisms have not been well defined.This study measured the direct effects of propofol on the cardiac conduction system by using intracardiac recording/stimulation in Langendorff‐perfused rabbit hearts. The underlying ionic mechanism was elucidated by using the whole‐cell voltage clamp on rabbit isolated atrial and ventricular myocytes.Propofol prolonged significantly the AV conduction (AH) interval at a clinically relevant concentration (3 μM). This AH interval prolongation was dose‐dependent (3 to 100 μM). At higher concentrations, the AV nodal Wenckebach cycle length and its refractory period were also prolonged (10 to 100 μM). In addition, the conduction through the His‐Purkinje system (HV interval) and the atrial tissue (SA interval), as well as the spontaneous cycle length, were lengthened dose‐dependently (30 to 100 μM).In isolated ventricular myocytes, Na current was decreased dose‐dependently by propofol. In part this was due to a negative‐shift of the steady‐state voltage‐dependent inactivation and a slowed rate of recovery from inactivation. TheINasuppression by propofol was frequency‐dependent. Propofol also blocked theICa. The ED50for peak current inhibition was 6.9±0.9 (n=6) and 8.3±1.5 μM(n=7) forINaandICa, respectively.The transient outward potassium current (Ito) of atrial myocytes was suppressed with an ED50of 5.7±0.8 μM(n=11), which was only partly caused by a left‐shift of the steady‐state inactivation. The inward rectifier K current (IK1) of the ventricular cells was reduced somewhat by propofol.In summary, propofol can cause direct dromotropic and chronotropic effects on the cardiac conduction system, especially the atrioventricular node. These changes can be attributed, at least in part, to its direct dose‐dependent suppression of the cardiacICa,INaandIto. Special concerns in the use of propofol anaesthesia for cardiac patients and the therapeutic antiarrythmic potential of propofol‐like compounds are addressed.British Journal of Pharmacology(1997)121, 617–624; doi:10.1038/sj.bjp.0701155
Differential activation of the epithelial and smooth muscle NK1 receptors by synthetic tachykinin agonists in guinea‐pig trachea
Authors: Figini Michela , Emanueli Costanza , Bertrand Claude , Sicuteri Riccardo , Regoli Domenico , Geppetti Pierangelo 
Published: August 2006

The presence of tachykinin NK1 receptors have been shown in the epithelium and smooth muscle of guinea‐pig airways. Previous data showed that substance P (SP), and the NK1 receptor agonist, [Sar9, Met (O2)11]‐SP, relax guinea‐pig tracheal tube preparations by stimulation of epithelial NK1 receptors and via nitric oxide (NO) release. However, the selective tachykinin NK1 receptor agonist, septide, was unable to produce this effect. The aim of the present study was to investigate the ability of a series of SP analogues to stimulate NK1 receptors of guinea‐pig airway epithelium.
Isometric tension was recorded in isolated tracheal tube preparations in which compounds were administered intraluminally in the presence of phosphoramidon, indomethacin (both 1 μM) and the tachykinin NK2 receptor antagonist, SR 48,968 ((S)‐N‐methyl N‐(4‐acetyl‐amino‐4‐phenylpiperidino)‐2‐(3,4‐dichlorophenyl)butyl)benzamide) (0.1 μM). Cumulative concentration‐response curves were obtained in preparations under resting tone or in preparations precontracted with acetylcholine (ACh, 10 μM).
Contractile responses to low concentrations (0.1–10 nM) of substance P (SP) and the selective agonist of NK1 receptors, [Pro9]‐SP, in non precontracted tracheae were higher in preparations pretreated with the NO‐synthase inhibitor, NG‐monomethyl L‐arginine (L‐NMMA, 100 μM) than in preparations pretreated with its inactive enantiomer D‐NMMA (100 μM). Tracheal tube preparations precontracted with ACh and pretreated with D‐NMMA were relaxed by low concentrations of SP and [Pro9]‐SP (0.1–10 nM). In contrast, after pretreatment with L‐NMMA, SP and [Pro9]‐SP contracted tracheae at all the concentrations tested.
Concentration‐response curves to the NK1 receptor agonists, SP methyl ester, [Apa9–10]‐SP and [pGlu6] SP (6–11) obtained in non‐precontracted tracheae were similar in the presence of either D‐NMMA or L‐NMMA. SP methyl ester, [Apa9–10]‐SP and [pGlu6] SP (6–11) did not produce any relaxation, but instead, cause contractions in tracheal tube preparations precontracted with ACh and pretreated with D‐NMMA. Concentration‐response curves produced by all these agonists were similar in preparations precontracted with ACh and pretreated with L‐NMMA or D‐NMMA.
In guinea‐pig tracheal tube preparations two groups of NK1 receptor agonists can be distinguished: one group, including [Pro9]‐SP, stimulator epithelial NK1 receptors, the other group, including SP methyl ester, [Apa9–10]‐SP and [pGlu6] SP (6–11), does not. One possible explanation for these findings and for the existence of compounds with a peculiar ‘septide‐like’ pharmacological profile in the guinea‐pig trachea could be the recently proposed phenomenon referred to as ‘agonist‐directed receptor trafficking’.

British Journal of Pharmacology (1997) 121, 773–781; doi:10.1038/sj.bjp.0701188
Involvement of nitric oxide synthesis in hepatic perturbations induced in rats by a necrogenic dose of thioacetamide
Authors: Díez‐Fernández Carmen , Sanz Nuria , Boscá Lisardo , Hortelano Sonsoles , Cascales María 
Published: August 2006

The biological actions of nitric oxide (NO), a highly diffusible and short‐lived radical, range from signal transduction to cytotoxicity. The present study investigated whether NO is released in the course of liver necrosis and regeneration induced by a single necrogenic dose of thioacetamide (6.6 mmol kg−1 body wt) to rats. Samples of liver were obtained at 0, 3, 12, 24, 48, 72 and 96 h after thioacetamide administration.
Inducible nitric oxide synthase (iNOS) activity was determined in purified liver homogenates and a sharp 6 fold increase (P<0.001) in iNOS activity was recorded at 48 h of intoxication, followed by a slight but progressive increase at 72 and 96 h. Changes in the expression of iNOS, as detected by its mRNA levels, were parallel to the NOS enzyme activity. Hepatocyte NO synthesis showed a progressive increase at 24, 48 and 72 h, to 8 (P<0.001), 13 (P<0.001) and 13 (P<0.001) times the initial values, respectively.
In isolated Kupffer cells, where initial NO release was ten fold higher than in hepatocytes, a progressive increase was detected from 48 h which reached two fold of initial at 72 h of intoxication (192%, P<0.001). Hepatic cyclic GMP concentration did not change significantly. However, mitochondrial aconitase activity decreased markedly at 12 and 24 h of intoxication showing a sharp increase towards normal values at 48 h which was maintained at 72 and 96 h.
As protein kinase C (PKC) is one of the likely candidates to mediate iNOS expression, translocation (activation) of PKC was assayed in hepatocytes, and a significant two fold increase (P<0.001) between 48 and 96 h after thioacetamide intoxication was observed. When peritoneal macrophages from control rats were incubated with serum from thioacetamide‐treated rats, a sharp increase in NO release was detected with serum obtained at 48 h, reaching at 96 h a value four fold (P<0.001) that of the control.
These results suggest that iNOS activity and NO release play a role in the pathophysiological mechanisms that trigger post‐necrotic hepatocellular regeneration following thioacetamide administration.

British Journal of Pharmacology (1997) 121, 820–826; doi:10.1038/sj.bjp.0701191
(+)‐WAY 100135, a partial agonist, at native and recombinant 5‐HT1B/1D receptors
Authors: Davidson Colin , Ho Michael , Price Gary W. , Jones Brian J. , Stamford Jonathan A. 
Published: August 2006

We have studied the effects of the purportedly selective 5‐HT1A receptor antagonist (+)‐WAY100135 on electrically stimulated 5‐hydroxytryptamine (5‐HT) efflux in the ventrolateral geniculate nucleus (vLGN), and its affinity at human 5‐HT1B and 5‐HT1D receptors stably expressed in Chinese hamster ovary (CHO) cells.
On short ‘pseudo single pulse’ stimulations (20 pulses at 100 Hz, 190 ms train duration), (+)‐WAY100135 (1.0 μM) decreased 5‐HT efflux in the vLGN to 68±8% of pre‐drug values (P<0.01). This decrease could be blocked by the 5‐HT1D/1B receptor antagonist GR 127935 (50 nM). Conversely, when long stimulations (20 pulses at 20 Hz, 950 ms train) were used, (+)‐WAY100135 had no effect on 5‐HT efflux (84±8% of pre‐drug values) although both methiothepin (200nM) and GR 127935 (50 nM) caused significant increases (to 175±18 and 130±10% of pre‐drug values, respectively).
Paroxetine (100 nM), the selective 5‐HT reuptake inhibitor, increased stimulated 5‐HT efflux and re‐uptake half‐life (to 145±18% and 649±121%, respectively) on pseudo single pulse stimulations. When (+)‐WAY 100135 was added in combination with the uptake blocker, the effect of paroxetine on stimulated 5‐HT efflux was potentiated to 282±48% (P<0.01) without further effect on the 5‐HT re‐uptake half‐life.
The affinity and intrinsic activity of (+)‐WAY 100135 were determined at recombinant human 5‐HT1B and 5‐HT1D receptors expressed in CHO cells, by use of radioligand binding and [35S]‐GTPγS binding. (+)‐WAY 100135 was a partial agonist at human 5‐HT1B and 5‐HT1D receptors with moderately high affinity for 5‐HT1D receptors (pEC50=7.61).
In conclusion, (+)‐WAY 100135 was found to be not a selective 5‐HT1A autoreceptor antagonist but may act as a partial agonist at the 5‐HT1B/1D receptor, displaying agonist or antagonist properties depending on the stimulation protocol used and the resultant 5‐HT ‘tone’ at the receptor.

British Journal of Pharmacology (1997) 121, 737–742; doi:10.1038/sj.bjp.0701197
The mechanisms of the relaxation induced by vasoactive intestinal peptide in the porcine coronary artery
Authors: Kawasaki Junya , Kobayashi Sei , Miyagi Yasushi , Nishimura Junji , Fujishima Masatoshi , Kanaide Hideo 
Published: August 2006

This study was designed to investigate the mechanism of the relaxation induced by vasoactive intestinal peptide (VIP) in medial strips of the porcine coronary artery, by determining the effect on the cytosolic Ca2+ concentration ([Ca2+]i), the [Ca2+]i‐force relation and the involvement of G‐protein.
Front‐surface fluorometry of fura‐2 revealed that U46619, a thromboxane A2 analogue, and the high K+‐depolarization induced increases in both the [Ca2+]i and force of the medial strips. At a steady state of contraction, the extent of an increase in [Ca2+]i induced by 100 nM U46619 was similar to that induced by 30 mM K+‐depolarization. VIP concentration‐dependently (1 nM–1 μM) induced transient decreases in both the [Ca2+]i and force of the medial strips precontracted with 100 nM U46619. The decreases in the [Ca2+]i and force induced by VIP during the contraction with U46619 were much greater than those with 30 mM K+‐depolarization.
The VIP‐induced decreases in the [Ca2+]i and force were attenuated by K+ channel blockers such as tetrabutylammonium (TBA: non‐selective K+ channel blocker), charybdotoxin (large conductance Ca2+‐activated K+ channel blocker), and 4‐aminopyridine (4‐AP: voltage‐dependent K+ channel blocker). However, neither glibenclamide (ATP‐sensitive K+ channel blocker) nor apamin (small conductance Ca2+‐activated K+ channel blocker) had any significant inhibitory effect.
In the 30 mM K+‐depolarized strips, pretreatment with thapsigargin, a specific Ca2+‐ATPase inhibitor of the Ca2+ store sites, completely abolished the VIP‐induced decrease in [Ca2+]i, but partially attenuated the VIP‐induced decrease in force.
VIP shifted the [Ca2+]i‐force relation of the U46619‐induced contractions to the right in a concentration‐dependent manner. In the α‐toxin‐permeabilized strips, VIP decreased the force development at a constant [Ca2+]i level (pCa=6.5) in a GTP‐dependent manner, which was antagonized by guanosine‐5′‐O‐(β‐thiodiphosphate) (GDPβS).
We thus conclude that VIP relaxes the coronary artery via three mechanisms: (1) a decrease in [Ca2+]i by inhibiting the Ca2+ influx presumably through the membrane hyperpolarization mediated by the activation of the large conductance Ca2+‐activated (charybdotoxin‐sensitive) K+ channels and voltage‐dependent (4‐AP‐sensitive) K+ channels; (2) a decrease in [Ca2+]i by sequestrating cytosolic Ca2+ into thapsigargin‐sensitive Ca2+ store sites; and (3) a decrease in the Ca2+‐sensitivity of the contractile apparatus through the activation of G‐protein.
Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals
Authors: Helyes Zsuzsanna , Németh József , Pintér Erika , Szolcsányi János 
Published: August 2006

Pretreatment with the novel neuropeptide nociceptin (20 μg kg−1, i.p.) caused an inhibition of plasma extravasation evoked by antidromic stimulation of the saphenous nerve or by topical application of 1% mustard oil on the skin of the acutely denervated hindleg of the rat. In contrast, it did not affect non‐neurogenic inflammation evoked by s.c. injection of bradykinin after chronic denervation. Release of substance P (SP) and calcitonin gene‐related peptide (CGRP) from rat isolated tracheae in response to electrical field stimulation was diminished by nociceptin (100 nM). It is concluded that nociceptin inhibits the release of sensory neuropeptides from terminals of nociceptive neurones.British Journal of Pharmacology (1997) 121, 613–615; doi:10.1038/sj.bjp.0701209
Nitric oxide‐dependent and ‐independent vascular hyporeactivity in mesenteric arteries of portal hypertensive rats
Authors: Heinemann Akos , Wachter Christof H , Holzer Peter , Fickert Peter , Stauber Rudolf E 
Published: August 2006

Increased production of nitric oxide (NO) has been suggested to underlie both the vascular hyporeactivity to vasoconstrictors and the splanchnic vasodilatation seen in portal hypertension. This study assessed the role of NO in the vasoconstrictor hyporeactivity of portal vein‐ligated (PVL) rats in isolated and in situ perfused mesenteric arterial beds.
Isolated perfused mesenteric arteries of PVL rats were significantly less reactive to noradrenaline (NA), methoxamine (METH), arginine vasopressin (AVP) and endothelin‐1 (ET‐1) than those from sham‐operated (Sham) rats.
Blockade of NO synthesis with NG‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM) in isolated perfused mesenteric arteries from PVL rats restored the reactivity to bolus injections of AVP and ET‐1, but had little effect on the hyporeactivity to NA or METH. Cyclo‐oxygenase inhibition with indomethacin (5 μM) likewise did not restore reactivity to METH of isolated perfused mesenteric arteries of PVL rats.
The hyporeactivity to METH seen in isolated perfused mesenteric arteries from PVL rats was reduced by low concentrations of AVP (20 nM) or ET‐1 (1 nM) which per se caused only a slight increase in perfusion pressure. When L‐NAME (100 μM) was combined with AVP (20 nM) or ET‐1 (1 nM), respectively, reactivity to METH of isolated perfused mesenteric arteries of PVL rats was restored to the level seen in Sham rats. These effects of AVP and ET‐1 were not mimicked by precontracting the vessels with 5‐hydroxytryptamine (5 μM).
The differential effects of L‐NAME and AVP on the hyporesponsiveness to methoxamine and AVP were corroborated by experiments performed with the in situ perfused mesenteric vascular bed preparation.
These data indicate that both NO‐dependent and NO‐independent mechanisms are involved in the vasoconstrictor hyporesponsiveness of mesenteric arteries from portal hypertensive rats. The hyporeactivity to AVP and ET‐1 is mediated by NO whereas the reduced responsiveness to adrenoceptor agonists appears to be predominantly NO‐independent. AVP and ET‐1, in addition, seem to inhibit the NO‐independent mechanism of vascular hyporeactivity, since the hyporesponsiveness to METH was reduced in the presence of AVP or ET‐1 and abolished by the combination of these peptides with L‐NAME.
Induction of bradykinin B1 receptors in rat colonic epithelium
Authors: Teather Sarah , Cuthbert Alan W 
Published: August 2006

Des‐Arg9 bradykinin (DAB), a classical B1‐kinin receptor agonist was without effect when applied to the basolateral surface of rat isolated colon epithelium. Three hours after tissues were isolated DAB caused, after a delay of up to 2 min, a maintained increase of short circuit current (SCC).
The SCC increase in colonic epithelia, mounted in vitro for three hours, caused by DAB was due to electrogenic chloride secretion as the current increase was reversed by frusemide and did not occur in the absence of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels. The EC50 for DAB was approximately 50 nM.
An inhibitor of transcription (actinomycin D) and of translation (cycloheximide) prevented the appearance of DAB sensitivity without affecting the responses to another secretagogue (forskolin).
The classical B1‐kinin receptor antagonist, Leu8‐des‐Arg9 bradykinin, was shown to be an agonist in rat colon epithelium. Other B1‐kinin receptor antagonists (des‐Arg10‐Hoe 140 and R‐715) inhibited the responses to DAB in ‘aged’ colonic epithelia, and the inhibition was easily surmounted by increasing the concentration of DAB.
Response to DAB did not appear to involve to any significant extent, the formation of prostaglandins, leukotrienes, histamine or nitric oxide. Furthermore, no neuronal involvement was apparent in the stripped colonic preparations. The responses to DAB were not significantly different in epithelia taken from different parts of the distal colon.
The differences between the responses of the colonic epithelium to B1‐ and B2‐kinin receptor agonists are discussed.