bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facilitation of noradrenaline release from sympathetic nerves through activation of ACTH receptors, β‐adrenoceptors and angiotensin II receptors
Authors: Costa Mary , Majewski Henryk 
Published: July 2012

In rabbit pulmonary artery and left atrial strips previously incubated with [3H]‐noradrenaline, the active fragment of adrenocorticotropic hormone (ACTH1–24, 0.1 μm) significantly enhanced the stimulation‐induced (S‐I) outflow of radioactivity when a cocktail containing corticosterone (40 μm), cocaine (30 μm) and propranolol (4 μm) was present, but not in the absence of these drugs. In rabbit pulmonary artery a facilitatory effect of ACTH1–24 (0.1μm) was also observed when only cocaine (30 μm) was present.
ACTH1–24 (0.1 μm) did not affect the S‐I outflow of radioactivity from rat atria, rat pulmonary artery or guinea‐pig pulmonary artery, either in the presence or in the absence of the cocktail containing corticosterone (40 μm), cocaine (30 μm) and propranolol (4 μm). These results suggest that the presence of facilitatory prejunctional ACTH receptors may be restricted to rabbit sympathetic nerve endings.
Angiotensin II (0.01 μm), but not isoprenaline (0.1 μm) or ACTH1–24 (0.1μm), significantly enhanced the S‐I outflow of radioactivity from rabbit pulmonary artery. In the presence of phentolamine (1 μm) to block inhibitory α2‐adrenoceptors, the facilitatory effect of angiotensin II (0.01 μm) was significantly enhanced, and a significant facilitatory effect of isoprenaline (0.1 μm) and of ACTH1–24 (0.1 μm) was then revealed. These results suggest that feedback inhibition of noradrenaline release, mediated through the prejunctional α2‐adrenoceptor mechanism, buffers increases in noradrenaline release during activation of facilitatory prejunctional receptors.
In rabbit pulmonary artery, two concentrations of 8‐Br‐cyclic AMP, (270 or 540 μm), enhanced the S‐I outflow of radioactivity in the presence of phentolamine (1 μm) to a similar extent. In the presence of 8‐Br‐cyclic AMP (270 μm) and phentolamine, the facilitatory effects of isoprenaline (0.1 μm) and of ACTH1–24 (0.1 μm) were blocked, whereas that of angiotensin II (0.01 μm) was not changed. These results suggest that both prejunctional β‐adrenoceptors and ACTH receptors enhance noradrenaline release by generating cyclic AMP. The mechanism by which angiotensin II facilitates noradrenaline release is probably independent of the cyclic AMP second messenger pathway.
N,N‐diallyl‐tyrosyl substitution confers antagonist properties on the κ‐selective opioid peptide [D‐Pro10]dynorphin A(1–11)
Authors: Gairin Jean Edouard , Mazarguil Honoré , Alvinerie Paul , Botanch Catherine , Cros Jean , Meunier Jean‐Claude 
Published: July 2012

In the search for κ‐opioid antagonists, we have designed two N,N‐diallyl substituted analogues of the κ‐selective peptide [D‐Pro10]dynorphin A (1–11)(DPDYN). In this study, we have examined (i) the binding properties of N,N‐diallyl‐DPDYN (analogue 1) and N,N‐diallyl‐[Aib2,3]DPDYN (analogue 2) at the three main types (μ, δ, κ) of opioid binding sites, (ii) their binding sensitivity to Na+ ions (120 mM NaCl) and guanine nucleotide (50 μm Gpp(NH)p) at μ‐ and κ‐binding sites and (iii) their biological activity in two pharmacological bioassays specific for μ‐ and κ‐(guinea‐pig ileum) and κ‐(rabbit vas deferens) opioid receptors.
Steric hindrance resulting from incorporation of two bulky allyl groups at the tyrosyl nitrogen atom greatly altered the binding properties of DPDYN. A dramatic fall in apparent affinity for the three types (μ, δ, κ) of site as well as selectivity for κ‐sites was observed for the two N,N‐diallyl‐substituted peptide analogues.
At κ‐sites of guinea‐pig cerebellum and μ‐sites of rabbit cerebellum, N,N‐diallyl‐substitution led to a complete loss of binding sensitivity to the inhibitory effect of 120 mM NaCl + 50 μm Gpp(NH)p compared to the high sensitivity of DPDYN. This may therefore suggest that the N,N‐diallyl‐DPDYN analogues are endowed with opioid antagonist properties.
No agonist activity of the analogues was observed in guinea‐pig myenteric plexus and rabbit vas deferens organ preparations. In contrast, both of the diallyl‐substituted peptides displayed similar antagonist properties against the κ‐agonist DPDYN in both preparations. In the guinea‐pig ileum, the affinities of the antagonist peptides against the μ‐agonist Tyr‐D‐Ala‐Gly‐MePhe‐NH(CH2)2OH(DAGOL) were approximately half that observed against DPDYN.
These results show that N,N‐diallyl‐tyrosyl substitution leads to analogues of DPDYN which act in vitro as pure opioid antagonists and exhibit a reasonable affinity at, but a weak selectivity for, the κ‐opioid receptors.
Electrical and mechanical effects of new aminosteroids on guinea‐pig isolated ventricular muscle
Authors: Adamantidis M.M. , Honoré E.R. , Dupuis B.A. 
Published: July 2012

LND 623 and LND 796 are two aminosteroid derivatives which exert similar positive inotropic effects to digitalis. Their electrophysiological, toxic and inotropic effects were investigated in both normal and partially K+‐depolarized ventricular muscle.
In guinea‐pig myocardial fibres, LND 623 and LND 796 required tenfold higher concentrations than digoxin to induce the same signs of toxicity; e.g. triggered activities generated from delayed afterdepolarizations, leading to the marked depression of action potential characteristics and inexcitability. These abnormal rhythms and delayed afterdepolarizations were abolished by 1 mM caffeine. The toxic effects were reversed by washout, particularly in the case of LND 796.
In normal‐K+ solution, LND 623 and LND 796 exhibited concentration‐dependent positive inotropic effects on guinea‐pig papillary muscle and increased concomitantly resting membrane potential and action potential amplitude. The range of active concentrations (0.1 to 1 μm) of LND 623 was larger than that of digoxin (0.3 to 1 μm). Like digoxin, LND 796 exerted negative inotropic effects at the lowest concentrations (0.01 to 0.03 μm) and positive inotropic effects at high concentrations (1 and 3 μm).
In partially K+‐depolarized papillary muscle, in the presence of 2 μm histamine, LND 623 (3 and 10μm) and LND 796 (10 and 30μm) enhanced the two components P1 and P2 of the contraction and increased slow action potential amplitude, resting potential and maximal rate of depolarization. Low concentrations (0.03 to 0.3 μm) of LND 796 induced negative inotropic effects. β‐Adrenoceptor blockade with atenolol (1 μm) did not modify the activity of LND 623 but significantly enhanced the negative inotropic effect on P2 induced by 1 and 3 μm LND 796 and reduced the positive inotropic effect on P1 and P2 of the highest concentration (30 μm) studied.
In the presence of either caffeine (1 mm) or Ca2+‐free, Sr2+‐rich (3.6 mm) solution, LND 623 and LND 796 produced a positive inotropic effect which was stronger with LND 623.
It is suggested that two mechanisms are involved in the inotropic effects of these aminosteroids: (i) an enhanced Ca2+ entry via the slow calcium channels partially brought about by a local release of endogenous catecholamines in the case of LND 796, (ii) an inhibitory effect on Na+‐K+ ATPase which, at the highest concentrations, lead to similar signs of cellular toxicity to those described for digitalis drugs. Because of their enlarged positive inotropic range, both aminosteroids may be of interest in the treatment of congestive heart failure.
Vasoconstrictor and vasodilator effects in normal and atherosclerotic conscious rabbits
Authors: Hof Robert P. , Hof Akiko 
Published: July 2012

Rabbits were fed a cholesterol‐rich diet for 5 two‐week intervals. Polyvinyl catheters were then implanted into the femoral artery and vein. Dose‐response curves to acetylcholine (ACh), noradrenaline (NA), phenylephrine (Phen) and angiotensin II (AII), were obtained in 6 cholesterol‐fed and 6 control rabbits before and after isradipine (code name PN200–110) 100μgkg−1. After these experiments the animals were killed and aortic rings were suspended in an organ bath. ACh but not nitroprusside‐induced relaxation was impaired in atherosclerotic but not in control preparations.
ACh decreased blood pressure dose‐dependently in both groups of rabbits even though ACh did not relax the aortae of the same rabbits in vitro.
Blood pressure effects reflect mostly changes in resistance vessels. The pressor effects of NA, Phen and AII were enhanced in atherosclerotic compared with normal rabbits.
After a dose of 100μgkg−1 isradipine the dose‐response curves of all agents were shifted to the right. The differences between atherosclerotic and control rabbits disappeared, except for the AII‐induced pressor response, which remained enhanced in atherosclerotic animals. The calcium antagonist thus only partly corrected the atherosclerosis‐associated hyperresponsiveness to vasoconstrictor agents.
Chronotropic effect of nizofenone fumarate in rabbit sino‐atrial node in vitro
Authors: Kotake Hiroshi , Nawada Takahiro , Matsumoto Tatsuhiko , Kitamura Hideyuki , Kaneda Takafumi , Hasegawa Junichi , Mashiba Hiroto 
Published: July 2012

The effects of nizofenone fumarate were studied on the membrane potentials and currents of rabbit sino‐atrial node preparations by means of the double‐microelectrode voltage clamp method.
In spontaneously firing pacemaker cells, nizofenone (above 1 μm) decreased the heart rate. Above 3 μm, nizofenone reduced the maximum upstroke velocity, the amplitude of the action potential and the slope of the phase 4 depolarization, and prolonged the action potential duration at 50% repolarization.
Under voltage clamp conditions, nizofenone decreased the slow inward current and the time‐dependent potassium outward current in a dose‐dependent manner.
These findings suggest that nizofenone exerts an inhibitory action on the automaticity of sinoatrial node preparations via effects on both inward and outward currents.
β ‐Adrenoceptor stimulation inhibits histamine‐stimulated inositol phospholipid hydrolysis in bovine tracheal smooth muscle
Authors: Hall I.P. , Hill S.J. 
Published: July 2012

Histamine and carbachol produced concentration‐related increases in the accumulation of 3Hinositol phosphates in slices of bovine tracheal smooth muscle.
Noradrenaline alone produced a small stimulation of 3H‐inositol phosphate accumulation which was inhibited by the α‐adrenoceptor antagonist phentolamine. In contrast, when noradrenaline (0.1 mm) was added simultaneously with histamine it significantly reduced the inositol phosphate response to high (≥0.1mm) concentrations of histamine. However, noradrenaline had no inhibitory effect on the carbachol‐induced inositol phosphate response.
The non‐selective β‐agonist isoprenaline (IC50 = 0.08 μm) and the β2‐selective agonist salbutamol (IC50 = 0.29 μm) both produced a dose‐related inhibition of the inositol phosphate response to 0.1 mM histamine. The inhibitory effect of salbutamol was antagonized by propranolol (KA = 2.4 × 109M−1) and the β2‐selective adrenoceptor antagonist ICI 118551 (KA = 1.7 × 109 M−1).
The accumulation of 3H‐inositol phosphates induced by histamine increased steadily over a 40 min period after an initial lag period of 3–4 min. Following the simultaneous addition of histamine and salbutamol there was a further delay of 3–4 min before the appearance of the inhibitory effect of salbutamol.
The effect of histamine on inositol phosphate accumulation was accompanied by a stimulation of [3H]‐inositol incorporation into membrane phospholipids which was reduced by the presence of salbutamol. However, when histamine was used to stimulate maximally [3H]‐inositol incorporation during the prelabelling period, salbutamol produced a marked inhibition of histamine‐stimulated 3H‐inositol phosphate accumulation under conditions in which there was no change in the level of incorporation.
α2‐Adrenoceptor‐mediated inhibition of histamine release from rat cerebral cortical slices
Authors: Hill S.J. , Straw R.M. 
Published: July 2012

Depolarization of rat cerebral cortical slices, prelabelled with [3H]‐histidine, in high potassium (40 mM KCl) medium stimulated the release of [3H]‐histamine. The K+‐evoked release of [3H]‐histamine was attenuated by incubation in calcium‐free medium and prevented by prior incubation of brain slices with the selective histidine decarboxylase inhibitor S‐(α)‐fluoromethylhistidine.
The K+‐evoked release of [3H]‐histamine was significantly (P < 0.001) reduced following stimulation of histamine H3‐receptors with R‐(α)‐methylhistamine (1 μm) and this effect was antagonized by the H3‐antagonist thioperamide (1 μm).
Noradrenaline and the α2‐selective adrenoceptor agonists clonidine and UK‐14,304 inhibited the K+‐evoked release of [3H]‐histamine in a concentration‐dependent manner yielding EC50 values of 2.5, 0.8 and 1.2 μm, respectively. However, the maximum response to clonidine was only 52 ± 8% of that obtained with noradrenaline.
The inhibitory effect of noradrenaline was antagonized by the non‐selective α‐antagonist phentolamine and by the selective α2‐antagonists yohimbine and idazoxan. However, the response to noradrenaline was not inhibited by the α1‐antagonist prazosin at concentrations up to 1 μm.
These results suggest that both histamine H 3‐receptors and α2‐adrenoceptors are present on histamine‐containing nerve terminals in rat cerebral cortex and can exert an inhibitory influence on neurotransmitter release.
Inhibition of leukotriene release in anaphylactic guinea‐pig hearts by a 5‐lipoxygenase inhibitor, CGS 8515
Authors: Yaacob H.B. , Piper Priscilla J. 
Published: July 2012

Ovalbumen (100μg)‐induced coronary vasoconstriction and decrease in cardiac developed tension were studied in isolated perfused hearts from sensitized guinea‐pigs. Leukotriene‐like material released in the cardiac effluent was assayed against synthetic leukotriene C4 (LTC4).
LTC4 was released in a time‐dependent fashion, and release was enhanced when hearts were challenged in the presence of indomethacin (2.8 μm). The release was maximal at 2–3 min and detectable for as long as 10 min following ovalbumen challenge. Immunoreactive (ir) thromboxane‐B2 (TxB2) was also detected in cardiac effluent which had been partially purified using C18 Sep‐Paks.
CGS 8515 (0.03–1.0 μm), an inhibitor of 5‐lipoxygenase, dose‐dependently inhibited ovalbumen‐induced coronary vasoconstriction and leukotriene‐C4 release. CGS 8515 inhibited ovalbumen‐induced decreases in cardiac developed tension at 0.3 and 1.0 μm, but did not antagonize coronary vasoconstriction induced by synthetic LTC4.
The release of cyclo‐oxygenase products following ovalbumen challenge was not inhibited by CGS 8515, but was markedly inhibited by indomethacin (2.8 μm) pretreatment.
We conclude that leukotrienes have a major role in guinea‐pig cardiac anaphylaxis, and that CGS 8515 has a cardio‐protective action. The results obtained in these experiments in vitro show that CGS 8515 is a potent and selective 5‐lipoxygenase inhibitor.
Pinacidil opens K+‐selective channels causing hyperpolarization and relaxation of noradrenaline contractions in rat mesenteric resistance vessels
Authors: Videbæk Lars M. , Aalkjær Christian , Mulvany Michael J. 
Published: July 2012

The effects of pinacidil on noradrenaline‐induced tone, smooth muscle membrane potential and42 K‐ and86 Rb‐efllux from isolated mesenteric resistance vessels (internal diameter 200 μm) of the rat have been studied.
Pinacidil (0.3–10 μM) produced concentration‐dependent suppression of noradrenaline‐induced tone.
Pinacidil (0.3–10 μM) caused concentration‐dependent hyperpolarization of the smooth muscle.
In rat resistance vessels loaded with42 K, pinacidil (1–10 μM) significantly increased the42 K‐efllux rate constant.
With the use of86 Rb as a marker for K+, 1 μM pinacidil did not affect the86 Rb‐efflux rate constant, while 10 μM pinacidil transiently increased the86 Rb rate constant.
The results indicate that the relaxant action of pinacidil in these vessels is due to the opening of K+‐channels and consequent hyperpolarization. The K+‐channels opened are selective for42 K over86 Rb.
Possible mechanism of acetaldehyde‐induced noradrenaline release from sympathetic nerve terminals in isolated blood vessels
Authors: Chiba S. , Tsukada M. 
Published: July 2012

Vasoconstrictor responses to acetaldehyde were investigated in isolated and perfused canine intermediate auricular (ear) arteries.
Single injections of small doses of acetaldehyde (1–3 μmol) induced vasoconstriction in a dose‐related manner and showed no tachyphylaxis. On the other hand, large doses of acetaldehyde (10–30 μmol) frequently caused tachyphylaxis when injected at 10 min intervals.
After tyramine treatment, constrictions induced by a large dose of acetaldehyde were consistently restored temporarily.
The acetaldehyde‐induced vasoconstriction was inhibited by bunazosin, a potent α1‐adrenoceptor antagonist.
A small dose of imipramine blocked tyramine‐induced vasoconstriction, but had no significant influence on noradrenaline (NA)‐induced constrictions, and caused slight potentiation of acetaldehyde‐induced constrictions.
Hydrocortisone treatment did not modify tyramine‐induced vasoconstrictions and slightly suppressed NA‐ and acetaldehyde‐induced constrictions but not significantly.
It is suggested that acetaldehyde causes a release of NA from a NA store of the sympathetic nerve terminals which is different from the tyramine‐sensitive NA store, and that the acetaldehyde‐sensitive NA store may be readily filled up with NA from the tyramine‐sensitive store.
Evidence that the histamine sensitivity and responsiveness of guinea‐pig isolated trachea are modulated by epithelial prostaglandin E2 production
Authors: Braunstein Guy , Labat RCarlos , Brunelleschi Sandra , Benveniste Jacques , Marsac Jean , Brink Charles 
Published: July 2012

Guinea‐pig isolated tracheal preparations in which the epithelium had been removed exhibited a greater contractile response to histamine (intact: 1.91 ± 0.12g; n = 6 and rubbed: 2.76 ± 0.15g; n = 11; P < 0.001). The histamine sensitivity (pD2 value) of these preparations was also significantly greater (intact: 4.80 ± 0.04 and rubbed: 5.40 ± 0.08; P < 0.01).
Indomethacin suppressed the basal tone of both intact and rubbed preparations but was more effective in the former tissues (intact: −0.70 ± 0.14g; n = 22 and rubbed: −0.17 ± 0.05g; n = 12; P < 0.02).
Arachidonic acid (AA; 10 μM) suppressed the basal tone of intact tissues but contracted such preparations following indomethacin treatment (1.7 μM; 30 min). However, in rubbed tissues AA (10 μM) induced a contraction which was attenuated following indomethacin treatment.
Prostaglandin E2 (PGE2; 0.01 and 0.1 μM) suppressed the basal tone of intact preparations and always evoked contraction of rubbed tissues. Following indomethacin treatment PGE2 (0.01 and 0.1 μM) generally evoked spasm of intact and rubbed tissues while at higher concentrations (1 μM) relaxant effects were observed.
Removal of the epithelium did not alter the relaxant effect of PGE2 (pD2 value) on histamine (50 μM)‐contracted tissues (intact: 6.86 ± 0.08 and rubbed: 7.10 ± 0.3; n = 4; P > 0.1).
In rubbed preparations treated with indomethacin, PGE2 (0.01 and 0.1 μM) evoked spasm. However, when added to preparations contracted with 5 μM histamine, PGE2 always caused relaxation.
The release of immunoreactive PGE2 by rubbed preparations during histamine and/or AA stimulation was significantly less than that produced by intact stimulated tissues.
Exogenous PGE2 (0.01‐1 μM) decreased the maximal response and sensitivity of rubbed tracheal preparations to histamine.
These results suggest that release of an epithelial derived cyclo‐oxygenase product, namely PGE2, may regulate basal tone, histamine response and sensitivity of the guinea‐pig isolated trachea.
Release‐regulating autoreceptors of the GABAB‐type in human cerebral cortex
Authors: Bonanno Giambattista , Cavazzani Paolo , Andrioli Gian Carlo , Asaro Daniela , Pellegrini Graziella , Raiteri Maurizio 
Published: July 2012

The depolarization‐evoked release of γ‐aminobutyric acid (GABA) and its modulation mediated by autoreceptors were investigated in superfused synaptosomes prepared from fresh human cerebral cortex.
The release of [3H]‐GABA provoked by 15 mM K+ from human cortex nerve endings was almost totally (85%) calcium‐dependent.
In the presence of the GABA uptake inhibitor SK&F 89976A (N‐(4,4‐diphenyl‐3‐butenyl)‐nipecotic; acid), added to prevent carrier‐mediated homoexchange, GABA (1–10 μm) decreased in a concentration‐dependent manner the K+‐evoked release of [3H]‐GABA. The effect of GABA was mimicked by the GABAB receptor agonist (−)‐baclofen (1–100 μm) but not by the GABAA receptor agonist muscimol (1–100 μm). Moreover, the GABA‐induced inhibition of [3H]‐GABA release was not affected by two GABAA receptor antagonists, bicuculline or SR 95531 (2‐(3′‐carbethoxy‐2′‐propenyl)−3‐amino‐6‐paramethoxy‐phenyl‐pyridazinium bromide).
(−)‐Baclofen also inhibited the depolarization‐evoked release of endogenous GABA from human cortical synaptosomes.
It is concluded that GABA autoreceptors regulating the release of both newly taken up and endogenous GABA are present in human brain and appear to belong to the GABAB subtype.
A local circuit neocortical synapse that operates via both NMDA and non‐NMDA receptors
Authors: Thomson Alex M. , Girdlestone Debbie , West David C. 
Published: July 2012

In slices of rat neocortex, spike triggered averaging was employed to record in one neurone the excitatory postsynaptic potential (e.p.s.p.) generated by a spike in another, neighbouring neurone. When recorded at different membrane potentials, some of these e.p.s.ps exhibited a voltage relation typical of neuronal responses to N‐methyl‐d‐aspartate (NMDA).
Selective NMDA antagonists reduced the amplitude of these e.p.s.ps, but had little effect on their early rising phase. In contrast, a less selective excitatory amino acid antagonist reduced all phases of the e.p.s.p.
By analyzing single axon e.p.s.ps we have been able to establish that the synaptic input to one cortical cell, delivered by a single presynaptic cortical cell, operates simultaneously via NMDA and non‐NMDA amino acid receptors.
The interaction of benzodiazepines with thyrotropin‐releasing hormone receptors on clonal pituitary cells
Authors: Joels Lesley A. , Drummond Alan H. 
Published: July 2012

Seven benzodiazepines were investigated for their ability to interact with receptors for thyrotropin‐releasing hormone (TRH) on GH3 and GH4C1 pituitary tumour cells.
Midazolam and chlordiazepoxide were the most potent inhibitors of TRH‐induced [3H]‐inositol phosphate formation with Ki values in the low micromolar range. The antagonism was competitive in nature and was increased in potency at sub‐physiological temperatures.
None of the agents examined antagonized bombesin‐induced [3H]‐inositol phosphate formation in GH4C1 cells.
While the ability of benzodiazepines to interact with the GABA receptor‐chloride channel ionophore is markedly stereospecific, little difference was evident in the ability of (+)− and (−)−4‐methylmidazolam (Ro 21–5656 and Ro 21–5657) to compete with TRH at its receptor.
Recently it has been suggested that, in contrast to phosphatidylinositol hydrolysis, the TRH‐induced breakdown of phosphatidylinositol polyphosphates is transient in clonal pituitary cells. Addition of chlordiazepoxide to TRH‐stimulated GH3 cells up to 60 min after initiating the reaction leads, however, to an immediate decline in the cellular content of inositol trisphosphate. This indicates that TRH‐induced phosphatidylinositol 4,5‐bisphosphate hydrolysis is not transient.