bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centrally administered ouabain aggravates rapid‐eye‐movement‐sleep‐related bradyarrhythmias in freely moving rats
Authors: Sato Takayuki , Seto Katsuo 
Published: July 2012

The effects of continuous infusions of ouabain on bradyarrhythmias (cardiac pauses for 0.5 s or longer) during sleep were examined in freely moving Wistar‐Kyoto rats.
In a control group (n = 7), saline was infused into both the lateral ventricle and the femoral vein. In an intracerebroventricular (i.c.v.) ouabain group (n = 7), ouabain was infused centrally, such that each rat received three stepped doses of 1, 10, and 100 ng kg−1 h−1 for 3 days at each dose, while saline was infused systemically. In an intravenous (i.v.) ouabain group (n = 7), ouabain was infused systemically at the same doses as the i.c.v. ouabain received, while the simultaneous i.c.v. infusion of saline was carried out.
Three‐day i.c.v. infusions of the three stepped doses of ouabain caused a dose‐dependent increase in the frequency of bradyarrhythmias during rapid‐eye movement (REM) sleep without affecting the time spent in REM sleep, arterial pressure, average heart rate, or the frequency of bradyarrhythmias during non‐REM sleep. Intravenous ouabain or i.c.v. saline had no effects on the frequency of bradyarrhythmias.
Intrinsic CNS activity during REM sleep may be involved in the centrally mediated arrhythmogenic properties of ouabain during sleep.
Functional evidence for multiple receptor activation by κ‐ligands in the inhibition of spinal nociceptive reflexes in the rat
Authors: Herrero Juan F. , Headley P. Max 
Published: July 2012

The evidence for κ‐receptor heterogeneity is equivocal. We have now investigated this question by comparing the effects of five putatively selective κ‐agonists. The parameters examined were: the relative potencies in depressing hindlimb flexor muscle reflexes to noxious pinch stimuli in both spinalized and sham‐spinalized rats; the reversibility of these effects by naloxone; and the effects on blood pressure.
Two types of drug effect was discriminated. One drug group, represented by U‐50,488, U‐69,593 and PD‐117,302, had a potency ratio between sham and spinalized rats approximately 10 fold lower than the other group, which comprised GR103545 and CI‐977.
Under sham‐spinalized conditions, CI‐977 and GR103545 at high doses caused only sub‐maximal reductions of spinal reflexes. U‐50,488 was still active when superimposed on these high doses of GR103545.
Naloxone reversed all effects, but different doses were required between compounds, with GR103545 taking some 20 times higher doses of naloxone to cause reversal than did U‐50,488.
The effects on mean arterial pressure were opposite between groups.
The results imply that more than one type of naloxone‐sensitive non‐μ opioid receptor must be involved in mediating these complex actions of ligands that have been claimed to be selective for κ‐receptors.
The effects of single and repeated anorectic doses of 5‐hydroxytryptamine uptake inhibitors on indole levels in rat brain
Authors: Caccia Silvio , Anelli Marina , Codegoni Anna Maria , Fracasso Claudia , Garattini Silvio 
Published: July 2012

The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5‐hydroxytryptamine (5‐HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite.
Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 μmol kg−1), fluvoxamine (60 μmol kg−1), paroxetine (20 μmol kg−1) and sertraline (49 μmol kg−1) slightly reduced brain 5‐hydroxyindoleacetic acid (5‐HIAA), with regional differences, this being compatible with 5‐HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5‐HT in the cortex.
The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus).
Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5‐HT and 5‐HIAA in all the brain regions compared to pair‐fed control animals, 1 h after the last dose.
One week later only fluoxetine‐treated animals still had reduced brain 5‐HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing.
Further studies on the relationship between the long‐term neurochemical changes and anorectic activity are required but it appears from these results that anorectic drugs with similar acute effects on 5‐HT uptake may differ in their long‐term effects on 5‐HT mechanisms.
Endothelin‐1 (ET‐1)‐induced contraction in rat isolated trachea: involvement of ETa and ETB receptors and multiple signal transduction systems
Authors: Henry Peter J. 
Published: July 2012

Quantitative autoradiographic, biochemical and functional studies were performed to investigate the endothelin receptor subtypes and signal transduction systems that mediate endothelin‐1 (ET‐1)‐induced contraction in rat isolated tracheal smooth muscle.
Specific binding of 0.5 nm [125I]‐ET‐1 to tracheal smooth muscle was inhibited by at least 40% in the presence of either the ETA receptor selective ligand BQ‐123 (1 μm) or the ETB receptor‐selective ligand sarafotoxin S6c (30 nm), indicating the presence of both ETA and ETB receptors in this tissue.
ET‐1 and sarafotoxin S6c were both potent spasmogens of rat isolated tracheal smooth muscle preparations. Sarafotoxin S6c‐induced contractions were unaffected in the presence of the ETA receptor antagonist BQ‐123 (10 μm), but were markedly attenuated in tissue previously exposed to 100 nm sarafotoxin S6c to induce ETB receptor desensitization. ET‐1‐induced contractions were, at most, only partially attenuated either by blocking the ETA receptor‐effector system (with 10 μm BQ‐123) or by desensitizing the ETB receptor‐effector system with sarafotoxin S6c. However, ET‐1‐induced contractions were markedly attenuated by blocking both receptor‐effector systems simultaneously. These findings suggest that ET‐1 could induce contraction by stimulating either ETA or ETB receptors.
ET‐1 (10 μm) induced a 7 fold increase in intracellular [3H]‐inositol phosphate accumulation over basal levels in rat isolated tracheal smooth muscle. In contrast, sarafotoxin S6c (2.5 μm) increased intracellular [3H]‐inositol phosphate accumulation by only 2 fold. ET‐1‐induced accumulation of [3H]‐inositol phosphates was abolished by 10 μm BQ‐123.
In Ca2+‐free Krebs bicarbonate solution, 100 nm ET‐1 induced a significantly larger contraction than that induced by 100 nm sarafotoxin S6c (46.6 ± 5.6% Cmax versus 8.8 ± 2.8% Cmax, n = 5–7). This presumed intracellular Ca2+‐dependent phase of contraction induced by ET‐1 was significantly inhibited by 10 μm BQ‐123 (7.5 ± 1.0% Cmax). Subsequent addition of 2.5 mm Ca2+ induced a second phase of contraction. The extracellular Ca2+‐dependent phase of contraction induced by ET‐1 was similar in magnitude to that induced by sarafotoxin S6c (63.6 ± 4.5% Cmax versus 58.0 ± 3.7% Cmax) and was not inhibited by BQ‐123. Sarafotoxin S6c‐induced contractions were not inhibited by the L‐type Ca2+‐channel antagonists, nicardipine or verapamil.
In summary, ETA and ETB receptors coexist in rat isolated tracheal smooth muscle and stimulation of both receptor subtypes contributes to ET‐1‐induced contraction in this tissue. However, stimulation of these receptor subtypes appears to induce contraction by activating different second messenger pathways; ETA receptor stimulation induces phosphoinositide turnover and subsequent release of intracellular Ca2+ whereas stimulation of ETB receptors facilitates the influx of extracellular Ca2+.
Endothelium‐dependent noradrenaline‐induced relaxation of rat isolated cerebral arteries: pharmacological characterization of receptor subtypes involved
Authors: Hempelmann Ralf G. , Ziegler Albrecht 
Published: July 2012

The endothelium‐dependence of catecholamine‐induced relaxation of rat cerebral arteries was investigated in vitro.
In the basilar artery (BA), the maximal relaxant response was most pronounced with noradrenaline (NA), less with isoprenaline (Iso), and only very little with terbutaline. Methoxamine and the α2‐adrenoceptor selective agonists BHT 933 and clonidine, had no relaxant effect.
In BA, the relaxation by NA or Iso was markedly attenuated by Nω‐nitro‐l‐arginine (l‐NOARG) 10−4 m. Short term perfusion of the vessels by Triton X 100 (1:1000) suppressed the NA‐induced relaxation.
The relaxation induced by NA or Iso was markedly reduced in presence of l‐NOARG in the posterior, medial and anterior cerebral artery.
In BA, NA‐induced relaxation was non‐competitively inhibited by propranolol, atenolol, and the β1‐ and β2‐adrenoceptor selective antagonists, CGP 20712 A and ICI 118551.
The relaxant NA‐effect was not affected by prazosin but was non‐competitively blocked by phentolamine.
The Iso‐induced relaxation was competitively blocked by propranolol, whereas atenolol, CGP 20712 A and ICI 118551 caused a non‐competitive inhibition.
The experiments indicate that the catecholamine‐induced relaxation in rat isolated cerebral arteries depends upon the endothelium. They suggest that the NA‐induced relaxation of BA is mediated by different α‐ and β‐adrenoceptors and that the Iso‐induced relaxation is mediated by different β‐receptors. The findings would also be compatible with the idea of a receptor type which cannot be characterized by the pharmacological tools that we have used.
Ca2+ dependency of the release of nitric oxide from non‐adrenergic non‐cholinergic nerves
Authors: Boeckxstaens Guy E. , De Man Joris G. , Pelckmans Paul A. , Cromheeke Kristel M. , Herman Arnold G. , Van Maercke Yvan M. 
Published: July 2012

The role of Ca2+ in nitrergic neurotransmission was studied in the canine ileocolonic junction.
The specific N‐type voltage‐sensitive Ca2+ channel blocker ω‐conotoxin GVIA (CTX, 10–100 nm) significantly reduced the electrically‐evoked (2–16 Hz, 1–2 ms pulse width) non‐adrenergic non‐cholinergic (NANC) relaxations, preferentially affecting those to low frequency stimulation, in circular muscle strips of the ileocolonic junction. In contrast, the nerve‐mediated NANC‐relaxations in response to acetylcholine (30 μm), γ‐aminobutyric acid (100 μm) and adenosine 5′‐triphosphate (100 μm), as well as the relaxations to nitric oxide (NO) (3–10 μm) and nitroglycerin (1 μm), remained unaffected.
A NO‐related substance (NO‐R), released from the ileocolonic junction in response to NANC nerve stimulation (4 and 16 Hz, 2 ms pulse width), was assayed with a superfusion bioassay cascade. CTX (50 nm) reduced the release of NO‐R induced by electrical impulses (4 Hz: from 18 ± 4% to 6 ± 4%; 16 Hz: from 33 ± 2% to 14 ± 4%, n = 5), but not that in response to the nicotinic receptor agonist, 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP, 0.3 mm). In Ca2+‐free medium, the release of NO‐R evoked by electrical impulses or DMPP was inhibited. The L‐type Ca2+ channel blockers verapamil (1–3 μm) and nifedipine (1 μm) had no effect.
From these results we conclude that the release of NO‐R in response to NANC nerve stimulation is Ca2+‐dependent. The electrically‐evoked release of NO‐R results from Ca2+ entry through CTX‐sensitive N‐type voltage‐sensitive Ca2+ channels, whereas that induced by nicotinic receptor activation involves CTX‐insensitive Ca2+ channels, different from the L‐ or N‐type.
Nasal administration of an ACTH(4–9) peptide analogue with dimethyl‐β‐cyclodextrin as an absorption enhancer: pharmacokinetics and dynamics
Authors: Schipper Nicolaas G.M. , Verhoef J. Coos , De Lannoy Larissa M. , Romeijn Stefan G. , Brakkee Jan H. , Wiegant Victor M. , Gispen Willem Hendrik , Merkus Frans W.H.M. 
Published: July 2012

The systemic absorption and the neurotrophic effect of the metabolically stabilized ACTH (4–9) analogue, Org2766, were investigated following intranasal (i.n.) administration.
Without additives the nasal bioavailability of the peptide was in the order of 15 and 10% in rats and rabbits, respectively. The absorption could be improved by addition of a variety of absorption enhancers to the nasal preparation. The β‐cyclodextrin derivative, dimethyl‐β‐cyclodextrin (DMβCD) at a concentration of 5% (w/v) improved the absorption in rats about 5 fold from 13 ± 4% (mean ± s.d.) for administration of the peptide alone to 65 ± 21%, and in rabbits 1 to 2 fold, from 10 ± 6% to 17 ± 8%.
The increased permeability of the rat nasal mucosa for Org2766 caused by DMβCD in rats reversed substantially within 1 h. However, the nasal absorption had not yet completely returned to the level without enhancer.
S.c. administered Org2766 accelerated the functional recovery from peripheral nerve damage in rats. However, the peptide did not facilitate nerve repair following i.n. administration with DMβCD, in spite of the fact that Org2766 was well absorbed. I.v. injection of Org2766 was also ineffective.
5‐HT3 antagonists reduce morphine self‐administration in rats
Authors: Hui Siu‐Chun G. , Sevilla Elenita L. , Ogle Clive W. 
Published: July 2012

The effects of the 5‐HT3 receptor antagonists, ondansetron and tropisetron, on morphine consumption were studied in naive and morphine‐dependent rats.
The administration of ondansetron (1 μg kg−1, i.p. twice daily) 7 days prior to, and during a 21‐day period of, morphine availability (increasing concentration from 0.1 to 0.4 mg ml−1) in 5% sucrose solution reduced opiate intake from the 9th day of morphine treatment.
The administration of ondansetron (0.1 μg kg−1, i.p. twice daily) or tropisetron (0.1 μg kg−1, i.p. twice daily) on the 14th day of the 21‐day period of morphine treatment failed to reduce opiate consumption. Administration of the larger doses of tropisetron (1 μg kg−1) or ondansetron (1 μg kg−1) reduced morphine consumption.
After receiving 21 days of treatment with morphine alone or with the ondansetron or tropisetron regimens identified above, the sucrose solutions were substituted with tap water for 7 days. These detoxified rats were then allowed a free choice of sucrose or morphine for 10 days. Animals that had received concomitant treatment with ondansetron or tropisetron showed reduced morphine intake when compared with the controls treated with morphine only or with vehicle‐treated controls.
The administration of cyproheptadine (100 or 250 μg kg−1, i.p. twice daily) on the 14th day of 21‐day morphine treatment failed to modify morphine intake and also failed to influence the subsequent intake of the opiate in the free choice situation.
It is concluded that ondansetron and tropisetron can reduce morphine intake in both naive and morphine‐dependent rats.
Binding and structure‐activity‐relation of benzo[f]isoquinoline‐ and norcodeinone‐derivatives at μ‐opioid receptors in the rat cerebral cortex
Authors: Freissmuth Michael , Beindl Wolfgang , Kratzel Martin 
Published: July 2012

We have probed the ligand binding site of the μ‐opioid receptor using a series of isoquinoline‐ and norcodeinone‐derivatives; in these morphine‐ and codeine‐analogues, the position of the piperidine‐nitrogen as well as its mobility is altered relative to that found in morphine.
The μ‐receptor in rat cortical membranes was labelled with [3H]‐naloxone and competition experiments were carried out in the absence and presence of Gpp(NH)p and NaCl: conditions, which are associated with affinity shifts for agonists whilst antagonist affinity remains unaffected. Moving the piperidine‐nitrogen closer to the phenolic ring or reducing its mobility by incorporation into an additional ring drastically decreases the affinity.
In contrast, we find that the piperidine‐nitrogen in a distal position is well tolerated provided that additional structural criteria, in particular a phenolic hydroxyl‐group and a 6 carbon ring corresponding to ring C in morphine, are met. This assumption was verified by the synthesis of WB4/PH (4aR, 10bS, 11R)‐10, 11‐epoxy‐1, 2, 3, 4, 5, 6‐hexahydro‐9‐hydroxy‐3‐methyl‐4a,10b‐butano‐benzo[f]isochinolin‐12‐on(10). This compound is an agonist with an affinity comparable to that of morphine.
We therefore conclude that both the mobility of the piperidine nitrogen of the ligand and of its counterpart anionic site in the ligand binding pocket of the μ‐opioid receptor (presumably aspartic acid) are important determinants for fruitful interaction. The mobility of the anionic site is restricted in one direction but is sufficient to bridge the 2Å distance that exists between the position of the nitrogen in morphine and WB4/PH.
Effects of selective antagonism of β‐adrenoceptor sub‐types on responses to isoprenaline in rat distal colon in vitro
Authors: MacDonald Allan , Lamont Michelle 
Published: July 2012

The effects of the β1‐ and β2‐adrenoceptor selective antagonists, CGP 20712A and ICI 118551 respectively, on responses to isoprenaline‐induced relaxation of rat distal colon were investigated in order to determine the contributions of these subtypes to relaxation. In addition, the properties of ICI D7114, a novel putative stimulant of atypical β‐adrenoceptors, were investigated. Our preliminary experiments with ICI D7114 showed that this compound lacked agonist activity in rat distal colon and in fact antagonized responses to isoprenaline. We therefore studied the antagonism of isoprenaline by ICI D7114 in more detail.
Longitudinal segments of rat distal colon were suspended in Krebs solution at 37°C for isometric recording. The Krebs solution contained EDTA (23 μm) and prazosin (0.1 μm) and was gassed with 95/5% O2/CO2. After an initial equilibration period, reproducible contractions to a submaximal concentration of methacholine (1 μm) were obtained before carrying out a concentration‐response curve (CRC) to isoprenaline in a non‐cumulative manner. Four consecutive CRCs to isoprenaline were carried out in each tissue with a 1 h interval between each curve. Antagonists were present in increasing concentrations during the intervals between CRCs. Control tissues received no antagonists to allow estimation of the magnitude of time‐dependent changes.
Isoprenaline produced a concentration‐dependent inhibition of methacholine‐induced contractions. CRCs to isoprenaline were reproducible with no significant time‐dependent changes. Propranolol produced no shift of the isoprenaline CRC at 0.01 μm and a 5 fold shift at 0.1 μm. No further shift was observed with 1 μm. CGP 20712A had no effect on the CRC to isoprenaline at 0.1, 1 and 3 μm. ICI 118551 produced little or no shift at 0.1 μm and a six fold shift with 1 μm. No further shift was observed with 3 μm. ICI D7114 produced a concentration‐dependent parallel rightward shift of the CRC to isoprenaline. Schild analysis gave a slope close to unity and a mean pA2 value of 7.29 for ICI D7114.
The results with propranolol and β1‐ and β2‐adrenoceptor antagonists confirm the mainly atypical nature of β‐adrenoceptors in rat distal colon. There may also be a small contribution from β2‐adrenoceptors in the response to isoprenaline but β1‐adrenoceptors are absent. ICI D7114 has no agonist activity and behaves as a relatively high affinity reversible competitive antagonist of atypical β‐adrenoceptors in this preparation.
Electrophysiological and antiarrhythmic actions of the κ agonist PD 129290, and its R,R (+)‐enantiomer, PD 129289
Authors: Pugsley M.K. , Saint D.A. , Penz M.P. , Walker M.J.A. 
Published: July 2012

The S,S (−)‐enantiomer PD 129290, a κ agonist, and its corresponding inactive R,R (+)‐enantiomer (PD 129289) were studied in rat isolated hearts and in intact rats for cardiovascular and antiarrhythmic actions. The electrophysiological actions of PD 129290 were also studied in rat isolated cardiac myocytes using voltage clamp.
Ventricular pressure, heart rate and ECG were studied in isolated hearts while blood pressure, heart rate and ECG were studied in pentobarbitone‐anaesthetized rats. In the latter, responses to electrical stimulation and coronary occlusion were also investigated.
In isolated hearts both enantiomers, over the concentration range 2–16 μm, dose‐dependently reduced systolic ventricular pressure and heart rate while prolonging the P–R and QRS intervals of the ECG.
At doses of 1–32 μmol kg−1 both enantiomers reduced blood pressure and heart rate in anaesthetized rats. In addition, both enantiomers increased the size of the RSh and increased P–R, QRS, and Q–T intervals of the ECG. The thresholds for premature beats and ventricular fibrillation were dose‐dependently increased by PD 129289. At lower doses PD 129290 decreased thresholds. These decreases were blocked by naloxone to reveal underlying increases similar to those seen with PD 129289. Both enantiomers increased refractory periods.
Naloxone (8 μmol kg−1) did not alter any of the actions of PD 129290, except to abolish the initial decreases in thresholds in intact rats seen with lower doses of PD 129290.
Both enantiomers (2 and 8 μmol kg−1) equally reduced arrhythmias in anaesthetized rats subject to occlusion of a coronary artery.
In rat isolated cardiac myocytes 20 μm PD 129290, in the presence and absence of naloxone decreased the amplitude of the transient sodium current by about 50% without affecting the voltage‐dependence of activation or inactivation of this current.
The antiarrhythmic actions of both enantiomers appear to primarily result from their Class I (sodium channel blockade) properties which are independent of κ agonism.
Electrophysiological effects of S 16257, a novel sino‐atrial node modulator, on rabbit and guinea‐pig cardiac preparations: comparison with UL‐FS 49
Authors: Thollon Catherine , Cambarrat Christine , Vian Joël , Prost Jean‐François , Peglion Jean Louis , Vilaine Jean Paul 
Published: July 2012

S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL‐FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes.
In the rabbit isolated sino‐atrial node (SAN) tissue, S 16257 and UL‐FS 49 (1 μm, 3 μm and 10 μm) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 μm, – 23.8 ± 3.9% and – 27.9 ± 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 μm. In these preparations, action potential duration at 50% of total repolarization (APD50) was more affected by UL‐FS 49 than S 16257 at any concentration tested (at 3 μm, + 8.9 ± 2.9% and + 29.1 ± 3.7% for S 16257 and UL‐FS 49, respectively; P ≤ 0.01).
To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea‐pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL‐FS 49 (0.1 to 10 μm, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL‐FS 49 (at 1 μm, + 6.1 ± 0.6% and + 11.2 ± 1.3% elevation of APD50, for S 16257 and UL‐FS 49, respectively).
Application of UL‐FS 49 (3 μm) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD50 and APD90 (+ 149.4 ± 51.2% and + 86.0 ± 15.4%, respectively). S 16257 (3 μm) induced only a weak prolongation of AP (+ 14.1 ± 5.0% and + 14.8 ± 3.3% for APD50 and APD90, respectively) significantly smaller than in the case of UL‐FS 49.
These results show that S 16257 slows the rate of spontaneous AP firing in isolated SAN mainly by a reduction of the diastolic depolarization of the cells, which suggests an inhibition of the pace‐maker current (If). S 16257 and UL‐FS 49 are equipotent in their bradycardic effect but S 16257 is more specific as it induces less increase in myocardial repolarization time.