bluuebunny/crossref_metadata_2025_split huggingface dataset:
An amplifying effect of exogenous and neurally stored 5‐hydroxytryptamine on the neurogenic contraction in rat tail artery
Authors: Szabó Csaba , Hardebo Jan Erik , Owman Christer 
Published: July 2012

The interactions between sympathetic neuroeffector transmission and 5‐hydroxytryptamine (5‐HT) were investigated in segments of rat isolated tail artery.
Contractile responses to field stimulation of the artery segments were abolished by tetrodotoxin (3 × 10−7 m). A subthreshold concentration of acutely applied exogenous 5‐HT (10−8 m) markedly enhanced the contractions induced by sympathetic nerve stimulation, through an action on postjunctional 5‐HT2‐receptors.
The amplifying effect of 5‐HT involved an enhanced influx of extracellular calcium into the smooth muscle cells. In contrast, the neurogenic contractions in vessels not exposed to 5‐HT were not dependent on extracellular calcium.
The adrenergic component of the amplified response involved postjunctional α1‐ but not α2‐ adrenoceptor activation.
Exposure of the vessels to 5‐HT (5 × 10−7 m) for 30 min resulted in uptake of the amine into the perivascular sympathetic nerves, as demonstrated by immunohistochemistry. After chemical sympathectomy with 6‐hydroxydopamine in vitro or in vivo, or surgical sympathectomy, there was little or no uptake.
Exposure to 5‐HT followed by repeated washing resulted in an enhancement of the neurogenic contraction, which was still fully tetrodotoxin‐sensitive. The enhanced response was blocked by ketanserin (10−8 m) and prevented by the presence of the 5‐HT uptake blocker, paroxetine (3 × 10−8 m), during the period of exposure to 5‐HT.
Effects of acute paroxetine administration on tryptophan metabolism and disposition in the rat
Authors: Badawy Abdulla A.‐B. , Morgan Christopher J. 
Published: July 2012

The effects of acute oral administration of paroxetine on tryptophan metabolism and disposition were examined in the rat.
Basal liver tryptophan pyrrolase activity was inhibited by paroxetine in vitro and after oral administration. Maximum inhibition was caused by a 1 mg kg−1 dose.
Paroxetine administration also inhibited pyrrolase activity that had previously been enhanced by hormonal induction by cortisol or cofactor activation by haematin. The cortisol induction of the enzyme was, however, not inhibited by pretreatment of rats with paroxetine.
Paroxetine increased tryptophan availability to the brain, because of the above pyrrolase‐inhibitory mechanism. Cerebral 5‐hydroxytryptamine (5‐HT) synthesis was accordingly enhanced, though this was apparent only with doses of the drug of up to 1 mg kg−1. With larger doses, decreased 5‐HT turnover, probably as a result of 5‐HT uptake inhibition, was the more dominant feature.
Paroxetine lowered circulating corticosterone concentration, but did not influence those of albumin, non‐esterified fatty acids or glucose.
It is concluded that, in addition to inhibiting brain 5‐HT turnover, paroxetine also, in common with 20 other antidepressants, enhances 5‐HT synthesis by increasing brain tryptophan concentration secondarily to inhibition of liver tryptophan pyrrolase activity.
Evidence for nitric oxide as mediator of non‐adrenergic, non‐cholinergic relaxations induced by ATP and GABA in the canine gut
Authors: Boeckxstaens Guy E. , Pelckmans Paul A. , Bult Hidde , De Man Joris G. , Herman Arnold G. , Van Maercke Yvan M. 
Published: July 2012

The effects of haemoglobin, and the nitric oxide (NO) biosynthesis‐inhibitors NG‐monomethyl‐l‐arginine (l‐NMMA), its enantiomer d‐NMMA, and NG‐nitro‐l‐arginine (l‐NNA) were investigated on non‐adrenergic non‐cholinergic (NANC)‐mediated relaxation of circular muscle strips of the canine terminal ileum and ileocolonic junction induced by electrical stimulation, adenosine 5′‐triphosphate (ATP), γ‐aminobutyric acid (GABA) and NO.
Tetrodotoxin, l‐NMMA and l‐NNA, but not d‐NMMA, inhibited the relaxations induced by electrical stimulation, ATP and GABA, but not those in response to NO.
The inhibitory effect of l‐NMMA and l‐NNA was prevented by l‐arginine, but not by d‐arginine. l‐Arginine did not potentiate any of the NANC relaxations.
Haemoglobin reduced the relaxation induced by electrical stimulation, ATP and GABA, and abolished those in response to NO.
Our results demonstrate that the ATP‐ and GABA‐induced relaxations resulting from stimulaton of intramural NANC neurones, in addition to those induced by electrical impulses, are mediated by NO or a NO releasing substance and thus provide further evidence in support of the proposal that NO is the final inhibitory NANC neurotransmitter in the canine terminal ileum and ileocolonic junction.
Effect of phorbol ester on the release of atrial natriuretic peptide from the hypertrophied rat myocardium
Authors: Kinnunen Päivi , Taskinen Tarja , Järvinen Mikko , Ruskoaho Heikki 
Published: July 2012

To determine the cellular mechanisms of atrial natriuretic peptide (ANP) release from ventricular cardiomyocytes, the secretory and the cardiac effects of a phorbol ester, 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), known to stimulate protein kinase C activity in heart cells, were studied in isolated, perfused heart preparations from 2‐ and 21‐month‐old Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats. TPA was added to the perfusion fluid for 30 min at a concentration of 46 nm after removal of atrial tissue. Additionally, atrial and ventricular levels of immunoreactive ANP (IR‐ANP) and ANP mRNA, the distribution of ANP within ventricles as well as the relative contribution of atria and ventricles in the release of ANP were studied.
Ventricular hypertrophy that gradually developed in hypertensive rats resulted in remarkable augmentation of ANP gene expression, as reflected by elevated levels of immunoreactive ANP and ANP mRNA. The total amount of IR‐ANP in the ventricles of the SHR rats increased 41 fold and ANP mRNA levels 12.9 fold from the age of 2 to 21 months. At the age of 21 months, levels of IR‐ANP and ANP mRNA in the ventricles of SHR rats were 5.4 fold and 3.7 fold higher, respectively, than in the normotensive WKY rats. Immunohistochemical studies demonstrated ANP granules within the hypertrophic ventricles of the old SHR rats, but not within normal ventricular tissue.
In isolated perfused heart preparations, the severely hypertrophied ventricular tissue of SHR rats after atrialectomy secreted more ANP into the perfusate than did the control hearts. The phorbol ester TPA caused a marked vasoconstriction in both the 2‐month and 21‐month old normal and hypertrophied hearts. Interestingly, the ANP release from the hypertrophied ventricles of the old SHR rats increased considerably (from 413 ± 30 to the maximum of 623 ± 75 pg ml−1, F = 10.8, P < 0.001, two‐way analysis of variance), whereas only a small increase was seen in old WKY rats and no effect was observed in young animals of either strain. When intact rat hearts (without atrialectomy) were used, infusion of phorbol ester also increased the ANP secretion into the perfusate in young animals.
Our present results indicate that the phorbol ester TPA increases the release of ANP from the hypertrophied, but not from normal rat myocardium. Thus, hypertrophied rat ventricular myocytes appear to possess the cellular mechanisms necessary to secrete ANP by a regulated pathway. The results further suggest that protein kinase C activity may be involved in the the regulation of ANP secretion from ventricular cells, as has been shown earlier for atrial myocytes.
Diabetes‐induced changes in cardiac β‐adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat
Authors: Austin Clare E. , Chess‐Williams Russell 
Published: July 2012

The responses of isolated left atria and papillary muscles to isoprenaline, forskolin and calcium have been examined in 3 week streptozotocin‐diabetic rats and the effects of oral ponalrestat administration (25 mg kg−1 daily) on diabetes‐induced changes in cardiac responsiveness investigated.
Three weeks after animals were made diabetic, cardiac responses to isoprenaline were enhanced and this was accompanied by an increase in the density of ventricular [3H]‐dihydroalprenolol binding sites. Treatment of animals with ponalrestat prevented the increase in cardiac β‐adrenoceptor responsiveness and receptor number.
Diabetes also enhanced the sensitivity of cardiac tissues to forskolin, an effect that was not prevented by the treatment of animals with ponalrestat.
Ponalrestat treatment increased the resting and maximum tensions developed by cardiac tissues from diabetic animals and increased the maximum tensions developed by tissues from control animals. Diabetes alone had no effect on resting or maximum developed tensions.
Ponalrestat therefore prevents the changes in β‐adrenoceptor density and responsiveness induced by short‐term diabetes in the rat and also increases the tension developed by cardiac muscle, an effect observed in diabetic and normal animals.
Relaxation of sheep cerebral arteries by vasoactive intestinal polypeptide and neurogenic stimulation: inhibition by l‐NG‐monomethyl arginine in endothelium‐denuded vessels
Authors: Gaw A.J. , Aberdeen J. , Humphrey P.P.A. , Wadsworth R.M. , Burnstock G. 
Published: July 2012

Perivascular nerves of the sheep middle cerebral artery show immunoreactivity for both vasoactive intestinal polypeptide (VIP) and calcitonin gene‐related peptide (CGRP).
Rings of endothelium‐denuded sheep middle cerebral artery precontracted with 5‐hydroxytryptamine were relaxed by CGRP (maximum relaxation = 87.8 ± 8.1%, pD2 = 7.81 ± 0.12, n = 12) and by VIP (maximum relaxation = 55.1 ± 4.1%, pD2 = 7.65 ± 0.04, n = 18). Rings of endothelium‐denuded cat middle cerebral artery precontracted with U46619 were also relaxed by vasoactive intestinal polypeptide (maximum relaxation = 53.1 ± 6.1%, pD2 = 7.82 ± 0.11, n = 6).
Haemolysate (1 μl ml−1) inhibited VIP‐induced relaxation in endothelium‐denuded sheep and cat middle cerebral artery (n = 6) but had no effect on the CGRP‐induced relaxation of the sheep middle cerebral artery (n = 6).
The relaxant response to VIP in endothelium‐denuded sheep middle cerebral artery was inhibited by methylene blue (10 μm) and augmented by either M&B 22948 (10 μm) or superoxide dismutase (150 units ml−1). Indomethacin (1 μm) had no effect.
The addition of l‐NG‐monomethyl arginine (100 μm) inhibited both neurogenic and VIP‐induced relaxation of endothelium‐denuded sheep MCA by 56 ± 6% and 60 ± 6% (n = 5) respectively. The CGRP‐induced relaxation was unaffected.
It is concluded that neurally mediated vasodilatation in the sheep middle cerebral artery is mediated largely by VIP through a direct action on smooth muscle through a cyclic‐GMP‐mediated mechanism that appears to involve synthesis of nitric oxide from l‐arginine. Vasodilatation by CGRP, which is also contained in perivascular nerves, does not utilize this pathway.
Local application of drugs to sympathetic nerve terminals: an electrophysiological analysis of the role of prejunctional α‐adrenoceptors in the guinea‐pig vas deferens
Authors: Brock J.A. , Cunnane T.C. 
Published: July 2012

Focal extracellular recording techniques were used to study the effects of clonidine, yohimbine and tyramine on the intermittent transmitter release mechanism in the guinea‐pig vas deferens in vitro. Drugs were applied locally to the varicosities located within the recording electrode. Statistical methods were used to determine whether noradrenaline (NA) acts locally to inhibit secretion from the same or a closely related release site (local regulation) on an impulse‐to‐impulse basis.
The α‐adrenoceptor agonist, clonidine, inhibited transmitter release, an effect reversed by the α‐adrenoceptor antagonist, yohimbine. Yohimbine alone increased action potential‐evoked transmitter release, findings consistent with the idea that transmitter release is regulated through prejunctional α‐adrenoceptors.
The indirectly acting sympathomimetic, tyramine, powerfully inhibited evoked transmitter release, an effect reversed by both yohimbine and phentolamine. The inhibitory effects of tyramine were greatly reduced in tissues taken from animals pretreated with reserpine. Clonidine powerfully inhibited transmitter release in reserpinized tissues showing that prejunctional α‐adrenoceptors were functionally intact. The inhibitory effects of tyramine on transmitter release are therefore mediated indirectly through the release of endogenous NA.
Paradoxically, when transmitter release from a small population of variscosities on a single nerve fibre was studied in the absence of α‐adrenoceptor antagonists, no evidence was found for local regulation of transmitter release.
The intermittent character of the transmitter release process makes it difficult to envisage how impulse‐to‐impulse regulation could occur. Furthermore, it is unlikely that NA will accumulate to any appreciable extent in the vicinity of the secreting varicosity.
The pharmacological evidence clearly supports the view that NA released from sympathetic nerve terminals by nerve impulses modulates subsequent transmitter release. However, the evidence does not support the view that released NA acts locally to inhibit secretion from recently activated varicosities.
The pressor response to central administration of β‐endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion
Authors: May Clive N. , Whitehead Catherine J. , Mathias Christopher J. 
Published: July 2012

The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of β‐endorphin (0.01, 0.1 and 1.0 nmol kg−1) were examined in conscious rabbits.
After i.c.v. β‐endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in Paco2 and fall in Pao2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg−1).
A combination of prazosin (2 mg kg−1) and yohimbine (1 mg kg−1), given i.v., prevented the rise in MAP induced by i.c.v. β‐endorphin.
After i.c. β‐endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression.
Clonidine (1.0 μg kg−1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 μmol kg−1).
These results demonstrate that β‐endorphin acts centrally, probably mainly on periventricular μ‐opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to α‐adrenoceptor‐mediated vasoconstriction. The respiratory depression is probably mediated by brainstem μ‐receptors.
A role for β‐endorphin in the central hypotensive action of α2‐adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.
Pharmacokinetic‐pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration
Authors: Mandema Jaap W. , Tukker Erica , Danhof Meindert 
Published: July 2012

The purpose of the present investigation was to quantify the concentration‐pharmacological effect relationship of midazolam in individual rats by use of effect parameters derived from aperiodic EEG analysis. By varying the rate and route of administration the role of (inter)active metabolites and development of acute tolerance was evaluated.
The pharmacokinetics and pharmacodynamics of midazolam were determined after intravenous administration of 10 mg kg−1 during 5, 30 and 60 min and oral administration of 15 mg kg−1. Following intravenous administration the pharmacokinetics were most adequately described by a bi‐exponential equation. The values (mean ± s.e.mean, n = 20) of clearance, volume of distribution at steady‐state and terminal half‐life were 67 ± 2 ml min−1 kg−1, 1.61 ± 0.071 kg−1 and 27 ± 1 min, respectively. Following oral administration midazolam was rapidly absorbed with a systemic availability of 45 ±9%.
The averaged amplitudes in the 11.5–30 Hz (beta) frequency band of the fronto‐central lead on the left‐hemisphere, as derived by aperiodic EEG analysis, was selected as a measure of the pharmacological effect of midazolam. By pharmacokinetic‐pharmacodynamic modelling the individual concentration‐EEG effect relationships of midazolam were derived, which were successfully quantified by the sigmoidal Emax model. No marked and systematic differences in pharmacodynamic parameters were found between the rates and routes of administration. The averaged pharmacodynamic parameters of midazolam obtained after combining the results of all rates and routes of administration were (mean ± s.e.mean, n = 27): Eo = 61 ± 3 μV s−1, Emax = 85 ± 3 μV s−1, EC50 = 40 ± 3ng ml−1 and N = 0.84 ± 0.04.
The results of the present study show that the concentration‐EEG effect relationship of midazolam can be characterized in individual animals using the amplitudes in the 11.5–30 (beta) frequency band as a measure of pharmacological response. Acute tolerance did not develop and (inter)active metabolites did not contribute to this effect parameter within the time span of the experiments.
Selectivity of Ca2+channel blockers in inhibiting muscular and nerve activities in isolated colon
Authors: Lecchini S. , Marcoli M. , De Ponti F. , Castelletti C.A. , Frigo G.M. 
Published: July 2012

Potency and efficacy of nifedipine, verapamil and diltiazem and of Bay K 8644 in modifying propulsion and nerve or smooth muscle activities have been compared in the guinea‐pig isolated distal colon. Both the neuronal and muscular effects of Ca2+channel blockers seem to develop at concentrations that are devoid of any significant effect apart from that on Ca2+channels.Nifedipine, verapamil and diltiazem were all able to impair propulsion, resting and stimulated acetylcholine (ACh) release and smooth muscle contractility in a concentration‐dependent way. However, some degree of selectivity for neuronal and muscular effects could be observed. Nifedipine was more than 500 fold more potent than verapamil in relaxing musculature but less than twice as potent in reducing ACh release. On the other hand, verapamil was the most efficacious Ca2+channel blocker tested in inhibiting ACh release, its effects being inversely correlated to the external Ca2+concentration, and completely abolished by Bay K 8644.By comparing the potencies exhibited by each drug against peristaltic reflex, smooth muscle contractility and ACh release, verapamil proved to be almost as potent in slowing the peristaltic reflex as in reducing ACh release, while nifedipine was about 100 fold more potent against the peristaltic reflex than against ACh release, but nearly equal against the peristaltic reflex and smooth muscle tone. Therefore, interference with cholinergic neurotransmission is likely to play a major role in the antipropulsive effect of verapamil, while peristaltic reflex impairment by nifedipine is likely to be dependent on inhibition of smooth muscle.A facilitatory effect of Bay K 8644 on both the efficiency of the peristaltic reflex and the non‐adrenergic, non‐cholinergic (NANC) nerve‐mediated relaxation could be observed at concentrations at least 10 fold lower than those required to affect ACh release or smooth muscle.It is concluded that the effects of Ca2+channel blockers on neurotransmitter release may be relevant to their effects on the gastrointestinal motor function.
4‐Aminopyridine‐induced increase in basal and stimulation‐evoked [3H]‐NA release in slices from rat hippocampus: Ca2+ sensitivity and presynaptic control
Authors: Hu Ping‐Sheng , Fredholm Bertil B. 
Published: July 2012

We have examined the mechanisms by which the K+‐channel blocker 4‐aminopyridine (4‐AP) can dose‐dependently increase both basal [3H]‐noradrenaline ([3H]‐NA) release and the [3H]‐NA release evoked by electrical stimulation, but not the release of [3H]‐acetylcholine ([3H]‐ACh), from slices of rat hippocampus.
Both the electrically evoked and the 4‐AP‐induced release were blocked by tetrodotoxin (TTX) (3 μm). The Ca2+‐dependence of the 4‐AP‐induced release (EC50 0.15 mm) was, however, different from that of the electrically evoked [3H]‐NA release (EC50 0.76 mm).
The 4‐AP‐induced release could be inhibited by CdCl2(10 μm) and ω‐conotoxin (30 nm), but not by nifedipine (1 μm).
Transmitter release evoked by 100 μm 4‐AP could be blocked by the α2‐adrenoceptor agonist, UK 14,304 (0.1 μm) and by the A1‐receptor agonist R‐N6‐phenylisopropyl adenosine (R‐PIA, 1 μm) and increased by the α2‐adrenoceptor antagonist, yohimbine (1 μm), both in 0.25 and 1.3 mm Ca2+‐containing medium. By contrast, the effect of α2‐adrenoceptor agonists and antagonists on transmitter release evoked by electrical stimulation was markedly reduced in the presence of 4‐AP (100 μm).
The results suggest that 4‐AP can depolarize some nerve endings in the central nervous system, leading to transmitter release that is dependent on nerve impulses and Ca2+. Furthermore, the fact that α2‐receptors and adenosine A1 receptor agonists can influence the release of NA evoked by 4‐AP suggests that these drugs may have actions that are independent of blockade of aminopyridine‐sensitive K+‐channels.
Hoe 140 a new potent and long acting bradykinin‐antagonist: in vivo studies
Authors: Wirth K. , Hock F.J. , Albus U. , Linz W. , Alpermann H.G. , Anagnostopoulos H. , Henke St. , Breipohl G. , König W. , Knolle J. , Schölkens B.A. 
Published: July 2012

The potency, duration of action and tolerability of Hoe 140, a novel and highly potent bradykinin (BK) antagonist in vitro, has been tested in different in vivo models and compared with the well‐known BK antagonist d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK.
Hoe 140 is highly potent and long acting in inhibiting BK‐induced hypotensive responses in the rat. Four hours after s.c. administration of 20 nmol kg−1, inhibition still amounted to 60% whereas the effect of 200 nmol kg−1 of d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK was not significant.
BK‐induced bronchoconstriction in guinea‐pigs was strongly inhibited by Hoe 140. The magnitude and duration of inhibition confirmed the findings obtained in the blood pressure experiments in the rat.
Carrageenin‐induced inflammatory oedema of the rat paw was considerably inhibited at i.v. doses between 0.1 and 1 mg kg−1.
In conscious dogs, intravenous doses of 0.01 and 0.1 mg kg−1 of Hoe 140 and d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK were well tolerated. At doses of 1 mg kg−1 adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds.
Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.