bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bacterial endotoxin rapidly stimulates prolonged endothelium‐dependent vasodilatation in the rat isolated perfused heart
Authors: Baydoun Anwar R. , Foale Robert D. , Mann Giovanni E. 
Published: July 2012

The effects of bacterial lipopolysaccharide (Escherichia coli 0111‐B4; LPS) on coronary vascular tone were examined in the isolated perfused heart of the rat. The role of nitric oxide and/or prostaglandin products of the cyclo‐oxygenase pathway in mediating the actions of LPS were also investigated.
Coronary vascular tone was raised and maintained by a continuous perfusion of the thromboxane‐mimetic U46619 (5 nm). LPS perfusion (0.1–100 μg ml−1) caused a concentration‐dependent fall in coronary tone without any significant change in the force of cardiac contractility.
At 5 μg ml−1, LPS reduced perfusion pressure by 38 ± 9 mmHg. This effect was rapid in onset, maximal within the first 5 min and sustained for 90 ± 10 min (n = 6).
The vasodilatation induced by LPS was dependent on the presence of an intact endothelium and abolished following endothelial damage caused by air embolism.
NG‐nitro‐l‐arginine methylester (l‐NAME; 50 μm) or NG‐nitro‐l‐arginine (l‐NOARG; 50 μm) blocked the vasodilatation induced by LPS (5 μg ml−1). The inhibition caused by these arginine analogues was partially reversed by 1 mm l‐ but not d‐arginine.
The vasodilator action of LPS was also completely blocked by the glucocorticoid, dexamethasone (10 μm) but unaffected by indomethacin (10 μm).
These results suggest that LPS evokes rapid release of nitric oxide (NO) in the microvasculature of the rat isolated heart presumably via activation of the constitutive l‐arginine‐NO pathway in the endothelium. Furthermore, the lack of effect of indomethacin suggests that prostaglandins released via the cyclo‐oxygenase pathway are not involved in mediating this action of LPS.
Heterogeneity of muscarinic receptors in lamb isolated coronary resistance arteries
Authors: Simonsen Ulf , Prieto Dolores , Rivera Luis , Hernández Medardo , Mulvany Michael J. , García‐Sacristán Albino 
Published: July 2012

In vitro experiments in a microvascular myograph were designed to characterize postjunctional muscarinic receptors producing contraction both in the presence and absence of the endothelium in coronary resistance arteries (normalized diameter of 150–450 μm), isolated from the left ventricle of hearts from 3–6 month old lambs. Preferential muscarinic receptor antagonists were used to determine the receptor subtype: pirenzepine (M1 receptor), AFDX 116 (M2 receptor), 4‐DAMP and pFHHSiD (M3 receptor).
The rank order of potency for muscarinic agonist‐induced increases in tension in endothelium‐intact preparations was oxotremorine‐M = methacholine = acetylcholine (ACh) > carbachol. Removal of the endothelium increased the potency of ACh, but this procedure did not change either the sensitivity or maximal response to carbachol.
The contractile response to ACh was reproducible. Incubation with 3 × 10−7–3 × 10−6 m pirenzepine induced non‐parallel rightward shifts and depressed the maximum of the concentration‐response curve to ACh in endothelium‐intact arteries. The slope by Schild analysis was 2.9 ± 0.8 (P < 0.05, n = 7). Atropine, AFDX 116, 4‐DAMP and pFHHSiD produced parallel rightward shifts of the curves to ACh and the slopes of the Schild plots were not significantly different from unity. The pKB values for the antagonists from plots constrained to unity in endothelium‐intact segments were: atropine (9.4), 4‐DAMP (9.0), pFHHSiD (7.9) and AFDX 116 (6.2).
In endothelium‐denuded arteries, pirenzepine, AFDX 116 and pFHHSiD caused concentration‐dependent, parallel rightward displacements of the concentration‐response curves to ACh and the slopes of the Schild plots were not significantly different from unity. The plots constrained to a slope of unity gave the following pKB values: pFHHSiD (8.7), pirenzepine (7.5) and AFDX 116 (6.2).
In the presence of the endothelium, low concentrations of pirenzepine (10−9–10−7m) produced leftward shifts of the ACh concentration‐response curves. This potentiating effect of pirenzepine was reversed by endothelial cell removal. In preparations precontracted with the thromboxane‐mimetic, U46619, the putative M1‐selective agonist, McN‐A‐343, induced a biphasic relaxation with log IC50 of 8.53 ± 0.14 and 5.02 ± 0.08 for the first and second phase of the relaxation, respectively, and maximal relaxations of 22.8 ± 4.3% and 41.1 ± 5.4% (n = 16). McN‐A‐343 relaxed the vessels in the presence of 10−7m pFHHSiD and 3 × 10−7 m AFDX 116, but not after incubation with 10−9m pirenzepine.
It is concluded from the pKB values for the antagonists used, that contraction induced by ACh in lamb coronary resistance arteries, in either the presence or the absence of the endothelium, is mediated via the M3 subtype of muscarinic receptors, while muscarinic receptors of another subtype at the endothelium seem to modulate the contractile response to ACh.
β1‐ and β2‐adrenoceptor‐mediated relaxation in human internal mammary artery and saphenous vein: unchanged β‐ and α‐adrenoceptor responsiveness after chronic β1‐adrenoceptor blockade
Authors: Ferro A. , Kaumann A.J. , Brown M.J. 
Published: July 2012

We have recently reported that patients taking β1‐adrenoceptor‐selective antagonists exhibit marked sensitization of β2‐adrenoceptor responses but unaltered β1‐adrenoceptor responses in the heart, both in vitro and in vivo. We therefore investigated β1‐ and β2‐adrenoceptor‐mediated relaxant responses in rings of human internal mammary artery and saphenous vein without endothelium, taken from β1‐blocked and non‐β‐blocked patients undergoing coronary artery bypass graft surgery, for comparison. We also examined α1‐adrenoceptor‐mediated contraction in these vessels, to determine whether β1‐blockade had any cross‐regulatory effect.
Following α‐blockade with 10 μm phenoxybenzamine, both noradrenaline and adrenaline produced concentration‐dependent relaxations in both blood vessels, their effects being mediated predominantly through β2‐adrenoceptors; a lesser β1‐adrenoceptor component to relaxation was also found in internal mammary artery and a minor β1‐adrenoceptor component was present in saphenous vein. No differences were found in β1‐ or in β2‐adrenoceptor‐mediated vasorelaxation between β1‐blocked and non‐β‐blocked patients.
Methoxamine produced concentration‐dependent contractions in both blood vessels, and the potency and efficacy were not significantly different between vessels from β1‐blocked and from non‐β‐blocked patients.
These findings indicate that, in these tissues, which possess a relatively minor β1‐adrenoceptor component in contrast to myocardial tissue, chronic β1‐blocker treatment does not alter either β1‐ or β2‐adrenoceptor responses. Likewise, in such tissues, α1‐adrenoceptor responses are unaffected by prior β1‐blockade.
Influence of epithelium on the inhibition of melittin‐induced contraction of guinea‐pig isolated trachea by the potassium channel opener NIP‐121
Authors: Shikada Ken‐ichi , Tanaka Sakuya 
Published: July 2012

We have investigated the effect of the potassium channel opener, NIP‐121, on contraction elicited by melittin (a phospholipase A2 activator) in epithelium‐intact and epithelium‐denuded trachea isolated from guinea‐pigs. The effects of NIP‐121 were compared with those of isoprenaline, aminophylline and hydrocortisone.
In the presence of the cyclo‐oxygenase inhibitor, indomethacin (5 μm), melittin (3 μg ml−1) caused time‐dependent contraction. The melittin‐induced contractile response was significantly augmented by removal of the epithelium and was concentration‐dependently and completely inhibited by the phospholipase A2 (PLA2) inhibitor, p‐bromophenacyl bromide (BPB 10–100 μm), and the lipoxygenase inhibitor, phenidone (10–300 μm). Similar inhibition of the melittin response by BPB (10 μm) and phenidone (10 μm) was observed in the epithelium‐denuded trachea.
Concentration‐dependent inhibition of the melittin response was induced by preincubation with NIP‐121 (0.03 and 0.1 μm), isoprenaline (0.001 and 0.01 μm), aminophylline (30 and 100 μm) and hydrocortisone (100 and 300 μm). The effect of NIP‐121 was abolished by glibenclamide (1 μm).
The inhibitory effect of NIP‐121 on the melittin response was greatly reduced by removing the epithelium while that of the isoprenaline, aminophylline or hydrocortisone was not changed.
The inhibition of the melittin response by these drugs was similar to their inhibition of the contraction elicited by a low concentration (3 nm) of leukotriene D4 (LTD4) in the epithelium‐intact trachea. Inhibition of the LTD4 response by NIP‐121 was not observed in the epithelium‐denuded trachea. However, higher concentrations of NIP‐121 (0.3 and 1 μm) did inhibit LTD4‐induced contractions of epithelium‐denuded trachea.
These findings suggest that melittin causes epithelium‐dependent contraction of the guinea‐pig isolated trachea which is mediated by products of lipoxygenase activity. NIP‐121 may inhibit the melittin response by activating glibenclamide‐sensitive potassium channels, which appear to be epithelium‐dependent (an indirect effect of NIP‐121 apart from its direct effect on the airway smooth muscle) while isoprenaline, aminophylline and hydrocortisone act directly to relax the trachealis smooth muscle.
Bicuculline‐resistant paired‐pulse inhibition in the rat hippocampal slice
Authors: Higgins M.J. , Stone T.W. 
Published: July 2012

An initial observation that paired‐pulse inhibition in hippocampal slices was increased rather than decreased by bicuculline prompted the present study to explore the mechanism underlying bicuculline‐resistant inhibition.
In the presence of bicuculline, paired‐pulse interactions were dependent on the interpulse interval (i.p.i.) but a medium‐latency inhibition was consistently observed at an i.p.i. of 300 to 500 ms.
The medium‐latency (300 ms) bicuculline‐resistant inhibition produced by paired orthodromic stimuli was substantially reduced by 2‐hydroxysaclofen and was probably largely mediated by GABAB‐receptor activation. Paired‐pulse inhibition produced by an orthodromic/antidromic stimulation sequence was not affected by 2‐hydroxysaclofen suggesting the possibility that the GABAB‐receptors involved in orthodromic inhibition may be located presynaptically on the Schaffer collateral terminals rather than on the postsynaptic surface. The medium latency inhibition was also reduced by baclofen and under some conditions, by adenosine.
In addition to the GABAB‐component, a hydroxysaclofen‐resistant depression of postsynaptic excitability contributed to bicuculline‐resistant paired‐pulse inhibition at the 300 ms latency.
[3H]‐5‐carboxamidotryptamine labels 5‐HT1D binding sites in bovine substantia nigra
Authors: Nowak Henry P. , Mahle Cathy D. , Yocca Frank D. 
Published: July 2012

[3H]‐5‐hydroxytryptamine (5‐HT) has been shown to radiolabel at least five types of 5‐HT binding sites in mammalian brain tissue, 5‐HT1A, 5‐HT1B, 5‐HT1C, 5‐HT1D and 5‐HT1E (Frazer et al., 1990). Selective masking of 5‐HT1A and 5‐HT1C receptors, has uncovered binding sites which display both high (5‐HT1D) and low (5‐HT1E) affinity for 5‐carboxamidotryptamine (5‐CT). By utilizing [3H]‐5‐CT we have eliminated a portion of the complex binding (5‐HT1E) seen when [3H]‐5‐HT is used as a radioligand.
[3H]‐5‐CT binding to 5‐HT1D sites in bovine substantia nigra was rapid, reversible and saturable, displaying high affinity (Kd = 0.38 ± 0.04 nm) and low non‐specific binding (> 90% specific binding).
In bovine substantia nigra, [3H]‐5‐CT labelled an equivalent number of binding sites to [3H]‐5‐CT (403 ± 18 and 362 ± 20 fmol mg−1 protein, respectively) and binding was sensitive to guanine nucleotides.
A linear correlation (r2 = 0.99) existed between the potency of compounds to displace [3H]‐5‐HT and [3H]‐5‐CT in bovine substantia nigra.
Therefore, [3H]‐5‐CT is a novel radioligand for the examination of 5‐HT1‐like binding sites, which under proper experimental conditions can be used to radiolabel selectively 5‐HT1D‐like binding sites.
Evaluation of ICI D7114, a putative stimulant of brown adipocytes, on histamine‐contracted guinea‐pig ileum
Authors: Growcott J.W. , Wilson Campbell , Holloway Brian , Mainwaring Sally 
Published: July 2012

Experiments were performed to characterize the effects of the novel brown adipocyte stimulant, ICI D7114, in the guinea‐pig isolated ileum, right atrium and tracheal chain. In the ileum, agonist‐induced inhibition of the contractile response to either histamine or prostaglandin E2 (PGE2) was assessed, along with effects on resting rate in the atrium and resting tone in the tracheal chain. In the latter two preparations, antagonism of isoprenaline‐induced responses by ICI D7114 was also assessed.
Inhibitory responses were obtained in the ileum to ICI D7114, isoprenaline, BRL37344, and noradrenaline. The responses to ICI D7114, isoprenaline and BRL37344 were resistant to blockade with propranolol (5 μm), naloxone (1 μm), methysergide (0.1 μm), cimetidine, indomethacin and 8‐phenyltheophylline (all 10 μm). These responses to isoprenaline, in the presence of propranolol (5 μm), were competitively antagonized by alprenolol (1–100 μm) with a pA2 value of 6.44. The responses to ICI D7114 and BRL37344 were antagonised by single concentrations of alprenolol (1 μm) with apparent pKB values of 6.53 and 6.57 respectively. These data indicate an effect of ICI D7114 at the atypical β‐adrenoceptor in the guinea‐pig ileum.
The order and relative potency of agonists at the atypical β‐adrenoceptor was BRL37344 (4) > isoprenaline (1) = ICI D7114 (1.1) > noradrenaline (0.5).
ICI D7114 (1 nm–10 μm) caused no significant change in the rate of beating or the resting tone of the guinea‐pig right atrium or tracheal chain respectively. It did, however, cause selective blockade of the responses to isoprenaline in these tissues (apparent pKB values 7.63 and 5.85 in atrium and tracheal chain respectively). Responses to histamine (atrium) and aminophylline (tracheal chain) were not significantly affected by 10 μm ICI D7114.
These results demonstrate that ICI D7114 possesses selective agonist activity at atypical β‐adrenoceptors in the guinea‐pig ileum and its use as a tool may help to establish a role for the atypical β‐adrenoceptor in the control of gastrointestinal motility.
Inhibition of the ATP‐sensitive potassium channel by class I antiarrhythmic agent, cibenzoline, in rat pancreatic β‐cells
Authors: Kakei Masafumi , Nakazaki Mitsuhiro , Kamisaki Takeshi , Nagayama Issei , Fukamachi Yuzo , Tanaka Hiromitsu 
Published: July 2012

Cibenzoline, a class I antiarrhythmic agent, was investigated for its effect on the ATP‐sensitive K+ channel of pancreatic β‐cells by the patch clamp technique.
In perforated patch clamp experiments, cibenzoline depolarized the membrane of single β‐cells and thereafter, caused firing of action potentials in the presence of 2.8 mm glucose.
Cibenzoline inhibited the activity of the ATP‐sensitive K+ channel in cell‐attached recordings in the presence of 2.8 mm glucose and evoked repetitive fluctuations of the baseline current, apparently reflecting the action potentials of the β‐cell.
In whole‐cell clamp experiments, time‐independent outward current was induced by depleting cytoplasmic ATP with 0.1 mm ATP and 0.1 mm ADP in the solution contained in the pipette. The outward current was inhibited by cibenzoline in a dose‐dependent manner in the concentration range of 1 μm to 100 μm and half maximum inhibition occurred at 1.5 μm.
Cibenzoline blocked substantially the ATP‐sensitive K+ channel current when applied at the inner side of the membrane in isolated inside‐out membrane patches.
It is concluded that cibenzoline blocks the ATP‐sensitive K+ channel of pancreatic β‐cells and, thereby, stimulates insulin secretion at sub‐stimulatory levels of glucose.
Differential inhibition of a transient K+ current by chlorpromazine and 4‐aminopyridine in neurones of the rat dorsal root ganglia
Authors: Ogata Nobukuni , Tatebayashi Hideharu 
Published: July 2012

K+ currents were recorded from neurones of the newborn rat cultured dorsal root ganglia, by a whole cell variation of the patch‐clamp technique.
Chlorpromazine (CPZ), a neuroleptic, reversibly reduced the amplitude of the transient K+ current (referred to as ‘IT’ hereafter) with a dissociation constant (Kd) of 4.5 μm. The inhibition of the delayed rectifier K+ current (IDR) was much less potent (Kd, 120 μm). CPZ (100 μm) had no effect on the inward rectifier K+ current.
The blocking action of CPZ on IT was about seven times more potent than that of 4‐aminopyridine (4‐AP) which had a Kd of 31 μm. The inhibition of IT followed one‐to‐one binding stoichiometry with both drugs.
The decay time course of IT was not affected by CPZ, whereas 4‐AP markedly accelerated the decay phase of IT.
The steady‐state inactivation curve of IT was shifted in the negative direction (about 5 mV) by CPZ, whereas the curve was shifted in the positive direction (about 13 mV) by 4‐AP.
The recovery from inactivation as measured by a conventional double pulse protocol was described by two exponential components in the control solution. CPZ markedly reduced the first component and slowed down the recovery from inactivation. In contrast, in the presence of 4‐AP, the peak amplitude of IT was rather increased by a preceding IT possibly through voltage‐dependent unbinding of 4‐AP molecules.
These results indicate that CPZ has a preferential blocking action on IT and the mechanism underlying this block is markedly different from the mechanism underlying the blocking action of 4‐AP.
Protection by nicorandil against the dysfunction of the central vagal baroreflex system following transient global cerebral ischaemia in dogs
Authors: Kurihara Junichi , Ochiai Nobuhiko , Kato Hitoshi 
Published: July 2012

A possible cerebroprotective effect of nicorandil was investigated in a canine model of 5 min global cerebral ischaemia, and compared with protective effects of nitroglycerin and nicardipine.
Cerebral ischaemia was produced by occlusion of the left subclavian and the brachiocephalic arteries with preceding ligation of the intercostal arteries. The decrease in baroreflex sensitivity (BRS), measured by phenylephrine‐induced reflex bradycardia, was used to assess the cerebroprotective effect.
Nicorandil (10 or 30 μg kg−1 min−1, i.v.), nitroglycerin (3 μg kg−1 min−1, i.v.) or nicardipine (0.3 μg kg−1 min−1, i.v.) were infused for 60 min just before ischaemia. Nitroglycerin and nicardipine decreased mean arterial blood pressure to an extent similar to that induced by the lower dose of nicorandil. Blood flow in the dorsal medulla oblongata was increased by nicorandil and nicardipine, but not by nitroglycerin.
Nicorandil at both doses and nitroglycerin prevented the post‐ischaemic decrease in BRS. In these cases, bilateral vagotomy during the reperfusion period decreased BRS, indicating that the vagal component of BRS was protected from ischaemia. On the other hand, nicardipine failed to exert a cerebroprotective effect.
The present study suggests that nicorandil may possess a direct cerebroprotective effect and that its property as a nitrate might, at least in part, be important for the observed cerebral protection.
Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog
Authors: Leboeuf J. , Basiez M. , Massingham R. 
Published: July 2012

The intravenous electrophysiological effects of a new antifibrillatory agent, Org 7797, were studied in closed chest anaesthetized dogs. Effects of fast sodium and slow calcium‐mediated action potentials were also examined in guinea‐pig isolated papillary muscle.
The major effects of a known antifibrillatory dose of Org 7797 (0.5 mg kg−1) were a protracted slowing of AV nodal conduction (for at least 20 min) and prolongation of the AV nodal functional refractory period. Conduction in the atria and His‐Purkinje system (reflected by the St‐A and HV intervals) were not significantly modified whilst ventricular conduction (reflected by the QRS interval) and the ventricular functional refractory period were only transiently prolonged. No other electrophysiological changes were seen.
A higher dose of Org 7797 (1.5 mg kg−1) slowed conduction at all levels of the myocardium (as evidenced by increases in the St‐A, AH, HV and QRS intervals), slightly shortened cardiac repolarization (as assessed from JTc) and decreased Wenckebach rate. Atrial refractory periods were increased whereas effects on ventricular refractory periods were modest.
Neither heart rate nor sinus node recovery time were modified by either dose of Org 7797.
Org 7797, at a concentration (20 μm) which reduced Vmax of fast sodium‐mediated action potentials in isolated papillary muscle by 83%, did not modify Vmax of slow calcium‐mediated action potentials. It prolonged duration of the latter but did not modify that of the former. However, the plateau phase of both the ‘fast’ and especially the ‘slow’ action potentials was prolonged.
It is concluded that the main electrophysiological effects of a known antifibrillatory dose of Org 7797 in dogs with normal cardiac function are seen at the level of the AV node, actions which are unlikely to be explained by calcium channel block. Higher doses display a class Ic profile. This preferential action on the AV node may contribute to the control of ventricular rate during atrial fibrillation in the absence of infra‐nodal conduction disturbances.
These results contrast with those previously obtained in infarcted dogs and might further suggest that myocardial infarction enhances the Class I action of Org 7797.