bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of acetylcholine‐induced contractions of the rat anococcygeus muscle by activation of nitrergic nerves
Authors: Rand M.J. , Li C.G. 
Published: July 2012

Acetylcholine‐induced contractions of the rat isolated anococcygeus muscle were blocked by atropine (0.1 μm), slightly enhanced by hexamethonium (0.1 mm) and tetrodotoxin (1 μm), but little affected by prazosin (0.1 μm).
In the presence of the α2‐adrenoceptor agonist, UK14304, which raised the tone of the muscle, acetylcholine had a biphasic effect consisting of an initial relaxation followed by a contraction.
Atropine (0.1 μm) enhanced the relaxant component and abolished the contractile component of the response, whereas tetrodotoxin, ω‐conotoxin GVIA or hexamethonium abolished or greatly reduced the relaxant component.
The nitric oxide synthesis inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME, 100 μm) increased acetylcholine‐induced contractions in the absence of UK14304 and markedly reduced the relaxant component to acetylcholine in the presence of UK14304. The effects of l‐NAME were annulled by l‐arginine (300 μm).
The results suggest that acetylcholine acts concurrently on muscarinic receptors of the smooth muscle to cause contraction and nicotinic receptors of nitrergic nerves to cause relaxation. The observed response is the resultant of these two opposing effects and depends also on the prevailing tone.
Cross‐tolerance between delta‐9‐tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212‐2 and anandamide
Authors: Pertwee R.G. , Stevenson L.A. , Griffin G. 
Published: July 2012

Mice pretreated intraperitoneally for 2 days with delta‐9‐tetrahydrocannabinol (delta‐9‐THC) at a dose of 20 mg kg−1 day−1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta‐9‐THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212‐2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide.
Vasa deferentia removed from mice pretreated intraperitoneally with delta‐9‐THC twice at a dose of 20 mg kg−1 day−1 were less sensitive to its inhibitory effect on electrically‐evoked contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the lower part of the concentration‐response curve of delta‐9‐THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212‐2 (9.6 fold) and anandamide (12.3 fold).
The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta‐9‐THC can produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance.
Further experiments are required to establish why tolerance to anandamide‐induced hypothermia was not produced by a pretreatment with delta‐9‐THC that did induce tolerance to the hypothermic effects of delta‐9‐THC, CP 55,940 and WIN 55,212‐2 and to the inhibitory effects of delta‐9‐THC, CP 55,940, WIN 55,212‐2 and anandamide on the twitch response of the vas deferens.
Effect of the platelet‐activating factor antagonist, TCV‐309, and the cyclo‐oxygenase inhibitor, ibuprofen, on the haemodynamic changes in canine experimental endotoxic shock
Authors: Yamanaka Shinya , Iwao Hiroshi , Yukimura Tokihito , Kim Shokei , Miura Katsuyuki 
Published: July 2012

The present study was conducted in order to examine the effects of the platelet‐activating factor (PAF) antagonist, TCV‐309, and the cyclo‐oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs.
Endotoxin (2 mg kg−1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels.
The endotoxin‐induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC.
The hypotension caused by endotoxin was attenuated by TCV‐309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV‐309 also abolished the increase in EVC. In contrast to ibuprofen, TCV‐309 did not affect the decrease in TPR caused by endotoxin.
Combined treatment with ibuprofen and TCV‐309 markedly attenuated the endotoxin‐induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV‐309 partly attenuated the endotoxin‐induced reduction in cardiac output and systemic vasoconstriction.
These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin‐induced hypotension. It is suggested that (i) both prostanoids and PAF are involved in dilatation of capacitance vessels, (ii) prostanoids, but not PAF cause dilatation of resistance vessels and (iii) PAF may partly contribute to prostanoid‐independent reduction in cardiac output in acute canine experimental endotoxin shock.
Regional haemodynamic responses to intravenous and intraarterial endothelin‐1 and big endothelin‐1 in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T. 
Published: July 2012

In the same chronically‐instrumented conscious Long Evans rats, we assessed regional haemodynamic responses to i.v. and i.a. injections of endothelin‐1 (ET‐1) and big endothelin‐1 at doses of 0.05 (n = 4) and 0.5 nmol kg−1 (n = 7).
For ET‐1, the cardiovascular effects (initial hypotension and tachycardia with transient hindquarters vasodilatation, followed by hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions) of i.v. and i.a. injections were not different.
Similarly, for big ET‐1, the cardiovascular effects (hypertension, bradycardia and renal, mesenteric, and hindquarters vasoconstrictions) of i.v. and i.a. injections were not different.
At a dose of 0.5 nmol kg−1, i.v. or i.a., the pressor effects of ET‐1 and big ET‐1 were not different (area under curve [AUC0–30 min), ET‐1 i.v. = 786 ± 115 mmHg min; ET‐1 i.a. = 880 ± 165 mmHg min; big ET‐1 i.v. = 878 ± 93 mmHg min; big ET‐1 i.a. = 833 ± 103 mmHg min); but ET‐1 caused greater renal, and lesser hindquarters, vasoconstrictions than big ET‐1 (renal ET‐1 i.v., AOC = 1550 ± 211% min; ET‐1 i.a., AOC = 1746 ± 139% min; big ET‐1 i.v., AOC = 1097 ± 128% min; big ET‐1 i.a., AOC = 1041 ± 119% min; hindquarters, ET‐1 i.v., AOC = 758 ± 176% min; ET‐1 i.a. AOC = 787 ± 184% min; big ET‐1 i.v., AOC = 1270 ± 88% min; big ET‐1 i.a., AOC = 1173 ± 77% min), while the mesenteric vasoconstrictor effects of both peptides were not significantly different (ET‐1 i.v. AOC =1419 ± 132% min; ET‐1 i.a., AOC = 1526 ± 172% min; big ET‐1 i.v., AOC = 1099 ± 166% min; big ET‐1 i.a., AOC = 1155 ± 120% min).
Under the conditions of our experiments, pulmonary clearance of ET‐1, or pulmonary activation of big ET‐1, was not apparent from the haemodynamic responses to i.v. and i.a. administration of the peptides. The results are consistent with previous findings indicating that local, rather than systemic, conversion of exogenous big ET‐1 to ET‐1 is responsible for its regional haemodynamic actions.
Relevance of the use of [3H]‐clonidine to identify imidazoline receptors in the rabbit brainstem
Authors: Bricca G. , Zhang J. , Greney H. , Dontenwill M. , Stutzmann J. , Belcourt A. , Bousquet P. 
Published: July 2012

[3H]‐clonidine binding was investigated in membranes isolated from the ventral medulla oblongata of the rabbit where clonidine produced a hypotensive effect which was not mediated by adrenoceptors. [3H]‐clonidine specific binding, as defined by the difference between the binding of [3H]‐clonidine in the presence and in the absence of 10 μm cirazoline, occurred at two sites: a high affinity site with a KD = 2.9 ± 0.7 nm and a Bmax of 40 ± 8 fmol mg−1 protein and a low affinity site with a KD = 18.2 ± 0.4 nm and a Bmax of 66 ± 14 fmol mg−1 protein.
The high affinity sites being catecholamine‐sensitive were identified as α2‐adrenoceptors. The low affinity binding of [3H]‐clonidine was insensitive to catecholamines, as well as to other α2‐adrenoceptor specific probes, and could be inhibited with high affinity only by compounds which lowered blood pressure when directly injected in the nucleus reticularis lateralis of the ventral brainstem, or by antagonists.
It was concluded that in the ventral medulla of the rabbit, [3H]‐clonidine labelled α2‐adrenoceptors and imidazoline receptors (IRs). Only the latter were related to the hypotensive effects of clonidine and rilmenidine directly injected into the rostroventrolateral medulla oblongata (RVLM) of the rabbit. The methodological problems regarding the study of IRs with [3H]‐clonidine are discussed.
5‐HT4 receptor mediated facilitation of the emptying phase of the peristaltic reflex in the guinea‐pig isolated ileum
Authors: Costall B. , Naylor R.J. , Tuladhar B.R. 
Published: July 2012

The influence of 5‐hydroxytryptamine (5‐HT) receptor agonists and antagonists on the emptying phase (circular muscle contraction) of the peristaltic reflex was investigated in the guinea‐pig isolated ileum.
The effect of drug application to the serosal surface was measured as the changes in threshold pressure required to trigger the peristaltic reflex and the interval between the peristaltic strokes. A facilitation or inhibition of peristalsis was defined as a reduction or increase in threshold pressure respectively.
Peristalsis was not modified by the inclusion of methysergide (1 μm) and/or ondansetron (2 μm) in the bathing medium. 5‐HT (0.1–1.0 μm) caused a facilitation of the perstaltic reflex; the response curve to 5‐HT was not altered by the presence of methysergide (1 μm) and ondansetron (2 μm).
In the presence of methysergide (1 μm) plus ondansetron (2 μm), 5‐HT (7.36 ± 0.06), 5‐methoxytryptamine (7.01 ± 0.17), 5‐carboxamidotryptamine (5.43 ± 0.06), renzapride (6.09 ± 0.17), (S)‐zacopride (5.99 ± 0.11), (R)‐zacopride (5.61 ± 0.13) and metoclopramide (4.8 ± 0.65) caused a concentration‐related facilitation of the peristaltic reflex, the pEC50 values (mean ± s.e.mean) being shown in parentheses. 2‐Methyl‐5‐HT was ineffective up to 10 μm.
The administration of SDZ 205–557 (1 μm) alone failed to modify the peristaltic reflex, but caused a parallel dextral shift in the concentration‐effect curve to 5‐HT (apparent pKB 7.38 ± 0.30). It failed to modify the effect of acetylcholine to enhance the peristaltic reflex.
It is concluded that the rank order of potency of the 5‐HT agonists from the indole and substituted benzamide series to facilitate the emptying phase of the peristaltic reflex in the guinea‐pig ileum closely correlates with their published actions as 5‐HT4 agonists in other systems. An agonist action on the 5‐HT4 receptor is also supported by the potency of the 5‐HT3/5‐HT4 antagonist SDZ 205–557 (but not the 5‐HT3 antagonist ondansetron) to inhibit the effects of 5‐HT.
Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP
Authors: Mühl Heiko , Kunz Dieter , Pfeilschifter Josef 
Published: July 2012

Treatment of rat mesangial cells with interleukin 1β (IL‐1β) or tumour necrosis factor α (TNFα) has been shown to induce a macrophage‐type of nitric oxide (NO) synthase. Here we report that adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) is another mediator that triggers induction of NO synthase in mesangial cells.
Incubation of mesangial cells with the β‐adrenoceptor agonist, salbutamol, forskolin or cholera toxin, which all activate adenylate cyclase and increase intracellular cyclic AMP concentration, increased nitrite formation in a dose‐dependent manner. Likewise, the addition of the membrane‐permeable cyclic AMP analogue, N6, 0–2′‐dibutyryladenosine 3′,5′‐phosphate (Bt2cyclic AMP) or the phosphodiesterase inhibitor, 3‐isobutyl‐1‐methylxanthine enhanced NO synthase activity in a dose‐dependent manner.
There was a lag period of about 8 h before a significantly enhanced secretion of nitrite could be detected upon exposure of cells to forskolin and for maximal stimulation, forskolin had to be present during the whole incubation period.
Treatment of mesangial cells with actinomycin D, cycloheximide or dexamethasone completely suppressed forskolin‐stimulated NO‐synthase activity, thus demonstrating that transcription and protein synthesis are necessary for nitrite formation.
Bt2 cyclic AMP, the most potent inducer of nitrite production, increased NO synthase mRNA levels in mesangial cells in a time− and dose‐dependent fashion. Dexamethasone completely inhibited the increase of NO synthase mRNA in response to Bt2 cyclic AMP.
Combination of Bt2 cyclic AMP and IL‐1β or TNFα revealed a strong synergy in terms of nitrite formation. Time‐course studies indicated that cyclic AMP needed to be increased during the whole period of IL‐1β stimulation for maximal nitrite production.
These observations suggest that cyclic AMP controls NO synthase expression in mesangial cells. Furthermore, the signalling cascades triggered by IL‐1β and TNFα synergize with the cyclic AMP pathway to stimulate NO synthase activity.
The effects of the endothelin ETA receptor antagonist, FR 139317, on infarct size in a rabbit model of acute myocardial ischaemia and reperfusion
Authors: McMurdo Lorraine , Thiemermann Christoph , Vane John R. 
Published: July 2012

The effects were investigated of the ETA receptor antagonist, FR 139317, on endothelin‐1 (ET‐1)‐induced coronary vasoconstriction in the isolated perfused heart of the rabbit. In addition, this study examined whether FR 139317 reduced infarct size in a rabbit model of coronary artery occlusion and reperfusion.
In the rabbit isolated perfused heart, ET‐1 (1–100 pmol) elicited a dose‐dependent increase in coronary perfusion pressure (CPP). For example, 30 pmol ET‐1 caused CPP to rise by 22 ± 8 mmHg and 100 pmol ET‐1 by 47 ± 10 mmHg (n = 8). Infusion of FR 139317 (1 μm) significantly attenuated the increase in CPP caused by ET‐1 (30 pmol: 3 ± 1 mmHg, 100 pmol: 8 ± 2 mmHg; n = 8).
In the anaesthetized rabbit, infarct size (expressed as a percentage of the area at risk) after 45 or 60 min of coronary artery occlusion followed by 2 h of reperfusion was 47 ± 6% (n = 6) and 55 ± 7% (n = 5), respectively. A continuous infusion of FR 139317 (0.2 mg kg−1 min−1 preceded by a loading dose of 1.0 mg kg−1, i.v.; n = 5–6) had no effect on the extent of the myocardial infarct size (45 min: 47 ± 6%; 60 min: 49 ± 7%). Even a three‐times higher dose (0.6 mg kg−1 min−1 preceded by a loading dose of 3 mg kg−1, i.v.; n = 4) of FR 139317 had no effect on myocardial infarct size (48 ± 5%) after 45 min occlusion of the antero‐lateral branch of the left coronary artery (LAL) and 2 h reperfusion.
In a separate group of experiments, the LAL was occluded for 60 min and subsequently reperfused for 6 h. FR 139317 (0.6 mg kg−1 min−1 preceded by a loading dose of 3 mg kg−1, i.v.; n = 4) had no significant effect on infarct size even in this long reperfusion model (control: 48 ± 3%, FR 139317: 61 ± 6%).
Thus, the vasoconstrictor effects elicited by ET‐1 in the coronary vasculature of the rabbit are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, FR 139317. However, an enhanced formation of endogenous ET‐1 does not play a major role in ischaemia/reperfusion injury of the rabbit heart, for FR 139317 had no effect on infarct size.
Anticonvulsant effects of the glycine/NMDA receptor ligands d‐cycloserine and d‐serine but not R‐(+)‐HA‐966 in amygdala‐kindled rats
Authors: Löscher Wolfgang , Wlaź Piotr , Rundfeldt Chris , Baran Halina , Hönack Dagmar 
Published: July 2012

The effects of the glycine/NMDA receptor partial agonists, d‐cycloserine and (+)‐HA‐966 and the full agonist, d‐serine, on focal seizure threshold and behaviour have been determined in amygdala‐kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA receptor antagonist, MK‐801, was used for comparison.
The high efficacy glycine partial agonist, d‐cycloserine, did not alter the threshold for induction of amygdaloid afterdischarges (ADT) at doses of 20–80 mg kg−1 i.p., but significant ADT increases were determined after application of higher doses (160 and 320 mg kg−1). The ADT increases after these high doses were long‐lasting; significant elevations were still observed 2 days after drug injection. Determination of d‐cycloserine in plasma and brain tissue showed that it was rapidly eliminated from plasma. Compared to peak levels in plasma, only relatively low concentrations of d‐cycloserine were measured in brain tissue.
The low efficacy glycine partial agonist, (+)‐HA‐966, 10–40 mg kg−1 i.p., did not alter the ADT or seizure recordings (seizure severity, seizure duration, afterdischarge duration) at ADT currents. However, the drug dose‐dependently increased the duration of postictal behavioural and electroencephalographic depression in kindled rats. At the higher dose tested, postictal immobilization was dramatically increased from 3 min to about 120 min. This might indicate that glutamatergic activity is decreased postictally, which is potentiated or prolonged by (+)‐HA‐966.
Like d‐cycloserine, the glycine receptor full agonist, d‐serine, injected bilaterally into the lateral ventricles at a dose of 5 μmol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 μmol).
The anticonvulsant effects observed with d‐cycloserine were completely antagonized by combined treatment with (+)‐HA‐966, indicating that the effects of d‐cycloserine were mediated by the glycine/NMDA receptor complex.
MK‐801, 0.1 mg kg−1, did not alter the focal seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)‐like behavioural alterations, such as hyperlocomotion, stereotypies and motor impairment. No PCP‐like behaviours were observed after d‐cycloserine, d‐serine or (+)‐HA‐966. High doses of (+)‐HA‐966 induced moderate motor impairment in kindled rats.
The long lasting increases in seizure threshold observed after the high efficacy glycine partial agonist, d‐cycloserine but not the low efficacy partial agonist, (+)‐HA‐966, may suggest that the effects of d‐cycloserine are mediated by adaptive changes in the NMDA receptor complex in response to glycine receptor stimulation.
Pharmacological intervention at the strychnine‐insensitive glycine receptor by high‐efficacy partial agonists with systemic bioavailability may be an effective means of increasing seizure threshold without concomitantly inducing PCP‐like adverse effects.
Effects of muscarinic M2 and M3 receptor stimulation and antagonism on responses to isoprenaline of guinea‐pig trachea in vitro
Authors: Watson N. , Eglen R.M. 
Published: July 2012

In guinea‐pig and canine airway smooth muscle, there is reduced β‐adrenoceptor agonist sensitivity in tissues pre‐contracted with muscarinic agonists when compared to tissues pre‐contracted with other spasmogens, such as histamine or leukotriene D4. This reduced sensitivity may be the result of an interaction between muscarinic receptors and β‐adrenoceptors. In this study the effects of M2 receptor antagonism and stimulation have been investigated on the relaxant potency of isoprenaline in guinea‐pig isolated tracheal smooth muscle.
(+)‐cis‐Dioxolane contracted isolated tracheal strips in a concentration‐dependent manner (EC50 = 11.5 ± 0.9 nm). The rank order of antagonist apparent affinities (with pA2 values in parentheses) was atropine (9.4 ± 0.1) > zamifenacin (8.2 ± 0.1) >para‐fluoro‐hexahydro‐siladiphenidol (p‐F‐HHSiD, 7.2 ± 0.1) > pirenzepine (6.5 ± 0.1) > methoctramine (5.5 ± 0.1). Schild slopes were not significantly different from unity. This was consistent with a role of muscarinic M3 receptors in mediating contraction.
In tissues pre‐contracted to 3 g isometric tension using (+)‐cis‐dioxolane (0.2 μm, approximately EC80), the relaxant potency of isoprenaline was significantly (P < 0.05) increased by 0.3 μm methoctramine (control EC50 = 32.2 ± 4.3 nm, plus methoctramine EC50 = 19.1 ± 4.5 nm). This concentration of methoctramine had no effect on contractile responses to (+)‐cis‐dioxolane (control, EC50 = 17.6 ± 3.2 nm, plus methoctramine, EC50 = 21.0 ± 4.4 nm).
When acetylcholine (non‐selective), (+)‐cis‐dioxolane (non‐selective), L‐660,863 ((±)‐3‐(3‐amino‐1,2,4‐oxadiazole‐5‐yl)‐quinuclidine, M2‐selective) or SDZ ENS 163 (thiopilocarpine, mixed M2 antagonist, partial M3 agonist) were used to achieve isometric tensions of 3 g, the relaxant potency of isoprenaline ranged from 3.7 ± 0.3 nm (SDZ ENS 163) to 49.4 ± 3.2 nm ((+)‐cis‐dioxolane). Reducing the concentration of these agonists (and therefore the level of developed tension to 2 g), significantly (P < 0.05) increased the relaxant potency of isoprenaline. In contrast, when histamine was used to pre‐contract tissues to either 2 or 3 g (EC50 = 4.2 ± 0.6 and 3.8 ± 1.1 nm, respectively), there was no significant effect on the relaxant potency of isoprenaline.
There was a slight but significant (P < 0.05) reduction in the relaxant potency of isoprenaline, in tissues pre‐contracted to 3 g using histamine in combination with (+)‐cis‐dioxolane (30 nm). This effect was reversed by M2 receptor antagonism, using methoctramine (1 μm).
These data suggest that in guinea‐pig isolated trachea, the relaxant potency of isoprenaline may depend not only on the level of developed tension but also, on the level of muscarinic M2 receptor stimulation/blockade of the spasmogen inducing the tension. However, the lack of selective M2 agonist and the low M2/M3 selectivity of antagonists in this tissue do not permit definitive conclusions to be made about the role of these receptors in modulating isoprenaline potency.