bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activities of endothelin‐1 in the vascular network of the rabbit ear: a microangiographic study
Authors: Randall Michael D. , Edwards David H. , Griffith Tudor M. 
Published: July 2012

The effects of endothelin‐1 on perfusion pressure and on arterial and venous diameters were examined simultaneously in a rabbit isolated ear preparation perfused with physiological buffer. The effects of hypoxia and inhibition of endothelium‐derived relaxant factor (EDRF) activity on vascular responses to endothelin‐1 were also investigated.
Endothelin‐1 was potent at increasing perfusion pressure (ED50 = 46.7 ± 11.0 pmol; Rmax = 85.3 ± 5.3 mmHg). The potency and maximum reactivity were not significantly affected by hypoxia, inhibition of EDRF activity with 50 μm N‐nitro‐l‐arginine methyl ester (NAME) or a combination of hypoxia and NAME.
Endothelin‐1 caused equipotent dose‐dependent constrictions of the first four generations of arterial branch vessels (G1‐G4) but did not influence the diameter of the central ear artery except at high doses of the peptide when ‘paradoxical dilatation’ was observed. The peptide was also equipotent at causing constriction of the smaller venous vessels (V1‐V4) but did not affect the large veins (V0).
Under conditions of hypoxia the potency of endothelin‐1 was reduced in G2 and G3, was unaffected in G4 and the peptide did not significantly constrict either G0 or G1. Hypoxia reduced the potency of endothelin‐1 in the smaller venous vessels (V1‐V4), but conversely unmasked a marked constriction of the large veins (V0), which was not observed under normoxic conditions.
NAME 50 μm abolished the vasodilator effects of acetylcholine in this preparation. Inhibition of EDRF activity with NAME under normoxic conditions did not influence the constrictor activity of endothelin‐1 on the arterial or venous branch vessels. However, inhibition of EDRF activity under hypoxic conditions prevented the reduction of potency of endothelin‐1 as a constrictor of arterial and venous branch vessels which occurred in hypoxia. In the presence of NAME endothelin‐1 constricted V0 in both normoxia and hypoxia with equipotency but the maximum effect was greatest in hypoxia.
In conclusion, endothelin‐1 is a powerful vasoconstrictor which acts with greater potency in veins than arteries in the rabbit isolated ear. Although hypoxia does not influence pressor responses it nevertheless alters the spatial pattern of vasoconstriction. In particular hypoxia unmasks constriction of the large veins by endothelin‐1. Constriction of these veins was also observed in the absence of EDRF in normoxia, but to a much lesser degree so that the effect of hypoxia may only be partially due to reduced EDRF activity. Hypoxia may therefore directly or indirectly increase the sensitivity of the main veins to endothelin‐1.
Myocardial uptake of lignocaine: pharmacokinetics and pharmacodynamics in the isolated perfused heart of the rabbit
Authors: Mazoit Jean Xavier , Kantelip Jean‐Pierre , Orhant Edith Elisabeth , Talmant Jean‐Michel 
Published: July 2012

The uptake kinetics and pharmacodynamics of lignocaine were studied in the isolated perfused heart of the rabbit.
Six hearts were perfused with increasing concentrations of lignocaine in a modified Krebs‐Henseleit buffer. The effluent concentration together with the increase in QRS duration were measured during lignocaine infusion and during 20 min after cessation of lignocaine infusion.
Lignocaine disposition and elimination were best described by a two‐compartment open model. Terminal half‐life was 11.0 ± 2.9 min. The unidirectional transfer was slower from central to peripheral compartment than from peripheral to central compartment (T1/2,12 = 42.6 ± 10.5 min whereas T1/2,21 = 10.7 ± 2.8 min). The myocardium/perfusate concentration‐ratio was 4.7 ± 0.4.
The pharmacodynamic effect was best described in the central compartment by using the Hill equation. Calculated maximum QRS duration (Emax) was 77 ± 8 ms. Emax was also directly measured in four additional rabbits by infusing ten times the dose of lignocaine used in the main experiment: the value of Emax measured in these conditions was 92.5 ± 9.6 ms, i.e. a QRS widening of 150%. The steady‐state perfusate concentration producing half the effect (C50) was 15.7 ± 7.6 μg ml−1.
In conclusion, the specific lignocaine binding leading to increase in QRS duration appeared to be more closely related to the vascular stream than non specific binding leading to a deeper accumulation process.
Sensitivity of hippocampal neurones to kainic acid, and antagonism by kynurenate
Authors: Stone T.W. 
Published: July 2012

The sensitivity to kainic acid of neurones in the CA1 and CA3 regions of rat hippocampal slices has been examined by microiontophoresis and by superfusion methods.
When the iontophoretic currents needed to produce comparable plateaux of firing were compared, neurones in the pyramidal cell layer of the CA3 region were approximately 5 times more sensitive than cells in the CA1 region. No difference was noted in sensitivity to N‐methyl‐d‐aspartate (NMDA) or quisqualate.
When kainate was superfused at known concentrations, the threshold for eliciting excitation in CA1 was 2.1 μm. The threshold concentration in CA3 was 0.24 μm.
Two weeks after the stereotaxic intrahippocampal injection of colchicine, the granule cells of the dentate gyrus and thus the mossy fibre projections to CA3 were destroyed. In slices prepared from animals thus treated the threshold concentration of kainate for eliciting excitation had risen to 1.64 μm.
Kainate was less effective in promoting the development of epileptiform bursts of neuronal firing in colchicine‐treated slices than in controls.
Kynurenic acid antagonized the excitation of CA1 neurones elicited by kainate, NMDA or quisqualate. In the CA3 region kynurenate antagonized selectively responses to microiontophoretic NMDA, with little effect on responses to kainate or quisqualate.
In slices taken from colchicine‐treated rats kynurenate was able to block responses to kainate in the CA3 area in parallel with responses to NMDA.
Taken together the results suggest that the excitatory responses to kainate in the CA3 region may be partly due to a presynaptic action on mossy fibre terminals to release endogenous amino acids. The differential action of kynurenate in normal and lesioned slices may, therefore, indicate that the postsynaptic kainate receptors are sensitive to antagonism by this compound whereas the presynaptic receptors are resistant to kynurenate.
Effects of repeated infusions of substance P and vasoactive intestinal peptide on the weights of salivary glands subjected to atrophying influences in rats
Authors: Månsson Bengt , Nilsson Bengt‐Olof , Ekström Jörgen 
Published: July 2012

The long‐term influence of substance P (SP) and vasoactive intestinal peptide (VIP) on rat salivary gland weight was investigated after parasympathetic denervation or on feeding soft food.
The parotid gland lost about one‐third of its weight within 4–5 days following parasympathetic postganglionic denervation or change in dietary regimen, from pellets to liquid diet, thought to reduce nerve reflex activity.
Daily i.v. infusions with SP or VIP diminished or largely prevented the fall in parotid gland weight, whereas infusions with pentagastrin, bethanechol and saline had no effect. The infusions were preceded by administration of α‐ and β‐adrenoceptor antagonists; these antagonists were also given to the control animals.
The effect of SP and VIP on the parotid gland weight appeared to be related to cell size rather than to cell number, as judged by measurements of RNA and DNA.
Observations on the two other major salivary glands underlined the fact that different gland types in the same animal behave differently. Parasympathetic preganglionic denervation (decentralization) lowered the weights of the sublingual and submandibular glands, whereas liquid diet only reduced the weight of the sublingual gland. SP and VIP did not affect the weights of the submandibular glands, but VIP prevented the slight fall in sublingual gland weight induced by liquid diet.
The present results suggest a trophic role in rats for SP and VIP on parotid glands and for VIP on sublingual glands. Such an influence may be exerted naturally as a result of their release from nerves containing these peptides around acini.
Rabbit brain contains an endogenous inhibitor of endothelium‐dependent relaxation
Authors: Moore P.K. , Al‐Swayeh O.A. , Evans R. 
Published: July 2012

Supernatants prepared from the rabbit brain, lung and liver caused an endothelium‐dependent and volume‐related contraction of the phenylephrine‐pretreated rabbit aorta and inhibited relaxation due to acetylcholine (ACh).
Perfusion in situ of the rabbit lung or liver with Krebs solution substantially reduced or removed the endothelium‐dependent inhibitor. Spectrophotometric analysis revealed the presence of substantial amounts of haemoglobin (1.8–2.1 μm) in these organ supernatants.
Supernatants prepared from the Krebs‐perfused rabbit brain retained the ability to contract the phenylephrine‐pretreated rabbit aorta and to inhibit relaxation due to ACh and substance P (SP). Rabbit brain supernatant did not reduce the vasodilator effect of sodum nitroprusside (NP) or nitric oxide (NO).
Rabbit brain supernatant contained low (< 0.35 μm) concentrations of haemoglobin.
The inhibitory effect of rabbit brain supernatant was reversed by l‐arginine (500 μm) but not d‐arginine (500 μm).
The inhibitor of endothelium‐dependent vasodilatation present in rabbit brain was not removed by dialysis (24 h, 4°C) but was partially precipitated by ammonium sulphate (30% w/v).
Rabbit brain contains an endogenous inhibitor of vascular NO biosynthesis. The identity of this inhibitor is not known although it seems likely to be a large peptide or protein.
Role of eicosanoids in PAF‐induced increases of the vascular permeability in rat airways
Authors: Sirois M.G. , Plante G.E. , Braquet P. , Sirois P. 
Published: July 2012

Platelet activating factor (PAF; 1.0 and 5.0 μg kg−1) injected in the tail vein of unanaesthetized rats dose‐dependently increased the vascular permeability of the trachea, upper and lower bronchi (up to 400%) as measured by the extravasation of Evans blue dye. The permeability of the parenchyma was not affected by PAF treatment.
Pretreatment of the animals with an intravenous injection of the PAF antagonist BN‐52021 (10 mg kg−1) abolished almost totally the vascular permeability changes elicited by PAF injection (5.0 μg kg−1).
Pretreatment of the animals with intravenous injections of inhibitors of thromboxane formation, indomethacin (10 mg kg−1) and compound OKY‐046 (10 mg kg−1), and thromboxane antagonist, compound L‐655,240 (5 mg kg−1), partially reduced PAF effects in the airways (from 28 to 69%). The thromboxane mimic U‐44069 (5.0 μg kg−1) did not modify the vascular permeability of rat airways. The effect of a low dose of PAF (0.1 μg kg−1) on the vascular permeability of the trachea and bronchi (but not of the parenchyma) was potentiated by compound U‐44069 (5.0 μg kg−1) or noradrenaline (400 ng kg−1) whereas the effect of a high dose of PAF (5.0 μg kg−1) was not affected.
Neither the peptidoleukotriene antagonist MK‐571 (10 mg kg−1) nor the 5‐lipoxygenase inhibitor, L‐663,536 (10 mg kg−1) given before the injection of PAF (5.0 μg kg−1) affected the protein extravasation in rat lung tissues.
These data suggest that the effect of PAF on rat vascular permeability is partly modulated by thromboxane formation although thromboxanes have no direct effect on the permeability. Thromboxane may act via a vasoconstriction that increases hydrostatic pressure and potentiates the extravasation elicited by PAF effect on endothelial cells.
Leukotrienes do not appear to be involved in the changes of rat airway permeability induced by PAF.
Differential effects of calcium antagonists and Bay K 8644 on contractile responses to exogenous noradrenaline and adrenergic nerve stimulation in the rabbit ear artery
Authors: Skärby Tor V. Ch. , Högestätt Edward D. 
Published: July 2012

The effects of three calcium antagonists (nifedipine, verapamil, diltiazem) and the calcium agonist Bay K 8644 were compared on contractile responses of similar amplitude elicited by noradrenaline (NA) and electrical nerve stimulation (ENS) in the rabbit isolated ear artery.
Contractions induced by both NA (3 × 10−7 m) and ENS (10 Hz, 10 s) were almost exclusively mediated by α1‐adrenoceptors, since 10−7 m prazosin abolished (NA) or almost abolished (ENS) the responses, and prazosin was more than three orders of magnitude more potent than rauwolscine on both types of response.
ENS‐induced contractions were considerably less inhibited by nifedipine, verapamil and diltiazem than were those elicited by NA. Bay K 8644 enhanced responses to NA more than those to ENS.
The inhibitory effect of nifedipine and Ca2+ deprivation on NA‐induced contractions decreased with increasing NA concentration. Reduction of the NA response by prazosin or phenoxybenzamine increased the nifedipine inhibition.
Reduction of the ENS‐induced contractions by prazosin or phenoxybenzamine, or by use of a lower stimulation frequency did not increase the inhibitory effect of nifedipine.
In conclusion, the differential effects of the calcium antagonists on NA‐ and ENS‐induced contractions were not related to differences in α‐adrenoceptor subtype (α1/α2), receptor reserve or response amplitude, but may rather reflect temporal and spatial differences in α‐adrenoceptor activation between the responses.
Impaired induction of nerve ornithine decarboxylase activity in the streptozotocin‐diabetic rat is prevented by the aldose reductase inhibitor ponalrestat
Authors: Pekiner C. , McLean W.G. 
Published: July 2012

The present study was designed to investigate if the aldose reductase inhibitor ponalrestat is capable of preventing the impairment of the response of ornithine decarboxylase (ODC) to nerve crush in streptozotocin (STZ)‐diabetic rats.
ODC activity was measured in the dorsal root ganglia of crushed and uncrushed contralateral sciatic nerve of non‐diabetic, ponalrestat‐treated non‐diabetic, STZ‐diabetic and ponalrestat‐treated STZ‐diabetic rats.
Twenty four hours after crush, a significant (P > 0.001) increase in the ratio of ODC activity in ganglia of crushed relative to uncrushed nerves was found in non‐diabetic but not in diabetic rats, as expected. In the ponalrestat‐treated diabetic rats the ratio was significantly higher (P > 0.001) than that in the untreated diabetic rats and was not different from that in the non‐diabetic group.
Ponalrestat also significantly decreased absolute levels of ODC activity in ganglia of uncrushed nerves from diabetic and non‐diabetic animals. Despite the near‐normal induction of ODC activity by nerve crush in the ponalrestat‐treated diabetic animals, absolute ODC activity remained lower than that in ganglia of uncrushed nerves from non‐diabetics.
We conclude that ponalrestat is able to prevent the impaired induction of ODC in experimental diabetes. The results, however, call into question the relationship between impaired ODC induction and diabetes‐induced defects in nerve regeneration, which are insensitive to ponalrestat.
Synaptosomal tryptophan uptake and efflux following lesion of central 5‐hydroxytryptaminergic neurones
Authors: Wilkinson Lawrence S. , Collard Keith J. 
Published: July 2012

This study attempted to determine whether the activation of the tryptophan carrier in rat forebrain synaptosomes caused by depolarization or by extracellular sodium depletion occurred exclusively in 5‐hydroxytryptaminergic nerve endings.
Ascending 5‐hydroxytryptaminergic neurones were lesioned either electrolytically or by intraventricular administration of 5,7‐dihydroxytryptamine. The extent of the lesion was assessed by comparing the uptake of [3H]‐5‐hydroxytryptamine (5‐HT) in lesioned animals and in sham‐operated controls. [3H]‐5‐HT uptake was reduced by 85.9 ± 1.63% (mean ± s.e.mean) in animals receiving electrolytic lesions, and by 87.4 ± 4.51% in those receiving 5,7‐dihydroxytryptamine.
The uptake of [3H]‐tryptophan by synaptosomes from lesioned animals incubated in standard Na+‐rich media was slightly lower (278.8 ± 27.3 pmol mg−1 protein min−1) than that observed in sham‐operated controls (360.6 ± 30.3 pmol mg−1 protein min−1). However, uptake in the absence of extracellular Na+ was increased to a similar extent in both the sham‐operated (539 ± 54.5 pmol mg−1 protein min−1) and lesioned animals (507.2 ± 42.4 pmol mg−1 protein min−1).
The efflux of [3H]‐tryptophan in response to extracellular Na+ depletion was similar in sham‐operated and lesioned animals. Release expressed as a percentage of tissue [3H]‐tryptophan released in response to the pulse of Na+‐free medium was 6.691 ± 0.585 (n = 4) in sham‐operated controls and 8.195 ± 0.906 in lesioned animals.
The efflux of [3H]‐tryptophan in response to K+ depolarization was also unchanged in lesioned animals when compared with sham‐operated controls. Release, expressed as described above was, in sham‐operated controls 3.76 ± 0.41 (n = 4) and 4.09 ± 0.30 in lesioned animals.
The results of this study show that the tryptophan carrier which is activated by depolarization or by extracellular Na+ depletion is not located exclusively on 5‐hydroxytryptaminergic nerve endings. Moreover the contribution made by 5‐hydroxytryptaminergic neurones appears to be only minor.
The effects of Ca2+ antagonists and hydralazine on central 5‐hydroxytryptamine biochemistry and function in rats and mice
Authors: Green A.R. , DeSouza R.J. , Davies E.M. , Cross A.J. 
Published: July 2012

The effects of calcium antagonists on behaviour mediated by 5‐hydroxytryptamine (5‐HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5‐HT synthesis in rat brain and endogenous 5‐HT release from brain slices.
Administration of felodipine (35 mg kg−1 i.p.) to rats pretreated with tranylcypromine (20 mg kg−1, i.p.) resulted in the animals displaying the complete 5‐HT‐mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5‐HT synthesis in brain regions differing between control and felodipine‐treated rats.
Pretreatment with felodipine (10 or 35 mg kg−1) enhanced the 5‐HT‐mediated behavioural syndrome induced by injection of tranylcypromine and l‐tryptophan. The rate of 5‐HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg−1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg−1).
The 5‐HT behavioural syndrome induced by injection of the 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) was unaltered by either acute injection of felodipine (35 mg kg−1) or administration of felodipine twice daily for 3 days.
Felodipine (10 μm), verapamil (10 μm) and Bay K 8644 (10 μm) did not alter either basal release of endogenous 5‐HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mm, or 35 mm.
Verapamil (25 mg kg−1, i.p.), nicardipine (25 mg kg−1, i.p.) and nifedipine (20 mg kg−1, i.p.) all markedly inhibited the 5‐HT2 receptor‐mediated head twitch response in mice produced by injection of 5‐methoxy‐N,N‐dimethyl‐tryptamine (5‐MeODMT). Felodipine had the same effect with an ED50 of 2.6 mg kg−1. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 μm) and nicardipine (IC50:8 μm) were 5‐HT2 antagonists as indicated by inhibition of [3H]‐ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5‐HT2 receptor binding only in the millimolar range.
Hydralazine (5 mg kg−1, i.p.) induced the 5‐HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/l‐tryptophan behavioural syndrome, inhibited 5‐MeODMT‐induced head twitch behaviour in mice and was not a 5‐HT2 receptor antagonist.
These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5‐HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2+ channels.
Effects of basal and acetylcholine‐induced release of endothelium‐derived relaxing factor on contraction to α‐adrenoceptor agonists in a rabbit artery and corresponding veins
Authors: McGrath J.C. , Monaghan S. , Templeton A.G.B. , Wilson V.G. 
Published: July 2012

The effects of an endothelium‐dependent (acetylcholine) and an endothelium‐independent (sodium nitroprusside) relaxant against noradrenaline‐induced contractions were compared in three isolated superficial blood vessels of the rabbit, the lateral saphenous vein, plantaris vein and distal saphenous artery. Both produced concentration‐related relaxations of all three vessels and were more effective against sub‐maximal than maximal contractions to noradrenaline. Transient contractions to high concentration of acetylcholine occurred only in endothelium‐intact preparations of saphenous vein and were inhibited by flurbiprofen.
In endothelium‐denuded preparations sodium nitroprusside was 3 times more effective than in endothelium‐intact preparations, while acetylcholine (< 3 μm) was inactive. Sensitivity was similar for each relaxant: lateral saphenous vein ≥ plantaris vein > distal saphenous artery. The similar profile of sodium nitroprusside and acetylcholine suggests that differences in susceptibility to endothelium‐derived relaxing factor (EDRF) are caused by inter‐vessel variations in the excitation‐coupling process for noradrenaline.
Haemoglobin inhibited acetylcholine‐induced relaxations in the endothelium‐intact preparation of the lateral saphenous vein and distal saphenous artery, which suggests a similar EDRF in each preparation and the likelihood that this is a single substance, presumably nitric oxide.
The influence of basal, spontaneously released EDRF on α‐adrenoceptor function was tested either by mechanical disruption of the endothelium or by adding haemoglobin to endothelium‐intact segments. Endothelial disruption slightly reduced contractions to noradrenaline (NA) in distal saphenous artery but increased response size of lateral saphenous and plantaris veins, in the latter also increasing sensitivity to NA: haemoglobin mimicked endothelial disruption. Thus, basal release of EDRF like acetylcholine and nitroprusside was more effective in the veins than in the corresponding artery.
In lateral saphenous vein responses to phenylephrine were enhanced by endothelial disruption, but without change in sensitivity: responses to UK‐14304, B‐HT 920 and cirazoline, which had a relatively slow speed of onset of contraction were not affected. There was no correlation between enhancement and α‐adrenoceptor sub‐type although the agonists which were enhanced all activate α1‐adrenoceptors. Competitive antagonists failed to reveal an α‐adrenoceptor subtype enhanced by endothelial disruption. However, effects of phenoxybenzamine suggest that α1‐adrenoceptors are necessary for the influence of basal EDRF.