bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of thromboxane receptor antagonists on oestrogen‐induced uterotrophic responses in the spontaneously hypertensive rat
Authors: Kerr M.B. , Marshall K. , Senior J. 
Published: July 2012

The possible role of thromboxane in the uterotrophic response to oestrogen, in the spontaneously hypertensive rat was investigated by use of the thromboxane receptor antagonists EP092, AH23848 and BM 13.505.
The parameters studied were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights and the concentrations of cytosolic and nuclear oestrogen receptors.
The antagonists attenuated oestradiol‐induced uterine blood flow and significantly reduced both wet and dry uterine weight. These changes were accompanied by decreases in nuclear oestrogen receptor levels.
The results suggest a supportive role for thromboxane in oestradiol‐induced uterine growth.
Naloxone‐induced cardiovascular depression in rats that had received chronic morphine‐treatment
Authors: Dai Soter , Wang Yu 
Published: July 2012

Cardiovascular changes in response to intravenous injection of naloxone were studied in pentobarbitone‐anaesthetized rats which had been given morphine in their drinking water for 1–21 days. The mechanisms of the observed changes were investigated in intact animals and in isolated hearts and tail arteries.
In rats that had received chronic morphine‐treatment, intravenous administration of naloxone caused immediate decreases in blood pressure, heart rate, left ventricular pressure and dLVP/dtmax which were followed by the occurrence of atrial or ventricular extrasystoles and other signs of opiate withdrawal such as faecal passage and muscle twitching.
The intensities of the naloxone‐precipitated cardiovascular changes were directly related to the duration of chronic morphine pretreatment, reaching statistically significant levels on day 2 or 3 and maximal levels on day 7 or 14. This phenomenon disappeared on days 3 to 14 following opiate withdrawal in animals which had been treated previously with morphine for 21 days.
Either atropine or clonidine pretreatment significantly prevented the occurrence of faecal passage or muscle twitching during naloxone‐precipitated opiate withdrawal. However, clonidine, but not atropine or yohimbine, abolished the decreases in various haemodynamic parameters. The occurrence of cardiac extrasystoles was not affected.
In isolated heart or tail artery preparations from chronically morphine‐treated rats, naloxone administration did not elicit reactions which differed from those of the preparations from naive animals.
These findings suggest that, under pentobarbitone anaesthesia, the cardiovascular systems of rats that had received chronic morphine treatment exhibit inhibitory, instead of excitatory, reactions to naloxone‐precipitated opiate withdrawal. The mechanisms remain unclear, but are unlikely to be due to cholinergic or noradrenergic hyperactivity, nor due to the direct withdrawal reactions of the cardiac or vascular tissues.
Response of the rat myometrium to phenylephrine in early pregnancy and the effects of 6‐hydroxydopamine
Authors: Kaulenas Andrew , Parkington Helena C. , Coleman Harold A. 
Published: July 2012

The contractile responses of the longitudinal and circular muscle layers of the rat uterus to the α1‐adrenoceptor agonist phenylephrine were measured on days 3–6 of gestation. There was a progressive increase in sensitivity to phenylephrine in both muscle layers between days 3 and 6 of gestation. Overall, this amounted to a 13 and 9 fold increase in sensitivity in longitudinal and circular muscles, respectively. In longitudinal muscle the slope of the Hill plot was 2 on day 3 of pregnancy and was decreased to 1 thereafter.
The sympathetic nerve terminals innervating the smooth muscle of the uterus were destroyed by administration of 6‐hydroxydopamine (2 × 50 mg kg−1) 4–7 days before testing with phenylephrine. Following this treatment there was a significant increase in sensitivity to phenylephrine on day 3 in both muscle layers. After day 4, the longitudinal muscle was less sensitive to phenylephrine.
In the longitudinal muscle there was a progressive increase in the contractile response to maximal concentrations of phenylephrine and to high potassium (100 mm) between days 3 and 6 of pregnancy. In the circular muscle the responsiveness to both phenylephrine and potassium remained unchanged between days 3 and 6 of gestation. 6‐Hydroxydopamine had no effect on the maximal responses to phenylephrine or high potassium in either muscle layer.
In conclusion, denervation supersensitivity of uterine smooth muscle following injection of 6‐hydroxydopamine is observed only on day 3 of pregnancy and appears to be replaced by subsensitivity by day 6. The decrease in the slope of the Hill plot in longitudinal muscle after day 3 may be explained by changes in events between activation of α1‐adrenoceptors and contraction.
Lack of correlation between the antiarrhythmic effect of l‐propionylcarnitine on reoxygenation‐induced arrhythmias and its electrophysiological properties
Authors: Barbieri M. , Carbonin P.U. , Cerbai E. , Gambassi G. , Giudice P. Lo , Masini I. , Mugelli A. , Pahor M. 
Published: July 2012

The antiarrhythmic effect of l‐propionylcarnitine (l‐PC) was evaluated in the guinea‐pig isolated heart; arrhythmias were induced with hypoxia followed by reoxygenation and by digitalis intoxication.
l‐PC 1 μm, was found to be the minimal but effective antiarrhythmic concentration against reoxygenation‐induced ventricular fibrillation. No antiarrhythmic effect was observed against digitalis‐induced arrhythmias. d‐Propionylcarnitine, l‐carnitine and propionic acid did not exert antiarrhythmic effects.
During hypoxia and reoxygenation l‐PC consistently prevented the rise of the diastolic left ventricular pressure, and significantly reduced the release of the cardiac enzymes creatine kinase (CK) and lactic dehydrogenase (LDH).
The electrophysiological effects of l‐PC were then studied on either normal sheep cardiac Purkinje fibres or those manifesting oscillatory afterpotentials induced by barium or strophanthidin.
l‐PC (1 and 10 μm) did not significantly modify action potential characteristics and contractility of normal Purkinje fibres, or the amplitude of OAP induced by strophanthidin or barium.
It is concluded that the antiarrhythmic action of l‐PC on reoxygenation‐induced arrhythmias is not correlated with its direct electrophysiological effects studied on normoxic preparations.
Mechanisms contributing to the differential haemodynamic effects of bombesin and cholecystokinin in conscious, Long Evans rats
Authors: Janssen Paul J.J.M. , Gardiner Sheila M. , Compton Alix M. , Bennett Terence 
Published: July 2012

Long Evans rats were chronically instrumented with intravascular catheters and pulsed Doppler probes to assess changes in renal, mesenteric and hindquarters blood flows and vascular conductances in response to bombesin (2.5 μg kg−1, i.v.) and cholecystokinin (CCK) (0.5 and 5.0 μg kg−1, i.v.).
Bombesin caused an increase in heart rate and blood pressure, together with a transient renal vasoconstriction and prolonged mesenteric vasodilatation; there was an early hindquarters vasodilatation followed by vasoconstriction.
In the presence of phentolamine, bombesin caused a fall in blood pressure due to enhanced hindquarters vasodilatation; these effects were reversed by propranolol and hence were possibly due to circulating adrenaline acting on vasodilator β2‐adrenoceptors.
During concurrent administration of phentolamine, propranolol and atropine, bombesin caused prolonged tachycardia and a rise in blood pressure. The renal vasoconstrictor and mesenteric vasodilator effects of bombesin were not reduced under these conditions and thus probably were direct and/or indirect non‐adrenergic, non‐cholinergic (NANC) effects.
CCK caused dose‐dependent increases in blood pressure accompanied by renal, mesenteric and hindquarters vasoconstrictions followed, after the higher dose, by vasodilatations. The lower dose of CCK increased heart rate but there was a bradycardia followed by a tachycardia after the higher dose.
Experiments with antagonists as described above indicated the pressor effect of CCK was mediated largely through α‐adrenoceptors, as were the mesenteric and hindquarters vasoconstrictor effects; CCK exerted NANC negative chronotropic effects.
All the effects of CCK were markedly inhibited by L364,718. This observation, and the finding that L364,718 had no effect on the responses to bombesin, together with the dissimilarities in the regional haemodynamic effects of exogenous CCK and bombesin, indicate that the cardiovascular actions of the latter were not dependent on the release of endogenous CCK.
New, long‐acting, potent bradykinin antagonists
Authors: Lembeck F. , Griesbacher T. , Eckhardt M. , Henke S. , Breipohl G. , Knolle J. 
Published: July 2012

Three new bradykinin (BK) antagonists, d‐Arg0‐Hyp3‐Thi5‐d‐Tic7‐Oic8‐BK (compound I), d‐Arg0‐Hyp3‐d‐Tic7‐Oic8‐BK (compound II), and Arg(Tos)1‐Hyp3‐Thi5‐d‐Tic7‐Oic8‐BK (compound III), were tested against the effects of BK in 9 bioassay preparations including visceral smooth muscles, vasoconstriction, plasma protein extravasation, release of prostaglandin E2, bronchoconstriction, and stimulation of afferent C‐fibre nociceptors. In some of these tests the effects of the new compounds were compared with those of the antagonist d‐Arg0‐Hyp2‐Thi5,8‐d‐Phe7‐BK (compound IV), described by Stewart & Vavrek (1987).
For all bioassays the general rank order of potency of the compounds was found to be I > II > III ≫ IV. The new antagonists were long‐acting; in some bioassays their effects outlasted the duration of the experiment.
The inhibitory effects of the new BK antagonists were specific for BK; actions of noradrenaline, angiotensin II, acetylcholine or histamine were unaffected by the antagonists. They did not stimulate the release of histamine or prostaglandins. An agonistic effect was observed only with very high concentrations of compounds I and II in the plasma protein extravasation test.
The long duration of action of the new BK antagonists is probably due to a high and long‐lasting affinity to the BK receptors. A high resistance of the antagonists to enzymatic destruction may be another reason.
The new BK antagonists will be valuable tools for the investigation of the pathophysiological role of BK. In addition they may offer a potential for therapeutic applications.
5‐Hydroxytryptamine‐stimulated accumulation of 1,2‐diacylglycerol in the rabbit basilar artery: a role for protein kinase C in smooth muscle contraction
Authors: Clark Angela H. , Garland C.J. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) produced a concentration‐dependent increase in the membrane concentration of 1,2‐diacylglycerol (DG) in the rabbit isolated basilar artery, but did not stimulate the hydrolysis of membrane phosphoinositide.
The 5‐HT‐induced accumulation of DG could be blocked with the putative phospholipase C inhibitor 2‐nitro‐4‐carboxyphenyl‐N,N‐diphenylcarbamate (NCDC; 70 μm), but not with the protein kinase C inhibitor, 1‐(5‐isoquinolinesulphonyl)‐2‐methyl piperazine (H7; 50 μm).
Direct stimulation of protein kinase C with phorbol 12,13‐dibutyrate (PDBu) produced sustained smooth muscle contraction which was fairly rapid in onset and could be reversed by H7 but not by NCDC. The inactive phorbol, 4α phorbol 12,13‐didecenoate, did not produce contraction in the basilar artery.
5‐HT‐induced contractions (1 nm–100 μm) were blocked or greatly reduced in the presence of the protein kinase inhibitor H7 or polymyxin B, and with the phospholipase C inhibitor, NCDC. The concentrations of these inhibitors which abolished contraction to 5‐HT, did not alter smooth muscle contraction produced in response to 30 mm K+‐physiological salt solution (PSS).
These data suggest that DG production and the subsequent activation of PKC forms an important component of the cerebrovascular contractile response to 5‐HT. As the DG does not appear to arise from membrane phosphatidylinositol, it appears that 5‐HT can stimulate the production of this second messenger in cerebral arteries by a mechanism which is different from peripheral arteries.
Characterization in rat aorta of the binding sites responsible for blockade of noradrenaline‐evoked calcium entry by nisoldipine
Authors: Morel Nicole , Godfraind Théophile 
Published: July 2012

The effectiveness of the calcium antagonist, 1,4‐dihydropyridine nisoldipine, as an inhibitor of contraction and 45Ca entry evoked by noradrenaline in rat aorta has been investigated and correlated with binding characteristics in intact artery.
Contractions evoked by noradrenaline were concentration‐dependently depressed by nisoldipine (0.3–300 nm). About 60% of the response was resistant to inhibition, while KCl‐induced contractions could be completely blocked. Noradrenaline‐induced contractions were also less sensitive to nisoldipine inhibition than were KCl‐induced contractions.
Preincubation of the aorta with nisoldipine in high KCl depolarizing solution increased the inhibition of the contraction evoked by a short application of noradrenaline or KCl to a similar extent.
The inhibition by nisoldipine of 45Ca influx evoked either by KCl depolarizing solution or by noradrenaline correlated well with the inhibition of the contractile responses. However, while KCl‐stimulated 45Ca influx was totally abolished by nisoldipine (300 nm), 38% of the noradrenaline‐stimulated 45Ca influx was resistant to inhibition by nisoldipine (300 nm).
The study of [3H]‐(+)‐PN 200‐100 ([3H]‐(+)‐isradipine) binding in intact aorta showed the presence of a homogeneous population of specific binding sites. KD values were dependent on the KCl concentration in the bath while Bmax was unaffected. Binding of [3H]‐(+)‐isradipine was also increased in tissue exposed to noradrenaline; in the presence of 10−5 m noradrenaline, binding parameters of [3H]‐(+)‐isradipine were close to the values obtained in aorta bathed in 20 mm KCl solution.
Displacement of [3H]‐(+)‐isradipine specific binding by nisoldipine was determined in segments of mesenteric artery and of aorta. The potency of nisoldipine was dependent on the incubation conditions applied to the vessel, as follows: KCl (100 mm) depolarizing solution > noradrenaline (10−5 m) = KCl (25 mm) solution > physiological solution. The Ki value measured in aorta exposed to noradrenaline (10−5 m) was close to the IC50 value of nisoldipine on the noradrenaline‐evoked contraction.
The membrane potential value of rat aorta was estimated by the distribution of [3H]‐tetraphenylphosphonium bromide ([3H]‐TPP+). [3H]‐TPP+ uptake concentration‐dependently decreased when the KCl concentration in the bath was increased from 5.9 to 130 mm. Noradrenaline also concentration‐dependently decreased [3H]‐TPP+ uptake; the maximum effect (1–10 μm noradrenaline) was comparable in amplitude to the effect of 25 mm KCl solution.
It is concluded that in rat aorta, noradrenaline activates voltage‐operated calcium channels that contain the specific, voltage‐sensitive binding sites for calcium antagonistic dihydropyridines. The existence of a fraction of noradrenaline‐stimulated 45Ca entry that is resistant to nisoldipine blockade suggests that another Ca2+ entry pathway is also opened by the agonist.
Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea‐pig vas deferens
Authors: Hall Judith M. , Morton Ian K.M. 
Published: July 2012

This study investigated the recognition characteristics of neurokinin receptors mediating potentiation of the contractile response to field stimulation in the guinea‐pig vas deferens.
A predominant NK1 receptor population is strongly suggested by the relative activities of the common naturally‐occurring tachykinin agonists, which fall within less than one order of magnitude. This conclusion is supported by the relative activities of the synthetic NK1 selective agonists substance P methyl ester, [Glp6,l‐Pro9]‐SP(6–11) and δ‐aminovaleryl‐[l‐Pro9,N‐MeLeu10]‐SP(7–11) (GR73632) which were 0.78, 9.3 and 120 as active as substance P, respectively. Furthermore, the NK2 selective agonist [Lys3, Gly8,‐R‐γ‐lactam‐Leu9]‐NKA(3–10) (GR64349) was active only at the highest concentrations tested (> 10 μm), and the NK3 selective agonist, succ‐[Asp6,N‐MePhe8]‐SP(6–11) (senktide) was essentially inactive (10 nm‐32 μm).
[d‐Arg1,d‐Pro2,d‐Trp7,9, Leu11]‐SP(1–11) antagonized responses to neurokinin A, neurokinin B, physalaemin, eledoisin, [Glp6,d‐Pro9]‐SP(6–11), GR73632 and GR64349 (apparent pKBs 5.6–6.2), but was less potent in antagonizing responses to substance P, substance P methyl ester and [Glp6,l‐Pro9]‐SP(6–11) (apparent pKBs ≤ 5.0–5.0).
In contrast, the recently developed NK1‐selective receptor antagonist [d‐Pro9[Spiro‐γ‐ lactam]Leu10, Trp11]‐SP(1–11) (GR71251) did not produce agonist‐dependent pKB estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pKB of 7.58 ± 0.13 for the four agonists of differing subtype selectivity tested (GR73632, GR64349, substance P methyl ester and neurokinin B). This estimate is similar to that we obtained for NK1‐mediated (substance P methyl ester) contraction in the guinea‐pig ileum preparation (pKB = 7.86 ± 0.05).
Tachykinin action appears not to depend on release of a number of intermediary mediators including acetylcholine, histamine or cyclo‐oxygenase products, nor to involve interaction with neuronal mechanisms including α2‐adrenoceptor feedback, noradrenergic Uptake‐1 or opioid‐release, since antagonism or inhibition of these mechanisms did not modify responses to tachykinins.
We conclude that tachykinin action in the field‐stimulated guinea‐pig vas deferens preparation is mediated through interaction with a predominant neurokinin NK1 receptor population and this preparation can therefore be used to study NK1 modulation of sympathetic neurotransmission.
Prejunctional prostanoid receptors on cardiac adrenergic terminals belong to the EP3 subtype
Authors: Mantelli Laura , Amerini Sandra , Rubino Annalisa , Ledda Fabrizio 
Published: July 2012

The effects of prostaglandin E2 (PGE2) and of several synthetic prostanoids on the cardiac response to sympathetic nerve stimulation in guinea‐pig atria have been evaluated.
PGE2 (0.01–100 nm), sulprostone (0.01–100 nm) and misoprostol (0.1–100 nm), but not butaprost (0.1–100 nm), dose‐dependently reduced the increase in cardiac contractility induced by electrical field stimulation of sympathetic terminals.
The EP1 antagonist AH6809 (1 μm) did not modify the inhibition of cardiac response induced by PGE2, sulprostone and misoprostol.
In preparations preloaded with [3H]‐noradrenaline, tritium overflow induced by electrical field stimulation was greatly and significantly reduced by 100 nm PGE2 and by 100 nm sulprostone.
These results indicate that PGE2 and other synthetic prostanoids reduce noradrenaline release from cardiac adrenergic nerve terminals acting on prejunctional inhibitory receptors belonging to the EP3 subtype.
The effects of adenosine triphosphate (ATP) and related purines on human isolated subcutaneous and omental resistance arteries
Authors: Martin G.N. , Thorn S.A.McG. , Sever P.S. 
Published: July 2012

Human resistance arteries were obtained from specimens of omentum and subcutaneous fat removed at surgery. They were studied in vitro by use of a myograph technique to determine the effects of purines on the arteries.
In preparations where tone had been raised with noradrenaline, low concentrations (1 nm–1 μm) of adenosine triphosphate (ATP) and 2‐methylthioATP, but not α,β‐methyleneATP, produced concentration‐dependent relaxation. There was a lack of relationship between the relaxation response to acetylcholine and that to ATP.
In preparations under basal tone, high concentrations (1 μm–1 mm) of ATP, 2‐methylthioATP and α,β‐methyleneATP produced concentration‐dependent contractions.
The rank order of potency of the purine nucleotide analogues for the relaxation response was 2‐methylthioATP > ATP > α,β‐methyleneATP and for the contractile response it was α,β‐methyleneATP > ATP = 2‐methylthioATP.
Adenosine produced concentration‐dependent relaxation in preparations under raised tone and was less potent than ATP but did not produce contraction in preparations at basal tone. Relaxation responses to adenosine, but not to ATP, were antagonized by 8‐phenyltheophylline.
These results indicate the presence of vasodilator P2y‐ and P1‐purinoceptors and vasoconstrictor P2x‐purinoceptors on human resistance arteries isolated from omental and subcutaneous sites.
Dissociation of a ferric maltol complex and its subsequent metabolism during absorption across the small intestine of the rat
Authors: Barrand Margery A. , Callingham Brian A. , Dobbin Paul , Hider Robert C. 
Published: July 2012

The fate and disposition of [59Fe]‐ferric [3H]‐maltol after intravenous administration were investigated in anaesthetized rats. Immediate dissociation of ferric iron from maltol took place in the circulation even with high doses of ferric maltol (containing 1 mg elemental iron). In plasma samples withdrawn within 1 min of injection and subjected to gel filtration, 59Fe eluted with the high molecular weight proteins whilst the tritium was associated with low molecular weight material.
The rates of elimination of 59Fe and of tritium from the plasma and their ultimate fate were very different. The half life for 59Fe in the plasma was around 70 min and 59Fe appeared mainly in the bone marrow and liver. There was an initial rapid exit of tritium from the plasma with a half life of around 12 min. This was followed either by a plateau or by a rise in tritium levels, involving entry of maltol metabolites into the circulation. These metabolites could be recovered in the urine.
Entry of 59Fe and of tritium into the blood plasma after intraduodenal administration of [59Fe]‐ferric [3H]‐maltol was also very different. At low doses of ferric maltol (containing 100 μg elemental iron), the tritium appeared in the plasma in highest amounts within seconds and then decreased whilst there was a slow rise in 59Fe levels. At higher doses of ferric maltol (containing 7 mg elemental iron), levels of 59Fe in the plasma were highest at 5 min and then fell whereas tritium levels rose steadily. Mucosal processing of 59Fe prevented further entry of iron at high dose into the circulation.
Initial rates of uptake of [3H]‐maltol into isolated intestinal fragments were measured over a range of concentrations and revealed that maltol alone could diffuse freely into the tissues whereas maltol complexed to iron showed saturable uptake kinetics similar to those seen with the iron itself.
After intestinal uptake, 59Fe and tritium were associated with different subcellular fractions, maltol itself being metabolized to the glucuronide conjugate within the intestinal mucosa.
It is concluded that dissociation of metal and ligand takes place before entry into the intestinal mucosa. Iron is then taken up on the endogenous carrier and processed in the normal way whilst maltol enters by diffusion, its rate of entry being limited by the degree of dissociation. It is subsequently metabolized by conjugation and eliminated rapidly from the body in the urine.