bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of (±)‐dobutamine and human α‐CGRP on cardiac and on regional haemodynamics in conscious Long Evans rats
Authors: Gardiner S.M. , Compton A.M. , Kemp P.A. , Bennett T. , Hughes B. , Foulkes R. 
Published: July 2012

Comparisons were made of the full haemodynamic profiles of the known cardiostimulant, (±)‐dobutamine, and the putative inotropic peptide, human α‐calcitonin gene‐related peptide (human α‐CGRP), in conscious, chronically‐instrumented Long Evans rats. Both substances were administered continuously i.v. for 60 min at two doses ((±)‐dobutamine, 2 and 10 μmol kg−1h−1; human α‐CGRP, 0.15 and 1.5 nmol kg−1 h−1).
In spite of their similar (small) effects on mean arterial blood pressure, the low doses of (±)‐dobutamine and human α‐CGRP influenced cardiac haemodynamics differently. Thus, (±)‐dobutamine caused an increase in cardiac index (due to a tachycardia), accompanied by rises in peak aortic flow, maximum rate of rise of aortic flow (dF/dtmax) and total peripheral conductance. However, the latter waned during the infusion, and after the infusion there was a significant systemic vasoconstriction and reductions in peak aortic flow, dF/dtmax and stroke index. Such ‘off’ effects following dobutamine infusion have not been described previously. The infusion of the lower dose of human α‐CGRP caused only a transient fall in central venous pressure.
The rise in total peripheral conductance during infusion of the lower dose of (±)‐dobutamine was associated with increases in hindquarters and common and internal carotid vascular conductances. The fall in total peripheral conductance after infusion was associated with renal vasoconstriction. Although there was no significant change in total peripheral conductance during the infusion of the lower dose of human α‐CGRP there were hindquarters and carotid vasodilatations together with mesenteric vasoconstriction.
Infusion of the higher dose of (±)‐dobutamine had greater effects than the lower dose on all cardiac haemodynamic variables and additionally, increased stroke index. However, the negative cardiac haemodynamic effects following the offset of infusion were also enhanced in association with marked renal and mesenteric vasoconstrictions. While infusion of the higher dose of human α‐CGRP increased cardiac index, peak aortic flow, dF/dtmax and total peripheral conductance, stroke index fell together with central venous pressure.
(±)‐Dobutamine caused greater cardiostimulation and increases in hindquarters blood flow than did human α‐CGRP. However, the latter at the higher dose caused substantially greater common and internal carotid hyperaemia than did (±)‐dobutamine, possibly indicating a selective and additional effect of human α‐CGRP on cranial blood flow. Furthermore, there were no adverse cardiovascular effects following infusion of human α‐CGRP.
The effect of cetirizine on antigen‐dependent leucopenia in the guinea‐pig
Authors: Coyle Anthony J. , Lefort Jean , Vargaftig B. Boris 
Published: July 2012

Intravenous administration of ovalbumin (1 mg kg−1) to guinea‐pigs that had previously been injected with 3.5 × 109 platelets from actively sensitized animals induced an approximately 40% decrease in the number of circulating leucocytes 30–60 min later, whereas the number of platelets was not affected.
In contrast, there was no change in the leucocyte number following antigen challenge of guinea‐pigs that had received platelets from non‐immunised animals.
This platelet‐dependent leucopenia was inhibited by prior treatment of the recipient animal with cetirizine (10–30 mg kg−1, i.v.). Terfenadine (50 mg kg−1, p.o.) and mepyramine (2 mg kg−1, i.v.) were completely inactive in this respect. All doses of anti‐histamines were used at concentrations which completely inhibited the bronchoconstriction to an i.v. injection of 5 μg kg−1 of histamine.
The site of action of cetirizine is most likely to be the platelet as leucopenia induced by the neutrophil agonists leukotriene B4 (LTB4) (30 ng kg−1) and platelet activating factor (PAF) (30 ng kg−1) were not modified by cetirizine treatment.
In these experiments, we failed to support a role for lipoxygenase products as mediators of the platelet‐dependent leucopenia, as the selective lipoxygenase inhibitor BWA4C (50 mg kg−1, p.o.) was ineffective.
Our present results confirm and extend previous data demonstrating that antigen stimulated platelets can induce leucopenia in non‐immunised animals and this can be inhibited by the anti‐allergic agent, cetirizine, by an action which is probably unrelated to its anti‐histamine properties. The precise nature of the platelet derived factor(s) and their target of action remains to be determined.
Early and late contraction induced by ouabain in human umbilical arteries
Authors: Sato Koichi , Aoki K. 
Published: July 2012

Ouabain (3 × 10−7–10−4 m) evoked a biphasic contraction in human umbilical artery that consisted of an early and a late contraction. The Ca2+‐antagonists, verapamil (10−7–10−5 m), diltiazem (10−7–10−5 m) and nifedipine (10−9–10−7 m) inhibited the early but not the late contraction. Caffeine (5 mm) changed neither the magnitude of the peak of the biphasic contraction nor the time needed to reach it.
Sodium concentration reduction (140 to 0 mm, replaced by N‐methyl‐d‐glucamine, NMG) produced dose‐dependent contraction of the arterial strip in 2.5 mm Ca2+ solution after the first treatment with verapamil (10−5 m) and caffeine (5 mm), but not in Ca2+‐free solution.
After prior treatment with verapamil and caffeine, the amplitude of the ouabain (10−4 m)‐induced late contraction varied, depending on the concentration of Ca2+ (0–2.5 mm) in the medium.
Amiloride (5 × 10−5 m–5 × 10−4 m), an inhibitor of the Na+–Ca2+ exchange system, produced dose‐dependent inhibition of the late contraction induced by ouabain (10−5 m) after prior treatment with verapamil and caffeine.
The time needed to reach the peak tension induced by monensin (5 × 10−7 m) together with ouabain (10−6 m) was less than that with ouabain alone, but the magnitude of the peak tension was not changed.
These results suggest that the early and late contractions caused by ouabain respectively produce a Ca2+ influx through voltage‐sensitive Ca2+ channels and Ca2+ entry through sodium‐calcium (Na+ — Ca2+) exchange.
Identification and characterization of histamine H1‐ and H2‐receptors in guinea‐pig left atrial membranes by [3H]‐mepyramine and [3H]‐tiotidine binding
Authors: Hattori Yuichi , Endou Masayuki , Gando Satoshi , Kanno Morio 
Published: July 2012

Histamine receptors in the membranes prepared from guinea‐pig left atria were characterized with [3H]‐mepyramine and [3H]‐tiotidine binding.
The binding of the H1‐antagonist, [3H]‐mepyramine, was saturable and of high affinity with a maximum binding capacity of 307 ± 27 fmol mg−1 protein (n = 14) and with an equilibrium dissociation constant (KD) of 1.5 ± 0.2 nm (n = 14). The binding was rapid and readily reversible.
The competition curve for [3H]‐mepyramine binding by histamine was biphasic and revealed high and low affinity states of binding. The addition of 5′‐guanylylimidodiphosphate (GppNHp) (100 μm) converted this heterogeneous binding into homogeneous binding of low affinity.
The competition curves of H1‐antagonists with [3H]‐mepyramine had Hill coefficients not significantly different from unity, consistent with competition with [3H]‐mepyramine at a single site. GppNHp did not shift the competition curves.
Dissociation constants for H1‐antagonists determined from inhibition of [3H]‐mepyramine binding correlated well with the constants derived from inhibition of the positive inotropic response of guinea‐pig left atria to histamine.
The H2‐antagonist, [3H]‐tiotidine, labelled an apparently homogeneous population of recognition sites with a maximum binding capacity of 41 ± 8 fmol mg−1 protein (n = 6) and a KD of 10.8 ± 1.2 nm (n = 6).
Although histamine competed for [3H]‐tiotidine binding in a concentration‐dependent manner, the curve was monophasic and was not shifted by GppNHp.
It is concluded that both H1 and H2‐receptors exist in guinea‐pig left atria. H1‐receptors probably couple to intracellular effector(s) through a guanine nucleotide‐dependent transducing mechanism. On the other hand, H2‐receptors seem unlikely to be linked to guanine nucleotide regulatory proteins in guinea‐pig left atria, which may explain the failure of histamine to cause an increase in cyclic AMP in spite of the presence of H2‐receptors.
Functional changes in GABAA receptor stimulation during the oestrous cycle of the rat
Authors: Westerling Peter , Lindgren Silvana , Meyerson Bengt 
Published: July 2012

Slices of rat cuneate nucleus were used to study whether or not gonadal steroids influence the γ‐aminobutyric acid (GABA) system in vivo. Females in different stages of the oestrous cycle as well as steroid‐treated (oestrogen, progesterone or both) ovariectomized animals were used.
Functional changes in the GABAA receptors were assayed using the effects of potentiators (benzodiazepine, barbiturate) and antagonists (picrotoxin) on the muscimol control dose‐response curves.
The potentiating effect of the benzodiazepine, flurazepam was unchanged during the oestrous cycle, and the hormone treatments did not alter this effect.
During oestrus, an increase was seen in the potentiating effect of the barbiturate (pentobarbitone). This suggests a synergistic effect between barbiturates and gonadal steroids. Progesterone treatment also increased the effect of pentobarbitone.
The antagonistic action of picrotoxin was unaffected during the oestrous cycle. However, progesterone (or progesterone and oestrogen) treatment reduced the potency of picrotoxin.
This study supports the idea that endogenous steroids (presumably progesterone) affect the GABAA receptors during the oestrous cycle by a mechanism associated with the barbiturate site of the GABAA receptor complex.
The effect of drugs acting on cholinoceptors and mucosal chloride on luminal bicarbonate transport by rat caecum under in vitro conditions
Authors: Canfield Paul , Abdul‐Ghaffar Tarik 
Published: July 2012

The transport of ĤO−3 (Jsm) from a ĤO−3‐buffered serosal to an unbuffered mucosal saline solution has been studied in rat caecum in vitro.
Carbachol, bethanechol and acetylcholine (ACh) caused a concentration‐dependent fall in Jsm with similar maximum effects. 1,1‐Dimethyl‐4‐phenyl‐piperazinium iodide (DMPP) also inhibited Jsm but the effect was less than with the other drugs. Maximum cholinoceptor inhibition was less than that obtained with anoxia.
Responses were blocked by atropine (10−5 m) but hexamethonium (2 × 10−4 m) significantly altered the response only to DMPP.
Physostigmine (10−5 m) shifted the ACh response curve to the left but physostigmine itself caused inhibition of Jsm which was blocked by atropine.
Substitution of mucosal Cl− by NO−3 reduced Jsm to a similar extent to maximum cholinoceptor effect and abolished responses to bethanecol. Anoxia further reduced Jsm in the presence of NO−3.
Mucosal SITS and DIDS (1 mm) reduced Jsm but this was less than the maximum inhibition seen with drugs acting on cholinoceptors or mucosal Cl− removal. Serosal DIDS caused a similar inhibition.
We conclude that cholinoceptor agonists inhibit but do not abolish luminal bicarbonate transport by an action on muscarinic receptors.
Differences between the effects of cromakalim and nifedipine on agonist‐induced responses in rabbit aorta
Authors: Bray K.M. , Weston A.H. , Duty S. , Newgreen D.T. , Longmore J. , Edwards G. , Brown T.J. 
Published: July 2012

The effects of cromakalim on endothelium‐denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine.
Pre‐incubation with cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)‐induced responses.
Cromakalim (0.3–10 μm), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of cromakalim were antagonized by raising extracellular [K+] or by glibenclamide.
Nifedipine inhibited contractions produced by KCl (40 mm) whereas cromakalim had no effect.
In Ca2+‐free physiological salt solution (PSS), cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA‐releasable Ca2+ stores, whereas nifedipine was ineffective.
In tissues preloaded with 42K+ cromakalim (0.3–10 μm) produced a concentration‐dependent increase in the 42K+ efflux rate coefficient. NA (0.3 μm) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 μm).
When microelectrodes were used, cromakalim (1–10 μm) produced a maintained concentration‐dependent membrane hyperpolarization. However, low concentrations of cromakalim (<1 μm) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential.
It is concluded that the ability of cromakalim to relax NA‐induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine‐sensitive Ca2+ channels. Instead, cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.
The differential contribution of endogenous prostaglandins to the release of acetylcholine from the myenteric plexus of the guinea‐pig ileum
Authors: Takeuchi Tadayoshi , Okuda Miho , Yagasaki Osamu 
Published: July 2012

Prostaglandin E (PGE) may be essential for maintaining the sensitivity of the myenteric plexus of guinea‐pig ileum to nicotine. The contributions of prostaglandins to nervous activity evoked by different stimuli have now been investigated by measuring the amount of acetylcholine (ACh) released from the myenteric plexus of the guinea‐pig ileum.
The amount of ACh released in response to dimethylphenylpiperazinium (DMPP) or substance P was depressed to about 40% of control by 2.8 μm indomethacin (Ind), whereas the release of ACh induced by 5‐hydroxytryptamine (5‐HT) was not affected. The inhibitory effects of Ind were oyercome by 14.3 nm PGE2.
Mepacrine 5 μm, an inhibitor of phospholipase A2, depressed the release of ACh in response to DMPP and substance P to the same extent as Ind. These inhibitory effects of mepacrine were overcome by arachidonic acid (10 μm), but not by arachidonic acid plus Ind. The release of ACh evoked by 5‐HT or electrical field stimulation (EFS) was also inhibited to about 60% of control by mepacrine but these inhibitions were overcome by arachidonic acid (10 μm) either in the absence or the presence of Ind.
The results suggest that endogenous prostaglandins and arachidonic acid contribute to the maintenance of the excitability of the myenteric plexus by DMPP and substance P. By contrast, the release of ACh induced by 5‐HT and EFS may be regulated by arachidonic acid and not by prostaglandins.
Adenosine‐ and α,β‐methylene ATP‐induced differential inhibition of cholinergic and non‐cholinergic neurogenic responses in rat urinary bladder
Authors: Parija S.C. , Raviprakash V. , Mishra S.K. 
Published: July 2012

The effects of adenosine and α,β‐methylene adenosine triphosphate (α,β‐Me ATP) on single pulse‐induced neurogenic responses and contractions caused by exogenously applied acetylcholine (ACh) and adenosine triphosphate (ATP) were examined in rat urinary bladder.
Application of single pulse stimulation (1 ms; 80 V) evoked a biphasic contractile response (abolished by tetrodotoxin, 0.5 × 10−7 m) consisting of a fast (time to peak: 1.02 ± 0.07 s) and a slow component (time to peak: 4.92 ± 1.6 s). The selective inhibition of the slow component by atropine (3 × 10−6 m) suggests the participation of both cholinergic and non‐cholinergic neurotransmitters.
α,β‐Me ATP (5 × 10−6 m) abolished ATP (10−4 m)‐induced contractions without altering those to ACh (10−6 m). Further, the selective inhibition of the fast component of the neurogenic response by α,β‐Me ATP is suggestive of the contribution of endogenous ATP to the non‐cholinergic component.
Adenosine (10−8 m to 10−4 m) caused dose‐related differential inhibition of the fast (IC50, 1.04 ± 0.25 × 10−5 m) and slow (IC50, 2.18 ± 0.69 × 10−6 m) components, thereby further supporting two modes of neurotransmission in bladder.
Theophylline (10−4 m) antagonized the inhibitory effects of adenosine on the non‐cholinergic component, thereby implicating the participation of P1‐purinoceptors in neuromodulation. In contrast, theophylline at this concentration enhanced the adenosine‐induced inhibition of the cholinergic component.
The magnitude of ATP (10−4 m)‐ and ACh (10−8 m)‐induced contractions were almost identical to those of the fast and slow components of the neurogenic response, respectively. Comparable reduction of ATP (30.2 ± 3.4%) and ACh (100%) contractions to those of fast (44.2 ± 6.5%) and slow (88.2 ± 5.5%) components suggests the involvement of a postjunctional mechanism in adenosine‐induced differential inhibition of neurogenic responses.
The lack of effect of erythro‐6‐amino‐9‐(2‐hydroxy‐3‐nonyl) adenosine hydrochloride (10−6 m) and dipyridamole (10−6 m) suggests that endogenous adenosine plays little part in modulation of single pulse‐induced neurogenic response.
The results of the present study suggest that fast and slow components of neurogenic response are mediated through ATP and ACh, respectively, possibly co‐released from the same neurone in the rat bladder.
Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca2+‐channel in Drosophila head membranes
Authors: Glossmann Hartmut , Zech Christina , Striessnig Jörg , Staudinger Robert , Hall Linda , Greenberg Robert , Armah Benjamin I. 
Published: July 2012

Piperazinylindoles (DPI 201‐106, BDF 8784), drugs known to act on voltage‐dependent Na+‐channels, bind with very high affinity to a Ca2+‐channel‐associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)‐tetrandrine, a naturally occurring Ca2+‐antagonist, were the most selective inhibitors for phenylalkylamine‐labelled Drosophila Ca2+‐channels compared to mammalian L‐type Ca2+‐channels.
Replacement of the cyano group by a methyl group in (+)‐DPI 201‐106 ((+)‐BDF 8784) increases the IC50 value for inhibition of phenylalkylamine labelling of Drosophila Ca2+‐channels from 0.29 to 2.1 nm but decreases the IC50 value for inhibition of phenylalkylamine labelling of mammalian skeletal muscle Ca2+‐channels from 3480 to 49 nm.
DPI 201‐106 enantiomers completely block (at 0.1 μm) phenylalkylamine photolabelling of a 136 K polypeptide in Drosophila head membranes whereas 10 μm aconitine or lidocaine are without effect.
Assessment of the Ca2+‐antagonist effects of the substituted DPI 201‐106 enantiomers in K+‐depolarized taenia strips from guinea‐pig caecum yielded pA2 values of 6.33 ± 0.07 for (−)‐BDF 8784 and 6.99 ± 0.17 for (+)‐BDF 8784, respectively.
Piperazinylindoles, previously believed to act nonspecifically on voltage‐dependent mammalian L‐type Ca2+‐channels, therefore have stereoselectivity for a novel binding site and chemical selectivity unrelated to local anaesthetic activity.
It is proposed that a very high affinity piperazinylindole‐selective site is coupled to the phenylalkylamine receptor of Drosophila Ca2+‐channels. These sites are still present on mammalian L‐type Ca2+‐channels but have lower affinity and/or are less tightly coupled to phenylalkylamine receptors on the α1‐subunit.
Pharmacological evidence for the possible involvement of repetitive action potentials in facilitation by GABA of catecholamine secretion in bovine adrenal chromaffin cells
Authors: Kitayama Shigeo , Nakatsukasa Yoichi , Morita Katsuya , Dohi Toshihiro , Tsujimoto Akira 
Published: July 2012

γ‐Aminobutyric acid (GABA) evokes catecholamine (CA) secretion and enhances the stimulation‐evoked CA secretion via facilitation of Ca2+ entry in a Cl−‐dependent manner. The present study was designed to investigate further the ionic mechanism of modulation by GABA of CA secretion from adrenal medulla, using a primary culture of bovine chromaffin cells.
Tetrodotoxin (TTX), a voltage‐sensitive Na+ channel blocker, reduced GABA‐evoked CA secretion.
Inhibition of the sodium pump by ouabain or removal of extracellular K+ enhanced GABA‐evoked CA secretion in a TTX‐sensitive manner.
Tetraethylammonium (TEA) and cesium, which are known to block some types of K+ channels, markedly enhanced GABA‐evoked CA secretion in a concentration‐related fashion. TEA‐induced enhancement of the GABA‐evoked CA secretion was attenuated by TTX or replacement of extracellular Na+ by choline. On the other hand, ouabain accelerated the effect of TEA.
TEA and ouabain also enhanced GABA‐induced Ca2+ influx and accumulation of cytosolic Ca2+, assessed with 45Ca2+ uptake and quin2 fluorescence.
Veratridine increased accumulation of cytosolic Ca2+ in a TTX‐sensitive manner. GABA facilitated the veratridine‐induced elevation of cytosolic Ca2+ even when the GABA‐induced rise of cytosolic Ca2+ levelled off.
These results suggest the involvement of repetitive action potentials in modulation of GABA by Ca2+ mobilization and, as a consequence, of the CA secretion in chromaffin cells.
Changes in neurotransmitter sensitivity in the mouse neocortical slice following propranolol and theophylline administration
Authors: Mally Judit , Connick J.H. , Stone T.W. 
Published: July 2012

The mouse neocortical slice has been used to examine the sensitivity of neurones to isoprenaline, 5‐hydroxytryptamine (5‐HT) and adenosine acutely and following chronic treatment of animals with propranolol or theophylline.
While having little effect alone, all three agonists enhanced the d.c. depolarizing potential produced by N‐methyl‐d‐aspartate (NMDA). The effect of (−)‐isoprenaline (0.2 μm) was shared by (+)‐isoprenaline at the much higher concentration of 10 μm.
Superfusion of slices with theophylline or 8‐phenyltheophylline blocked responses to adenosine with evidence of selectivity. A single injection of theophylline 24 h before slice preparation did not alter agonist sensitivity, but when administered daily at 100 mg kg−1 for 14 days, the xanthine caused a loss of sensitivity to adenosine and (−)‐isoprenaline but not 5‐HT. The lower dose of theophylline, 10 mg kg−1 daily, also led to a loss of adenosine responses but no change of sensitivity to the amines.
Following the 14 day treatment with theophylline at 100 mg kg−1 daily in two groups of mice, responses to adenosine recovered to control levels after 20 days.
Propranolol superfusion blocked responses to both isomers of isoprenaline and 5‐HT but did not affect sensitivity to adenosine.
Chronic treatment with propranolol at 25 mg kg−1 daily for 14 days induced a loss of sensitivity to (−)‐isoprenaline and 5‐HT but not adenosine. A lower dose of 5 mg kg−1 daily caused no change in responses to adenosine or 5‐HT, but yielded an increased sensitivity to (−)‐isoprenaline.
The results are discussed with respect to reports of receptor up‐regulation in binding studies; caution is clearly required in extrapolating from such work to receptor activity in a functional system, especially in the case of theophylline and adenosine.