bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of correlation of hypotensive effects with prevention of cardiac hypertrophy by perindopril after ligation of rat coronary artery
Authors: Chiba Kiyoshi , Moriyama Sachiko , Ishigai Yutaka , Fukuzawa Akiko , Irie Kiyoshi , Shibano Toshiro 
Published: July 2012

The present study was designed to test the hypothesis that beneficial effects of angiotensin converting enzyme (ACE)inhibitors are independent of a fall in blood pressure in rat experimental heart failure following coronary ligation.
The animals were assigned randomly to six groups; sham operation, controls subjected to coronary ligation (control), coronary ligation plus chronic treatment with ACE inhibitors at non‐ and hypotensive doses; perindopril (0.2 or 2 mg kg−1 day−1) or enalapril (2 or 20 mg kg−1 day−1) for three weeks starting one week after the ligation.
Systemic blood pressure was measured every week during the experiments. At the end of the treatments, cardiac function and heart weight (an index of myocardial hypertrophy) were determined. In the other animals, ACE activities in plasma and tissues including heart, kidney, lung and blood vessels were measured.
In the controls, cardiac ACE activity, weight of right ventricle and left ventricular end‐diastolic pressure (LVEDP) were higher compared to those in the sham‐operated animals four weeks after the coronary ligation. However, ACE activities were not changed in plasma, kidney, lung and aorta by ligation of the coronary artery.
The chronic treatment with perindopril at a dose of 0.2 mg kg−1 day−1 inhibited the increase in ACE activity in cardiac tissue and suppressed the right ventricular hypertrophy without affecting systemic haemodynamics. In contrast, enalapril at a dose of 20 mg kg−1 day−1, but not 2 mg kg−1 day−1, prevented the development of the right ventricular hypertrophy. Enalapril at 20 mg kg−1 day−1 also lowered systemic blood pressure.
There is no significant correlation between systemic blood pressure and right ventricular hypertrophy at the end of the treatment with perindopril (r = 0.06) or enalapril (r = 0.1).
These findings demonstrate that perindopril, an ACE inhibitor, prevents cardiac hypertrophy without affecting systemic blood pressure in the rat with heart failure after coronary ligation, and suggest that selective augmentation of ACE activity in cardiac tissue is involved in the progression of hypertrophy in this model.
The effect of allosteric antagonists in modulating muscarinic M2‐receptor function in guinea‐pig isolated trachea
Authors: Spina D. , Minshall E. , Goldie R.G. , Page C.P. 
Published: July 2012

We have assessed the influence of a range of synthetic cationic polypeptides with putative inhibitory actions at prejunctional muscarinic M2‐receptors on electrical field stimulation‐induced contraction of guinea‐pig isolated tracheal preparations. Electrical field stimulation of epithelium‐denuded guinea‐pig trachea resulted in frequency‐dependent contractile responses. As expected, tracheal smooth muscle sensitivity to electrical field stimulation was increased in tissues pretreated with the muscarinic M2‐receptor antagonist, gallamine. In contrast, gallamine did not significantly alter the contractile potency to acetylcholine.
Unlike gallamine, the synthetic cationic polypeptides, poly‐l‐arginine, poly‐l‐lysine, poly‐d‐lysine, the cationic dye ruthenium red and the anionic polysaccharide, heparin, failed to increase significantly tracheal smooth muscle sensitivity to electrical field stimulation.
Poly‐l‐arginine, ruthenium red and heparin had no effect on the contractile response to exogenously applied methacholine.
These data are consistent with the concept that in guinea‐pig tracheal smooth muscle, gallamine is an allosteric antagonist of guinea‐pig tracheal muscarinic M2‐receptors, whereas the various cationic polypeptides and the polyanion, heparin, are not.
Lack of effect of microinjection of noradrenaline or medetomidine on stimulus‐evoked release of substance P in the spinal cord of the cat: a study with antibody microprobes
Authors: Lang C.W. , Hope P.J. , Grubb B.D. , Duggan A.W. 
Published: July 2012

Experiments were performed on barbiturate anaesthetized, spinalized cats to investigate the effect of microinjected noradrenaline or medetomidine on the release of immunoreactive substance P in the dorsal spinal cord following peripheral nerve stimulation. The presence of immunoreactive substance P was assessed with microprobes bearing C‐terminus‐directed antibodies to substance P.Noradrenaline or medetomidine were microinjected into the grey matter of the spinal cord, near microprobe insertion sites, at depths of 2.5, 2.0, 1.5 and 1.0 mm below the spinal cord surface with volumes of approximately 0.125 μl and a concentration of 10−3m.In the untreated spinal cord, electrical stimulation of the ipsilateral tibial nerve (suprathreshold for C‐fibres) elicited release of immunoreactive substance P which was centred in and around lamina II. Neither noradrenaline nor medetomidine administration in the manner described produced significant alterations in this pattern of nerve stimulus‐evoked release.In agreement with recent ultrastructural studies these results do not support a control of substance P release by catecholamines released from sites near to the central terminals of small diameter primary afferent fibres.
Sensitivity of G‐protein involved in endothelin‐1‐induced Ca2+ influx to pertussis toxin in porcine endothelial cells in situ
Authors: Aoki Hiroki , Kobayashi Sei , Nishimura Junji , Kanaide Hideo 
Published: July 2012

We designed a new method to determine quantitatively the intracellular Ca2+ concentration ([Ca2+]i) in endothelial cells in situ, using front‐surface fluorometry and fura‐2‐loaded porcine aortic valvular strips. Using this method, we investigated the characteristics of the G‐protein involved in endothelin‐1 (ET‐1)‐induced changes in [Ca2+]i of endothelial cells in situ.
Endothelial cells were identified by specific uptake of acetylated‐low density lipoprotein labelled with 1,1′‐dioctadecyl‐3,3,3′,3′‐tetramethyl‐indocarbocyanine perchlorate (DiI‐Ac‐LDL). Double staining with DiI‐Ac‐LDL and fura‐2 showed that the valvular strip was covered with a monolayer of endothelial cells and that the cellular component which contributed to the fura‐2 fluorescence, [Ca2+]i signal, was exclusively endothelial cells.
ET‐1 (10−7 m) induced an elevation of [Ca2+]i consisting of two components: the first was a rapid and transient elevation to reach a peak, followed by a second, sustained elevation (the second phase). The first phase was composed of extracellular Ca2+‐independent and ‐dependent components, while the second phase was exclusively extracellular Ca2+‐dependent. The extracellular Ca2+‐independent component of the first phase was due to the release of Ca2+ from intracellular storage sites. The second phase and part of the first phase of [Ca2+]i elevation were attributed to the influx of extracellular Ca2+. The Ca2+ influx component was completely inhibited by 10−3 m Ni2+ but was not affected by 10−5 m diltiazem.
Pertussis toxin (IAP) markedly inhibited the extracellular Ca2+‐dependent elevation of [Ca2+]i, but had no effect on the extracellular Ca2+‐independent elevation of [Ca2+]i caused by ET‐1 (10−7 m).
Bradykinin (10−7 m) or ATP (10−5 m) elevated [Ca2+]i and these responses also consisted of extracellular Ca2+‐independent and extracellular Ca2+‐dependent components. IAP had no effect on either component of the [Ca2+]i elevation induced by bradykinin or ATP.
From these findings we conclude that, in porcine endotheliel cells in situ, ET‐1 elevates [Ca2+]i as a result of a Ca2+ influx component from the extracellular space and release of intracelluarly stored Ca2+. The Ca2+ influx is regulated by an IAP‐sensitive G‐protein, while the release of Ca2+ from the intracellular store is not.
Effect of duration of ischaemia on reduction of myocardial infarct size by inhibition of neutrophil accumulation using an anti‐CD18 monoclonal antibody
Authors: Williams F.M. , Kus M. , Tanda K. , Williams T.J. 
Published: July 2012

Neutrophil accumulation is a characteristic feature of the inflammatory response in myocardial tissue which has undergone a period of ischaemia. The aim of this study was to examine whether inhibition of myocardial neutrophil infiltration, using an antibody to the CD18 leukocyte adhesion molecule, was effective in reducing infarct size in anaesthetized rabbits.
Anaesthetized rabbits underwent coronary artery occlusion (CAO) for periods of 30 or 45 min followed by reperfusion for 3 h. Animals were treated intravenously 10 min prior to reperfusion with IB4, a monoclonal antibody to CD18 (1 mg kg−1) or saline (1 ml kg−1). In one group undergoing 45 min CAO, a control antibody, OKMI (1 mg kg−1) was given.
Following either 30 or 45 min of CAO, administration of IB4 resulted in a <75% inhibition in neutrophil accumulation in the area at risk myocardium (AR) compared with control animals.
With the 30 min occlusion period, IB4 significantly reduced myocardial infarct size, 27.2 ± 3.2% vs 67.4 ± 5.6% in the saline control group (n = 5 P < 0.01). In contrast, IB4 did not reduce infarct size following a 45 min period of ischaemia.
In the same animals administration of IB4 significantly inhibited oedema formation in skin elicited by intradermal administration of the neutrophil chemoattractant f‐Met‐Leu‐Phe, but had no effect on coronary microvascular plasma protein leakage in the AR.
Our results indicate that infiltrating neutrophils exacerbate tissue injury following a relatively short, 30 min period of myocardial ischaemia in the rabbit. However, protection with IB4 was no longer seen if the period of CAO was extended to 45 min. The results in this model suggest neutrophils are not a major determinant of tissue injury following more than a very short period of ischaemia.
Modulation by central postsynaptic α2‐adrenoceptors of the jaw‐opening reflex induced by orofacial stimulation in rats
Authors: García‐Vallejo Pascual , Barturen Fernando , García‐Sevilla Jesús A. 
Published: July 2012

The modulation by α2‐adrenoceptors of the jaw‐opening reflex (digastric electromyographic responses) elicited by orofacial electrical stimulation (OF‐JOR) in pentobarbitone anaesthetized rats was investigated.
Increasing doses of clonidine (0.1–1000 μg kg−1, i.v.) reduced, in a dose‐dependent manner until abolition, the amplitude and duration of the OF‐JOR and increased the latency to onset. The sum of amplitudes of the reflex was the most sensitive parameter to the inhibitory effects of clonidine (ED50 = 13.9 μg kg−1).
Pretreatment with the α2‐adrenoceptor antagonist, idazoxan (0.03–1 mg kg−1, i.v.), caused a dose‐dependent shift (1.5 to 37 fold) to the right of the dose‐response curve for clonidine without significant change of maximum inhibitory effect, in a manner compatible with competitive antagonism (ED50B = 29.0 μg kg−1). Pretreatment with yohimbine (0.3 mg kg−1, i.v.) also antagonized the inhibitory effect of clonidine on the OF‐JOR. In contrast, the α2‐adrenoceptor antagonist ARC‐239 (0.3 mg kg−1, i.v.) did not antagonize the effect of clonidine on the reflex.
In rats pretreated with reserpine (5 mg kg−1, s.c., 18 h) the OF‐JOR was not modified, but the potency of clonidine in inhibiting the reflex was potentiated (ED50 value decreased to 6.8 μg kg−1) without a significant change of maximum inhibitory effect.
Increasing doses of amphetamine (0.1–3000 μg kg−1, i.v.) caused a dose‐related, but partial, inhibition of the OF‐JOR (IC50 = 135 μg kg−1; Emax = 67%). Pretreatment with idazoxan (0.1 mg kg−1, i.v.) induced a nine fold shift to the right of the dose‐response curve for amphetamine, while treatment with the depleting drug α‐methyl‐p‐tyrosine (150 mg kg−1daily, i.p., for 14 days) abolished the inhibitory effect of this indirect adrenoceptor agonist on the OF‐JOR.
Morphine (0.1–3000 μg kg−1, i.v.) also reduced the OF‐JOR in a dose‐dependent manner (ED50 value about 325 μg kg−1) but, in contrast to clonidine, it failed to inhibit the reflex fully (Emax = 48%). As expected, pretreatment with the opioid antagonist naloxone (1 mg kg−1, i.v.) abolished the inhibitory effect of morphine on the OF‐JOR, while it did not alter that of clonidine.
Chronic, but not acute, pretreatment with idazoxan (3 mg kg−1daily, i.p. for 14 days) led to a marked potentiation of the inhibitory effect of clonidine on the OF‐JOR (ED50 value decreased to 4.2 μg kg−1), without a significant change of maximum inhibitory effect.
Together the results indicate that clonidine evokes a potent inhibition of the OF‐JOR in rats through the activation of postsynaptic α2‐adrenoceptors. It is suggested that this functional response represents a simple and useful in vivo model for studying various regulatory mechanisms of central α2‐adrenoceptors.
The pharmacological properties of Y‐23684, a benzodiazepine receptor partial agonist
Authors: Yasumatsu Hiroshi , Morimoto Yasuto , Yamamoto Yoshinobu , Takehara Shuzo , Fukuda Takemi , Nakao Tohru , Setoguchi Michihide 
Published: July 2012

The pharmacological properties of a benzodiazepine receptor (BZR) partial agonist, Y‐23684 were investigated in comparison with those of diazepam, a conventional BZR full agonist.
Y‐23684 and diazepam showed high and selective affinity for the BZR with Ki values of 41 and 5.8 nm, respectively.
In contrast to diazepam, variability was noted in the anticonvulsive potency of Y‐23684 depending on convulsants (bicuculline, pentylenetetrazol and maximal electrical shock). Y‐23684 produced the most potent protective effect against bicuculline in rats and mice with ED50s of 1.3 and 1.2 mg kg−1, respectively.
In rat conflict models (Geller‐Seifter and water‐lick tests), Y‐23684 produced an antipunishment action at doses 2–4 times lower than diazepam. In contrast to diazepam, Y‐23684 did not affect unpunished responding up to 50 mg kg−1in the Geller‐Seifter test.
In other rat models of anxiety (social interaction and elevated plus‐maze tests), Y‐23684 was as efficacious as and ten fold more potent than diazepam. In a mouse model of anxiety (exploration (light/dark box) test), Y‐23684 was as efficacious and two fold less potent as diazepam. In these paradigms, Y‐23684 showed a selective anxiolytic profile over a wide dose‐range without loss of efficacy and sedative action.
The impairment of motor coordination (rotarod) and potentiation of CNS depressants (ethanol and hexobarbitone) by Y‐23684 was much weaker than that of diazepam.
These results suggest that Y‐23684 would be a potent and selective anxiolytic agent in man with less side‐effects than conventional BZ‐anxiolytics.
IgE‐receptor activated chloride uptake in relation to histamine secretion from rat mast cells
Authors: Friis U.G. , Johansen T. , Hayes N.A. , Foreman J.C. 
Published: July 2012

Antigen‐stimulated histamine secretion from rat peritoneal mast cells was inhibited when extracellular chloride was replaced by either isethionate or gluconate anions, but the histamine release still remained quite substantial.
Rat peritoneal mast cells take up 36Cl and the uptake reaches a steady state after 60 min incubation with the isotope. At steady state, the intracellular chloride level in the cells was calculated to be 29 ± 11.5 mm.
The chloride uptake in mast cells was exponential with a rate constant of 0.036 min−1in resting cells. When the cells were stimulated with antigen, and rate constant for chloride uptake increased to 0.90 min−1: an increase of 25 fold. Under identical experimental conditions histamine release increased 3 fold.
The rate of chloride uptake in either resting cells or in antigen‐stimulated cells was not changed when the extracellular medium was nominally calcium‐free but histamine release was almost completely inhibited in the absence of extracellular calcium.
The putative chloride channel blocker DIDS (4,4′‐diisothiocyanatostilbene‐2,2′‐disulphonic acid) 0.3 to 30 μm, produced a concentration‐related inhibition of antigen‐stimulated histamine secretion but DIDS (30 μm) did not inhibit the antigen‐stimulated increase of chloride uptake.
The cyclic AMP analogue, dibutyryl cyclic AMP (1 mm) produced a delayed increase in chloride uptake in resting mast cells but neither dibutyryl cyclic AMP nor 8‐bromo cyclic AMP per se induced any histamine secretion.
Ouabain (1 mm) which inhibits the Na+/K+ATPase in rat peritoneal mast cells, failed to affect the uptake of chloride in resting mast cells.
The Na/K/2Cl‐cotransport inhibitor, furosemide (0.7 mm), slowed the unstimulated chloride uptake in resting mast cells and abolished the increased antigen‐induced chloride uptake when added together with antigen. In contrast, spontaneous and antigen‐induced histamine release were unaffected by the presence of furosemide. However, when furosemide was added to the cell suspension 5 min before stimulation, furosemide was without effect on the antigen‐induced chloride uptake.
In addition to the chloride uptake mediated by chloride channels which may be related to the mechanism of histamine secretion, crosslinking of the high affinity membrane receptors for IgE is followed by a fast chloride uptake that is likely to occur through a furosemide‐sensitive Na/K/2Cl‐cotransporter.
Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea‐pig
Authors: Turner Nicholas C. , Dolan John S. , Grimsditch David , Lamb Janine , Worby Angela , Murray Kenneth J. , Coates William J. , Warrington Brian H. 
Published: July 2012

We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea‐pigs using the potent and selective PDE V inhibitor, SK&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram.
Administered as an i.v. infusion SK&F 96231 (0.6 and 1 mg kg−1min−1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg−1, i.v.)‐induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea‐pig. SK&F 96231 (0.1 and 0.3 mg kg−1min−1, i.v.) was without effect on histamine‐induced bronchoconstriction. In the presence of a sub‐threshold infusion of SNP (0.1 μmol kg−1min−1, i.v.) there was a marked enhancement of SK&F 96231‐induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated.
Administered directly into the airway, SK&F 96231 (300 μg in 5 mg lactose carrier) was largely without effect on histamine‐induced bronchoconstriction (4.9 ± 1.9% inhibition). In the presence of SNP (0.1 μmol kg−1min−1, i.v.) or isosorbide dinitrate (200 μg administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK&F 96231 (40 ± 4% and 62 ± 1.8% respectively).
Salbutamol and rolipram (3–300 μg by insufflation) caused a dose‐related inhibition of histamine responses with a maximum of 91 ± 2% and 59 ± 10% respectively. The PDE III inhibitor, siguazodan, was without effect on histamine responses but they were reduced (27.7 ± 4.8% at 300 μg) by SK&F 95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654.
We conclude that SK&F 96231 has weak anti‐spasmogenic activity in the guinea‐pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti‐spasmogenic activity of SK&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity.
We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea‐pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.
Effect of a 5‐lipoxygenase inhibitor, ZM 230487, on cutaneous allergic inflammation in the guinea‐pig
Authors: Teixeira Mauro M. , Hellewell Paul G. 
Published: July 2012

Leukotrienes have potent biological effects in vitro and in vivo and are found in tissue and in biological fluids in various pathological conditions including allergic diseases. Leukotriene B4 (LTB4) is a potent stimulus for eosinophil accumulation and activation and there is much interest in determining its importance in mediating the accumulation of eosinophils at sites of allergic inflammation in vivo. In this study, we investigated the effects of a potent 5‐lipoxygenase inhibitor, ZM 230487, on the accumulation of eosinophils and on local oedema formation in cutaneous inflammation in the guinea‐pig.
The i.d. injection of increasing concentrations of arachidonic acid (AA) led to a dose‐dependent accumulation of 111In‐eosinophils but oedema formation was only significant at the top dose of AA tested (3 × 10−8mol per site). Co‐injection of ZM 230487 with AA inhibited 111In‐eosinophil accumulation up to 99% but the small oedema response to AA was only partially inhibited. AA‐induced oedema formation was only effectively inhibited when a combination of a PAF antagonist, an antihistamine and ZM 230487 was used.
Local administration of the cyclo‐oxygenase inhibitor, ibuprofen, partially inhibited AA‐induced oedema formation suggesting that vasodilator prostaglandins may be released following i.d. injection of AA. AA‐induced 111In‐eosinophil accumulation was also partially inhibited by ibuprofen.
PAF‐induced 111In‐eosinophil accumulation was partially suppressed by local administration of ZM 230487. In contrast, LTB4‐induced 111In‐eosinophil accumulation was enhanced by ZM 230487. These data suggest that locally‐released leukotrienes may modulate mediator‐induced eosinophil accumulation. ZM 230487 had no effect on PAF‐or LTB4‐induced oedema formation.
ZM 230487 significantly inhibited the accumulation of 111In‐eosinophils, but did not affect local oedema formation, in a passive cutaneous anaphylaxis (PCA) reaction. However, the PAF antagonist WEB 2086 either alone or in combination with ZM 230487 had no effect on 111In‐eosinophil accumulation or oedema formation in the PCA reaction.
In conclusion, it appears that a product of 5‐lipoxygenase, probably LTB4, is important for the accumulation of 111In‐eosinophils, but not local oedema formation, in the PCA reaction in guinea‐pig skin. These data support a major role for LTB4 in allergic inflammation in the guinea‐pig and make this animal (and the PCA model) suitable for studying the effects of inhibitors of leukotriene synthesis or action in vivo.