bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative study of endotoxin‐induced hypotension in kininogen‐deficient rats with that in normal rats
Authors: Ueno Akinori , Ishida Hideki , Oh‐ishi Sachiko 
Published: July 2012

1 The aim of this study was to clarify the role of endogenous bradykinin (BK) in the hypotensive response induced by lipopolysaccharide (LPS) by comparing the degree of hypotension caused by LPS in a strain of specific pathogen‐free (SPF) Brown Norway (B/N), kininogen‐deficient mutant Katholiek rats with that of B/N normal Kitasato rats.2 The dose‐dependent hypotensive responses caused by intravenous injection of BK (1–100 nmol kg−1) or platelet‐activating factor (PAF, 0.003–1 μg kg−1), were not different in the two strains of rats used. However, there was a strong difference in the hypotensive response induced by LPS in kininogen‐deficient and normal rats; in normal rats the hypotensive response was composed of two phases (15 min and 70–80 min after LPS injection), but in kininogen‐deficient rats LPS caused a delayed (second phase), but not an acute (first phase) hypotension.3 We demonstrate that Hoe 140 (1 mg kg−1, i.v.) is a potent, selective, and long‐lasting antagonist of the hypotensive effects of BK. Hoe 140 diminished the hypotension caused by LPS in normal rats to the level observed in kininogen‐deficient rats, but had no effect on the hypotension caused by LPS in kininogen‐deficient rats.4 TCV309 (0.1 mg kg−1, i.v.) selectively inhibited the hypotension caused by repetitive injection of PAF for up to 180 min. Pretreatment with TCV309 caused a near complete inhibition of the LPS‐induced hypotension in kininogen‐deficient and normal B/N rats.5 In the normal rats, dexamethasone (0.5 mg kg−1, i.p.) inhibited the second phase of the hypotension induced by LPS, but not the first phase of the hypotension.6 A small amount of BK (0.1 nmol kg−1) potentiated the hypotensive action of PAF (0.01 μg kg−1), when they were injected simultaneously.7 In conclusion, we demonstrate that formation of endogenous BK contributes primarily to the acute, but not to the delayed hypotension afforded by endotoxin in the rat. In contrast, formation of endogenous PAF contributes to both the acute and the delayed hypotension afforded by endotoxin in vivo.
Subgroups among μ‐opioid receptor agonists distinguished by ATP‐sensitive K+ channel‐acting drugs
Authors: Ocaña Maria , Del Pozo Esperanza , Barrios Manuel , Baeyens José M. 
Published: July 2012

1 We evaluated the effects of the i.e.v. administration of different K+ channel blockers (gliquidone, 4‐aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several μ‐opioid receptor agonists in a tail flick test in mice.2 The s.c. administration of all agonists of μ‐opioid receptors tested (morphine, 1–16 mg kg−1; methadone, 1–6 mg kg−1; buprenorphine, 0.04–0.64 mg kg−1; fentanyl, 0.02–0.32 mg kg−1 and levorphanol, 0.2–3.2 mg kg−1) elicited a dose‐dependent antinociceptive effect.3 The ATP‐sensitive K+ channel blocker, gliquidone (0.06–16 μg per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and methadone. In contrast, gliquidone (0.25–160 μg per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol.4 Cromakalim (4–64 μg per mouse, i.c.v.), an opener of ATP‐sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol.5 The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 μg per mouse) or 4‐aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any μ‐opioid receptor agonist tested.6 These results suggest that the opening of ATP‐sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among μ‐opioid receptor agonists, each inducing antinociception through different effector mechanisms.
Neuroprotective profile of lifarizine (RS‐87476) in rat cerebrocortical neurones in culture
Authors: May Gillian R. , Rowand William S. , McCormack James G. , Sheridan Robert D. 
Published: July 2012

1 The ability of the neuroprotective agent, lifarizine (RS‐87476), to mitigate veratridine‐, cyanide‐ and glutamate‐induced toxicity in rat embryonic cerebrocortical neurones in primary culture has been compared with that of tetrodotoxin (TTX), nitrendipine, (+)‐MK‐801 and (−)‐MK‐801. Lactate dehydrogenase (LDH) released into the culture medium was used as the indicator of cell viability.2 Incubation of cultures for 16 h in a medium containing veratridine (10−4 M), sodium glutamate (10−3M) or sodium cyanide (10−3M) resulted in consistent elevations of LDH activity in the culture medium. The ability of compounds to attenuate these elevations was expressed as the concentration required to inhibit the increases in LDH release by 50% (IC50).3 Neurotoxicity induced by veratridine was inhibited by lifarizine (IC50 = 4× 10−7M), TTX (IC50 = 3 × 10−8 M) and nitrendipine (IC50 = 3 × 10−5 M). In contrast, (+)‐MK‐801 (up to 3 × 10−5 M) was ineffective against this insult.4 Glutamate‐induced neurotoxicity was inhibited by (+)‐MK‐801 (IC50 = 1.4 × 10 −8 M) and to a lesser extent by (−)‐MK‐801 (IC50 = 1 × 10−7 M), but was unaffected by lifarizine, TTX or nitrendipine (up to 10−6M).5 (+)‐MK‐801 was effective against sodium cyanide‐induced neurotoxicity (IC50= 1.9 × 10−8M), whereas lifarizine and TTX (up to 10−6 m) and nitrendipine (up to 3 × 10−6 m) were without protective activity against this insult.6 The results demonstrate that lifarizine potently protects rat cortical neurones in vitro against a neurotoxic insult that requires activation of sodium channels for its expression, and that the compound is ineffective against insults mediated by N‐methyl‐D‐aspartate receptor activation. The weak efficacy of nitrendipine against veratridine‐induced cell death argues against the involvement of L‐type calcium channels in this insult. These data are consistent with the notion that the neuroprotective activity of lifarizine observed in vivo may be mediated by inhibition of neuronal sodium currents.
Sustained contraction produced by caffeine after ryanodine treatment in the circular muscle of the guinea‐pig gastric antrum and rabbit portal vein
Authors: Chowdhury J.U. , Pang Y.‐W. , Huang S.‐M. , Tsugeno M. , Tomita T. 
Published: July 2012

1 Caffeine inhibited spontaneous mechanical activity at 0.3‐1 mM, but produced a tonic contraction at concentrations higher than 3 mM in the circular muscle of the guinea‐pig gastric antrum. In the circular muscle of the rabbit portal vein, caffeine at concentrations higher than 1 mM produced an early phasic contraction followed by a small tonic component. The caffeine‐induced contraction was abolished by removal of the external Ca2+ more rapidly in the gastric antrum than the portal vein.2 When the preparations were pretreated with ryanodine (1 μm) a sustained contraction developed on wash‐out of caffeine (10 mM) both in the gastric antrum and portal vein. This contraction was not affected by nicardipine (3 μm) or verapamil (3 μm), but was readily abolished by removal of the external Ca2+ or by addition of cobalt (1 mM). Spontaneous electrical activity, the slow wave, in gastric muscles was blocked in the presence of 10 mM caffeine, but reappeared during the sustained contraction.3 Both the contractions induced directly by caffeine and those produced following caffeine wash‐out after ryanodine treatment were accompanied by a maintained increase in intracellular Ca2+ concentration measured with fura‐2.4 The presence or absence of Ca2+ during the application of ryanodine did not affect the ability of caffeine to initiate sustained contractions, provided Ca2+ was present during the exposure to caffeine.5 It is concluded that caffeine can induce a sustained contraction after ryanodine treatment both in the guinea‐pig gastric antrum and rabbit portal vein, by activating a Ca2+ influx pathway insensitive to organic Ca2+ channel blockers. No clear evidence was obtained for involvement of the Ca2+ influx pathway activated through depletion of intracellular Ca2+ stores. A hypothesis is proposed that the plasma membrane of these preparations is similar to the sarcoplasmic reticulum membrane in that Ca2+ permeability can be increased almost irreversibly by a combination of caffeine and ryanodine in the presence of the external Ca2+.
Comparison of the transplacental transfer of enalapril, captopril and losartan in sheep
Authors: Stevenson Kathleen M. , Gibson Karen J. , Lumbers Eugenie R. 
Published: July 2012

1 The transplacental transfers of three drugs (enalapril, captopril and losartan) which block the renin angiotensin system and have different lipophilicities were studied in chronically catheterized foetal sheep (125–139 days gestation).2 The ability of the foeto‐placental unit to convert enalapril to enalaprilat was studied in two chronically catheterized foetuses. Enalapril (3 mg kg−1, 7.9 fimol kg−1 given i.v. to the foetuses abolished the foetal pressor response to 5 μg angiotensin I (AI) in one foetus and attenuated the pressor response in the other.3 Enalapril (100 mg, 5.7 fimol kg−1) given i.v. to the ewe (n = 5) abolished the maternal pressor response to 2.5 μg AI (n = 1) and attenuated the maternal pressor response to 5 μg AI (n = 5, P< 0.001). The foetal pressor response to 5 μg AI (n = 2) and 10 μg AI (n = 3) did not change. The maternal and foetal pressor responses to angiotensin II (All; n = 5) did not change.4 Foetal pressor responses to 5 μg AI (n = 1) and 10 μg AI (n = 2) were attenuated within 11 min of their mothers (n = 3) being given i.v. captopril (15 mg, 1.5 fimol kg‐1). Foetal pressor responses to 5 μg All (n = 1) and to 10 μg All (n = 2) did not change.5 Losartan (10 mg kg−1, 21.7 fimol kg‐1) given i.v. to the foetus (n = 9) attenuated the foetal pressor response to 5 μg All (P< 0.001) but the maternal pressor response to 5 μg All did not change.6 Losartan (100 mg, 21.7 μmol kg‐1) given i.v. to the ewe (n = 5) attenuated the maternal pressor response to 5 μg All (P< 0.002) but the foetal pressor response to 5 μg All did not change.7 It is concluded that the foeto‐placental unit of the sheep can metabolize enalapril to enalaprilat. Captopril readily crosses the sheep placenta but enalapril and losartan do not. Thus, the transplacental transfer of these drugs does not parallel their lipid solubilities. Furthermore the results show that AT1 receptors are important in mediating the vasoconstrictor effects of All in the foetus.
Modulation of acetylcholine release at mouse neuromuscular junctions by interaction of three homologous scorpion toxins with K+ channels
Authors: Vatanpour H. , Harvey A.L. 
Published: July 2012

1 The effects of three scorpion toxins, charybdotoxin (CTX), iberiotoxin (IbTX), and noxiustoxin (NTX) have been studied on acetylcholine release and on K+ channels by means of twitch tension and electrophysiological recording techniques using isolated skeletal muscle preparations and by a radioligand binding assay using 125I‐labelled dendrotoxin I (DpI) and rat brain synaptosomal membranes.2 On chick biventer cervicis preparations, CTX and IbTX (125 nM) augmented the twitch responses to indirect muscle stimulation. Further, the increase (about 70–80% of control twitch height) was fast in onset, reaching a maximum within 25–30 min. NTX at 125 nM produced a slower augmentation of the twitch responses to indirect muscle stimulation, with the maximum response being seen after 40–50 min.3 On mouse triangularis sterni preparations, CTX (300 nM after 35–40 min) and IbTX (100 nM after 15 min) increased quantal content of the evoked endplate potentials (e.p.p.) by about two fold. However, NTX (300 nM) caused only a small increase in e.p.p. amplitude, which was followed by repetitive e.p.ps in response to single shock nerve stimulation after 40–50 min.4 Extracellular recording of nerve terminal current waveforms in triangularis sterni preparations revealed that CTX and IbTX (3‐100nM), but not NTX (100 nM), blocked the Ca2+‐activated K+ current, 7K.ca‐ However, there was no major change in the portion of the nerve terminal waveform associated with voltage‐dependent K+ currents, IKv.5 In the radioligand binding assay, NTX potently displaced labelled [125I]‐DpI, whereas CTX produced only partial displacement. However, IbTX did not displace [125I]‐DpI from its binding sites on rat brain synaptosomal membranes.6 We conclude that these three structurally homologous scorpion toxins act on different K+ channels and that this leads to different patterns of facilitation of acetylcholine release. IbTX acts selectively on high conductance Ca2+‐activated K+ channels, leading to an increase in the amplitude of e.p.ps without any other changes. NTX acts on voltage‐dependent K+ channels that are sensitive to dendrotoxin and causes repetitive e.p.ps. CTX shares amino acid residues that exist in the structures of IbTX and NTX; CTX acts on both Ca2+‐ and voltage‐dependent K+ channels.
In vitro characterization of tripitramine, a polymethylene tetraamine displaying high selectivity and affinity for muscarinic M2 receptors
Authors: Chiarini A. , Budriesi R. , Bolognesi M.L. , Minarini A. , Melchiorre C. 
Published: July 2012

1 The antimuscarinic effects of tripitramine were investigated in vitro in isolated driven left (force) and spontaneously beating right (force and rate) atria as well as in the ileum of guinea‐pig and rat and in the trachea and lung strip of guinea‐pig and compared with the effects of methoctramine.2 Tripitramine was a potent competitive antagonist of muscarinic M2 receptors in right and left atria. The pA2 values ranged from 9.14 to 9.85. However, in the guinea‐pig and rat left atria but not in guinea‐pig right atria, tripitramine at lower concentrations (3–10 nM) produced a less than proportional displacement to the right of agonist‐induced responses owing to the presence of a possible saturable removal process.3 Tripitramine was about three orders of magnitude less potent in ileal and tracheal than in atrial preparations (pA2 values ranging from 6.34 to 6.81) which makes it more potent and more selective than methoctramine.4 Another intriguing finding was the observation that the pA2 value of 7.91 observed for tripitramine in guinea‐pig lung does not correlate with that found at both muscarinic M2 and M3 receptor subtypes, which clearly indicates that the contraction of guinea‐pig lung strip is not mediated by these muscarinic receptor subtypes.5 A combination of tripitramine with atropine resulted in addition of the dose‐ratios for left atria as required for two antagonists interacting competitively with the same receptor site, whereas the same combination gave a supra‐additive antagonism on guinea‐pig ileum which suggests that tripitramine interacts with a second interdependent site.6 Tripitramine was more specific than methoctramine since, in addition to muscarinic receptors, it inhibited only frog rectus abdominis muscular (pIC50 value of 6.14) and rat duodenum neuronal (pIC50 value of 4.87) nicotinic receptors among receptor systems investigated, namely α1‐, α1‐, and β1‐ adrenoceptors, H1‐ and H2‐histamine receptors, and muscular and neuronal nicotinic receptors.
Endotoxin inhibition of distension‐stimulated gastric acid secretion in rat: mediation by NO in the central nervous system
Authors: Barrachina M.D. , Whittle B.J.R. , Moncada S. , Esplugues J.V. 
Published: July 2012

The involvement of nitric oxide in the acute inhibitory effects of low doses of endotoxin, following intracerebroventricular (i.c.v.) or intravenous (i.v.) administration, on gastric acid secretion stimulated by distension or i.v. infusion of pentagastrin has been investigated in the continuously perfused stomach of the anaesthetized rat.
The i.c.v. administration of E. coli endotoxin (800 ng kg−1) abolished the acid secretory response induced by gastric distension (20 cm water intragastric pressure) within 30 min of administration.
By contrast, submaximal rates of acid secretion induced by i.v. infusion of pentagastrin (8 μg kg−1 h−1) were not inhibited by i.c.v. administration of endotoxin (800 ng kg−1).
Prior i.c.v. administration of the NO synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME, 800 μg kg−1) restored the acid secretory responses to distension in rats treated with endotoxin (i.c.v.).
Likewise, i.v. administration of endotoxin (5 μg kg−1) abolished the acid secretory response induced by gastric distension within 30 min of administration. Prior i.c.v injection of l‐NAME (800 μg kg−1) or its i.v. administration (10 mg kg−1) restored acid secretory responses in rats receiving i.v. endotoxin.
The reversal by l‐NAME (i.v.) of the acid inhibitory effects of endotoxin (i.v.) was prevented by l‐arginine (12 mg kg−1, i.c.v. or 100 mg kg−1, i.v), but not by its enantiomer d‐arginine.
The present results imply the existence of an acute response to endotoxin involving NO synthesis in the brain. NO may act as a neuromodulator or neurotransmitter in a nervous reflex leading to the inhibition of acid secretion stimulated by gastric distension.
Pharmacological characterization of bradykinin receptors in canine cultured tracheal smooth muscle cells
Authors: Yang Chuen Mao , Luo Shue‐Fen , Hsia Hui‐Chuan 
Published: July 2012

[3H]‐bradykinin was used to characterize the bradykinin receptors associated with canine cultured tracheal smooth muscle cells (TSMCs). Receptor binding assay showed that TSMCs had specific, saturable, high‐affinity binding sites for [3H]‐bradykinin.
The specific [3H]‐bradykinin binding increased linearly with increasing cell concentrations. The equilibrium for association of [3H]‐bradykinin with the bradykinin receptors was attained within 2 h at 4°C and 1 h at room temperature, respectively.
Analysis of binding isotherms yielded an apparent equilibrium dissociation constant (KD) of 2.5 ± 0.3 nm and a maximum receptor density (Bmax) of 25.1 ± 0.3 fmol mg−1 protein. The Hill coefficient for [3H]‐bradykinin binding was 1.00 ± 0.02. The association (K1) and dissociation (K‐1) rate constants were (8.67 ± 2.60) × 106 m−1 min−1 and 0.024 ± 0.005 min−1, respectively. KD, calculated from the ratio of K‐1 and K1 was 2.8 ± 0.5 nm, a value close to that of KD calculated from Scatchard plots of binding isotherms.
The B1 receptor selective agonist, (des‐Arg9‐bradykinin, 0.1 nm–10 μm) and antagonist ([Leu8, des‐Arg9]‐bradykinin, 0.1 nm–10 μm) did not inhibit the [3H]‐bradykinin binding to TSMCs, which excludes the presence of B1 receptors in canine TSMCs.
The specific binding of [3H]‐bradykinin to canine TSMCs was inhibited by B2 receptor selective antagonists ([d‐Arg0, Hyp3, Thi5, d‐Tic7, Oic8]‐bradykinin, Hoe 140, 0.1 nm–10 μm and [d‐Arg0, Hyp3, Thi5,8, d‐Phe7]‐bradykinin, 0.1 nm–10 μm) and agonists (bradykinin and kallidin, 0.1 nm–10 μm) with a best fit by a one‐binding site model. The order of potency for the inhibition of [3H]‐bradykinin binding was kallidin = bradykinin = Hoe 140>[d‐Arg0, Hyp3, Thi5,8, d‐Phe7]‐bradykinin.
Preincubation of TSMCs with forskolin for 24 h led to an up‐regulation of B2 receptors, increasing in Bmax from 25.1 ± 0.3 to 218 ± 24 fmol mg−1 protein without changing the KD values. [3H]‐bradykinin binding to TSMCs was inhibited by the B2 receptor selective antagonists and agonists, but not by the B1 receptor selective reagents. The up‐regulation of the B2 receptor by forskolin was mediated through protein synthesis, since cycloheximide blocked this response.
It is concluded that the pharmacological characteristics of the bradykinin receptors in canine cultured TSMCs are primarily of the B2 receptor subtype.
Reduction of carrageenin oedema and the associated c‐Fos expression in the rat lumbar spinal cord by nitric oxide synthase inhibitor
Authors: Honoré Prisca , Chapman Victoria , Buritova Jaroslava , Besson Jean‐Marie 
Published: July 2012

Three hours after intraplantar carrageenin (6 mg/150 μl of saline) Fos‐like immunoreactivity (Fos‐LI) was mainly observed in L4 and L5 segments of the dorsal horn. Both superficial (I–II) and deep laminae (V–VI) neurones were labelled.
We have studied the effect of systemic administration of a nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME) on carrageenin evoked c‐Fos expression and thus the contribution of nitric oxide to this expression.
Pre‐administration of l‐NAME (10, 25, 50, 100 mg kg−1, i.v.) dose‐dependently reduced the number of superficial and deep laminae Fos‐LI neurones, 100 mg kg−1 produced a 63 ± 2% and 72 ± 4% reduction of Fos‐LI neurones respectively, P < 0.0001 for both superficial and deep neurones.
Pre‐administered l‐NAME dose‐relatedly reduced the carrageenin‐evoked paw and ankle oedema, with 100 mg kg−1 of l‐NAME resulting in a 74 ± 2% and 103 ± 2% reduction respectively.
Post‐administration of l‐NAME (10 mg kg−1, i.v.) reduced the number of superficial and deep laminae Fos‐LI neurones (65 ± 7% and 53 ± 8% reduction respectively, P <0.01 for both superficial and deep neurones).
Post‐administered l‐NAME reduced both the paw and ankle oedema (52 ± 8% and 62 ± 10% reduction respectively, P<0.0001 for both paw and ankle).
Pre‐administered d‐NAME (100 mg kg−1, i.v.), the inactive isomer of l‐NAME, produced a weak reduction of the number of superficial laminae Fos‐LI neurones (26 ± 8% reduction, P<0.05), without influencing the deep Fos‐LI neurones (5 ± 8% enhancement) or the oedema.
Systemic l‐arginine (1200 mg kg−1) did not reverse the reduction of the total number of Fos‐LI neurones induced by 100 mg kg−1 of l‐NAME, or the effect of l‐NAME on the paw and ankle oedema.
Intraplantar l‐arginine (30 mg) did not reverse the effect of l‐NAME (100 < mg kg−1) on the total number of Fos‐LI neurones. However, the inhibitory effects of l‐NAME on the paw and ankle oedema were partially reversed by intraplantar l‐Arginine (34 ± 9% and 45 ± 11% reduction of carrageenin oedema respectively) with these effects being significant as compared to the effect of l‐NAME alone (P<0.05 for both).
There is a strong correlation between the reduction of the number of Fos‐LI neurones and the oedema by l‐NAME, clearly demonstrating a predominant role of peripheral NO in the development of one of the signs of carrageenin inflammation.
Interaction between gallopamil and cardiac ryanodine receptors
Authors: Zucchi Riccardo , Ronca‐Testoni Simonetta , Yu Gongyuan , Galbani Paola , Ronca Giovanni , Mariani Mario 
Published: July 2012

In a sarcoplasmic reticulum fraction obtained from rat hearts, the analysis of equilibrium [3H]‐ryanodine binding showed high and low affinity sites (KD = 1.3 nm and 2.8 μm, Bmax = 2.2 pmol mg−1 and 27.8 pmol mg−1). The dissociation rate constant increased at 1 μm VS 4 nm [3H]‐ryanodine concentration, and micromolar ryanodine slowed the dissociation of nanomolar ryanodine.
The binding of 4 nm [3H]‐ryanodine was not affected by gallopamil, while the binding of 100 nm to 18 μm [3H]‐ryanodine was partly displaced. Data analysis suggested that gallopamil inhibited low affinity [3H]‐ryanodine binding, with IC50 in the micromolar range.
Gallopamil decreased the dissociation rate constant of 1 μm [3H]‐ryanodine. While gallopamil alone did not affect the dissociation of 4 nm [3H]‐ryanodine, gallopamil and micromolar ryanodine slowed it to a greater extent than micromolar ryanodine alone.
Our results are consistent with the hypothesis that the ryanodine receptor is a negatively cooperative oligomer, which undergoes a sequential alteration after ryanodine binding. Gallopamil has complex actions: it inhibits ryanodine binding to its low affinity site(s), and probably modulates the cooperativity of ryanodine binding and/or the transition to a receptor state characterized by slow ryanodine dissociation. These molecular actions could account for the previously reported effect of gallopamil on the sarcoplasmic reticulum calcium release channel.