bluuebunny/crossref_metadata_2025_split huggingface dataset:
GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea
Authors: Gentilini Grazia , Franchi‐Micheli Sergio , Mugnai Sabrina , Bindi Daniela , Zilletti Lucilla 
Published: July 2012

In sensitized guinea‐pigs, the effects of γ‐aminobutyric acid (GABA) and GABAmimetic drugs have been investigated on tracheal segments contracted by cumulative application of an allergen (ovoalbumin, OA) and on serosal mast cells. The same drugs have also been tested on activation of alveolar macrophages isolated from unsensitized guinea‐pigs.
Superfusion with GABA (1–1000 μM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 μM) was not affected by the carrier blockers, nipecotic acid and β‐alanine (300 μM each). It was mimicked by the GABAB agonist (−)−baclofen (100 μM) but not 3‐aminopropanephosphinic acid (100 μM, 3‐APA). The GABAA agonist, isoguvacine (100 μM) did not exert any effect. GABA (10 μM)‐induced inhibition of tracheal contractions was reduced by the GABAB antagonist, 2‐hydroxysaclofen (100 μM, 2‐HS), but not by the GABAA antagonist, bicuculline (30 μM).
The reduction in contraction intensity induced by GABA (100 μM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 μM), but not tetrodotoxin (TTX, 0.3 μM). The effect of GABA (1000 μM) was absent after preincubation with indomethacin (2.8 μM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 μM) was used. Finally, removal of the epithelium prevented the GABA effect.
Anaphylactic histamine release from serosal mast cells isolated from sensitized animals was not affected either by GABA (10–1000 μM) or the selective receptor agonists (−)−baclofen (0.1–1000 μM) and isoguvacine (10–1000 μM). The release of platelet‐activating factor (PAF) from alveolar macrophages stimulated by formyl‐Met‐Leu‐Phe (FMLP; 1 μM) was modified neither by GABA (100 μM) nor by (−)−baclofen (100 μM).
In conclusion, these data show that GABA can inhibit allergic phenomena in the guinea‐pig airways through activation of GABAB receptors. An involvement of neuropeptidergic sensory structures is suggested but a role for epithelial cells and arachidonate metabolites is not definitely proved.
Effects of vitamin E deficiency on vasomotor activity and ultrastructural organisation of rat thoracic aorta
Authors: Rubino Annalisa , Loesch Andrzej , Goss‐Sampson Mark A. , Milla Peter , Burnstock Geoffrey 
Published: July 2012

The effects of vitamin E deficiency were evaluated in aortic rings isolated from rats maintained on a diet deficient in vitamin E.
Endothelium‐dependent vasodilator responses to acetylcholine (ACh) and calcium ionophore, A23187, were reduced in preparations from treated animals, compared to the age‐matched controls. The maximal vasodilatation to ACh was 66.4±9 (n = 4) and 38.8±7 (n = 4) % in control and 10 month‐treated preparations, respectively.
The endothelium‐independent vasodilator responses to sodium nitroprusside as well as the concentration‐dependent contractile responses to noradrenaline, did not differ between treated and control preparations.
Electron microscopic examination of vascular segments and revealed that, following vitamin E deficiency, normal tissue organisation was disrupted, the endothelial monolayer either not being in contact with the underlying tissue or being absent in most of the areas analysed.
It is concluded that during vitamin E deficiency both morphological disruption and functional impairment of endothelium occur without observable modification of muscle cell function and morphology.
Activation of rabbit platelets by Ca2+ influx and thromboxane A2 release in an external Ca2+‐dependent manner by zooxanthellatoxin‐A, a novel polyol
Authors: Rho Mun‐Chual , Nakahata Norimichi , Nakamura Hideshi , Murai Akio , Ohizumi Yasushi 
Published: July 2012

Zooxanthellatoxin‐A (ZT‐A), a novel polyhydroxylated long chain compound, isolated from a symbiotic marine alga Simbiodinium sp., caused aggregation in rabbit washed platelets in a concentration‐dependent manner (1–4 μM), accompanied by an increase in cytosolic Ca2+ concentration ([Ca2+]i).
ZT‐A did not cause platelet aggregation or increase [Ca2+]i in a Ca2+‐free solution, and Cd2+ (0.1‐1 mM), Co2+ (1–10 mM) and Mn2+ (1–10 mM) inhibited ZT‐A‐induced aggregation. SK&F96365 (1–100 μM), a receptor operated Ca2+ channel antagonist, and mefenamic acid (0.1–10 μM), a non‐specific divalent cation channel antagonist, inhibited platelet aggregation and the increase in [Ca2+], induced by ZT‐A.
Indomethacin (0.1–10 μM), a cyclo‐oxygenase inhibitor, and SQ‐29548 (0.1–10 μM), a thromboxane A2 (TXA2) receptor antagonist, inhibited platelet aggregation and the increase in [Ca2+]i induced by ZT‐A.
Methysergide (0.01‐1 μM), a 5‐HT2 receptor antagonist, inhibited ZT‐A‐induced platelet aggregation but did not affect the increase in [Ca2+]i induced by ZT‐A.
Tetrodotoxin (1 μM), a Na+ channel blocker and chlorpheniramine (1 μM), a H1‐histamine receptor antagonist, neither affected ZT‐A‐induced platelet aggregation nor the increase in [Ca2+]i induced by ZT‐A.
Genistein (1–100 μM), a protein tyrosine kinase inhibitor, and staurosporine (0.01‐1 μM), a protein kinase C inhibitor, also inhibited ZT‐A‐induced platelet aggregation.
The present results suggest that ZT‐A elicits Ca2+‐influx from platelet plasma membranes. The resulting increase in [Ca2+]i subsequently stimulates the secondary release of TXA2 from platelets. Furthermore, the response to ZT‐A may be associated with tyrosine phosphorylation.
The effect of opiates on the terminal nerve impulse and quantal secretion from visualized amphibian nerve terminals
Authors: Lavidis Nickolas A. 
Published: July 2012

Secretion of transmitter from amphibian motor nerve terminal release sites is intermittent, spatially non‐uniform and varies considerably throughout the year and during development. The role of opioid receptors in modulating transmitter secretion from amphibian motor nerve terminals is evaluated in this study.
Dynorphin‐A (24 μM) and morphine (500 μM) did not significantly change the shape of the nerve impulse or the consistency with which it was observed, but decreased evoked quantal secretion by more than 50%. These effects of dynorphin‐A and morphine were largely reversed by naloxone (50 μM).
Dynorphin‐A and morphine did not significantly change either the amplitude or the frequency of spontaneous quantal secretions.
There was a uniform decrease in evoked quantal secretion from release sites along terminal branches, irrespective of the quantal content value before drug treatment, indicating no difference in the susceptibility of proximal vs distal release sites to opiates.
Increasing the extracellular calcium concentration (0.3 to 0.4 mM) or trains of conditioning‐test impulses (25 to 100 Hz) resulted in smaller dynorphin‐A or morphine‐induced decreases in evoked quantal secretion.
The decrease in evoked quantal secretion occurs as a result of a uniform decrease in the probability of quantal secretion from release sites without any affect on the propagation of the nerve terminal impulse. Low probability release sites become effectively silent.
Enhancement by GABA of the association rate of picrotoxin and tert‐butylbicyclophosphorothionate to the rat cloned α1β2γ2 GABAA receptor subtype
Authors: Dillon Glenn H. , Im Wha Bin , Carter Don B. , McKinley Denise D. 
Published: July 2012

We examined how y‐aminobutyric acid (GABA) influences interaction of picrotoxin and tert‐butylbicyclophosphorothionate (TBPS) with recombinant rat α1β2γ2 GABAA receptors stably expressed in human embryonic kidney cells (HEK293), as monitored with changes in Cl− currents measured by the whole‐cell patch clamp technique.
During application of GABA (5 μM) for 15 s, picrotoxin and TBPS dose‐dependently accelerated the decay of inward GABA‐induced currents (a holding potential of −60 mV under a symmetrical C1− gradient). The drugs, upon preincubation with the receptors, also reduced the initial current amplitude in a preincubation time and concentration‐dependent manner. This indicates their interaction with both GABA‐bound and resting receptors.
The half maximal inhibitory concentration for picrotoxin and TBPS at the beginning of a 15 s GABA (5 μM) pulse was several times greater than that obtained at the end of the pulse. GABA thus appears to enhance picrotoxin and TBPS potency, but only at concentrations leading to occupancy of both high and low affinity GABA sites, i.e., 5 μM. Preincubation of the receptors with the drugs in the presence of GABA at 200 nM, which leads to occupancy of only high affinity GABA sites in the α1β2γ2 subtype, produced no appreciable change in potency of picrotoxin or TBPS. This indicates that they preferentially interact with multiliganded, but not monoliganded receptors, unlike U‐93631, a novel ligand to the picrotoxin site, which has higher affinity to both mono‐ and multiliganded receptors than resting receptors.
The time‐dependent decay and preincubation time‐dependent reduction of initial amplitude of GABA‐induced Cl− currents followed monoexponential time courses, and time constants thus obtained displayed a linear relationship with drug concentration. Analysis of the data using a kinetic model with a single drug site showed that GABA (5 μM) enhanced the association rate for picrotoxin and TBPS nearly 100 fold, but their dissociation rate only 10 fold. The dissociation rate obtained from current recovery from picrotoxin or TBPS block yielded nearly identical values to the above analysis.
We conclude that picrotoxin and TBPS interact with both resting and GABA‐bound receptors, but their affinity for the latter is about 10 times greater than that for the former, largely due to a markedly increased association rate to the multiliganded receptors (but not monoliganded ones). This and our earlier study with U‐93631 improves our understanding of functional coupling between GABA and picrotoxin sites, which appears to be useful in characterizing the mode of interaction for various picrotoxin site ligands.
Effect of diabetes on relaxations to non‐adrenergic, non‐cholinergic nerve stimulation in longitudinal muscle of the rat gastric fundus
Authors: Jenkinson Karl M. , Reid Julianne J. 
Published: July 2012

The effect of 8‐week streptozotocin‐induced diabetes has been examined on relaxations to non‐adrenergic, non‐cholinergic (NANC) nerve stimulation in longitudinal strips of rat gastric fundus.
In the presence of noradrenergic and cholinergic blockade and raised tissue tone, electrical field stimulation (0.5‐4 Hz, 30 s trains) induced frequency‐dependent relaxations that were significantly smaller in gastric fundus strips from diabetic rats than in strips from control rats.
NG‐nitro‐L‐arginine methyl ester (NAME, 100 μM) significantly reduced NANC relaxations in muscle strips from both control and diabetic rats, but the reduction was greater in muscle strips from diabetic rats than in those from control rats at frequencies of 2 and 4 Hz. α‐Chymotrypsin (1 u ml−1) slightly reduced relaxations to nerve stimulation in muscle strips from both control and diabetic rats.
> The duration of NANC nerve relaxations (1‐4 Hz, 30 s trains) was smaller in muscle strips from diabetic rats than in those from control rats. The duration of NANC relaxations was reduced by α‐chymotrypsin (1 u ml−1) in muscle strips from control rats but not in muscle strips from diabetic rats.
Relaxations to both nitric oxide (NO; 1–30 μM) and vasoactive intestinal polypeptide (VIP; 0.1‐30 μM) were concentration‐dependent and did not differ between muscle strips from control and diabetic rats.
The results suggest that streptozotocin‐induced diabetes impairs relaxations to NANC nerve stimulation in the rat gastric fundus, which are largely mediated by NO and to a lesser extent by VIP. The impairment appears to occur at the prejunctional level, as smooth muscle reactivity to NO and VIP is not altered.
Effect of trilinolein on cyclic nucleotide formation in human platelets: relationship with its antiplatelet effect and nitric oxide synthesis
Authors: Shen Y.C. , Hong C.Y. 
Published: July 2012

Trilinolein, a triacylglycerol with linoleic acid as the only fatty acid residue in all three esterified positions of glycerol, was recently reported to have an inhibitory effect on adrenaline‐induced platelet aggregation. In the present study, we found that trilinolein at concentrations ranging from 0.01 to 1 μM. increased cyclic GMP formation and decreased cyclic AMP formation in washed human platelets. Both NG‐nitro‐L‐arginine methyl ester (L‐NAME) and methylene blue attenuated the trilinolein‐induced increase in cyclic GMP.
Adrenaline decreased not only the production of cyclic AMP but also that of cyclic GMP. Trilinolein antagonized the inhibitory effect of adrenaline on cyclic GMP formation, but potentiated the inhibitory effect of adrenaline on cyclic AMP accumulation.
Both trilinolein and adrenaline enhanced intracellular calcium but the increment of intracellular calcium induced by them was much less than that produced by thrombin.
We propose that the anti‐platelet effect of trilinolein is mediated through an increase in cyclic GMP, and that the change in cyclic GMP results from stimulation of nitric oxide synthesis in platelets.
We also propose that reduction of both cyclic AMP and cyclic GMP are involved in adrenaline‐induced platelet aggregation.
A comparison of the effects of SCA40, NS 004 and NS 1619 on large conductance Ca2+‐activated K+ channels in bovine tracheal smooth muscle cells in culture
Authors: Macmillan S. , Sheridan R.D. , Chilvers E.R. , Patmore L. 
Published: July 2012

The effects of imidazopyrazine derivative, SCA40, on the activity of single large conductance, Ca2+‐activated K+ (BKCa) channels in inside‐out and outside‐out patches from bovine tracheal smooth muscle (BTSM) cells in culture have been compared with those of two established BKCa channel openers, NS 004 and NS 1619.
The presence of BKCa channels on inside‐out patches of BTSM membranes was confirmed by the single channel conductance (240 pS), selectivity for K+, dependence of channel activity on [Ca2+], and sensitivity to the selective BKca channel blocker, iberio toxin.
NS 004 and ND 1619 (3‐30 μM) induced concentration‐related increases in open state probability of BKca channels when applied to either inside‐out or outside‐out BTSM patches, thus confirming that these compounds are activators of the BKCa channel in this preparation.
SCA40 (0.1‐10 μM) had no effect on the activity of BKCa channels when applied to either inside‐out or outside‐out patches which subsequently responded to the application of NS 004 (10‐20 μM).
It is concluded that SCA40 does not have a direct effect on BKca channel activity in BTSM patches and that the previously reported relaxant action of SCA40 on tracheal smooth muscle is unlikely to be mediated by this mechanism.
Peripheral GABAA receptor‐mediated effects of sodium valproate on dural plasma protein extravasation to substance P and trigeminal stimulation
Authors: Lee Won Suk , Limmroth Volker , Ayata Cenk , Cutrer F. Michael , Waeber Christian , Yu Xianjie , Moskowitz Michael A. 
Published: July 2012

The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA‐agonist muscimol on dural plasma protein ([125I]‐bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg−1, i.v.) in anaesthetized Sprague‐Dawley rats.
Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (≤10 mg kg−1, i.p.) dose‐dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6±1.4 mg kg−1, i.p., and 58 + 18 μg kg−1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2±1.4 mg kg−1, i.p. and 385±190 μg kg−1, i.p. for valproate or muscimol, respectively).
Valproate (6.6 mg kg−1, i.p.) or muscimol (58 μ kg−1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration.
The GABAA‐antagonist bicuculline (0.01 mg kg−1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB‐receptor antagonist, phaclofen (0.01‐1 mg kg−1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration.
Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline‐reversible mechanism. This suggests that GABAA‐receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.
We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA‐mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAA receptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.
Pharmacological profile of semotiadil fumarate, a novel calcium antagonist, in rat experimental angina model
Authors: Mori Tomohiro , Ishigai Yutaka , Fukuzawa Akiko , Chiba Kiyoshi , Shibano Toshiro 
Published: July 2012

The aim of the present study was to determine whether antianginal efficacy of semotiadil fumarate (SD‐3211), a structurally novel calcium antagonist, is distinct from those of diltiazem, nifedipine and nisoldipine.
First, the duration of the inhibitory effects of semotiadil was compared with that of other Ca2+ antagonists in rat experimental angina evoked by vasopressin. Semotiadil (10 mg kg−1, p.o.) was effective for at least 9 h in the anginal model and those effects of semotiadil were longer‐lasting than those of diltiazem (30 mg kg−1, p.o.), nifedipine (10 mg kg−1, p.o.), and nisoldipine (3 mg kg−1, p.o.).
Second, the selectivity of actions of these Ca2+ antagonists for the coronary arteries and myocardium was evaluated in rat isolated perfused hearts. Diltiazem (10−6 M) reduced cardiac contractility without inhibiting the elevation of perfusion pressure evoked by acetylcholine. Semotiadil (10−7 M) significantly suppressed cardiac contractility and inhibited the coronary response to acetylcholine. In contrast, nifedipine (3 × 10−9‐3times 10−8 M) and nisoldipine (3 × 10−10‐10−08 M) did not reduce cardiac contractility at concentrations which significantly inhibited the increase in perfusion pressure to acetylcholine.
The selectivity of semotiadil for coronary artery and myocardium is intermediate between diltiazem and dihydropyridines tested in the present study.
These findings suggest that semotiadil has an advantage of diltiazem, nifedipine, and nisoldipine in the treatment of angina with regard to long‐lasting action and selectivity for coronary artery and myocardium.
Effects of 8‐bromoguanosine 3′:5′‐cyclic monophosphate on phenylephrine‐induced phosphatidylinositol hydrolysis and contraction in rat caudal artery
Authors: Min Suyin A. Lum , Tabrizchi Reza 
Published: July 2012

The effects of 8‐bromoguanosine 3′:5′‐cyclic monophosphate (8‐bromo‐cyclic GMP) on phenylephrine‐induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of felodipine, a dihydropyridine Ca2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor‐mediated signal transduction in vascular smooth muscle.
Phenylephrine induced a concentration‐dependent increase in PI hydrolysis that reached a maximum at 10 μM phenylephrine. Pre‐incubation with felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca2+ (2 mM ethylene glycol‐bis(β‐amino‐ethyl ether) N, N, N′, N′‐tetraacetic acid (EGTA)) blocked phenylephrine‐induced PI hydrolysis, but did not affect basal turnover. In contrast, 8‐bromo‐cyclic GMP (10 μM) did not affect phenylephrine‐induced PI hydrolysis, nor did it affect basal turnover.
Phenylephrine induced concentration‐dependent contractions that were inhibited by each of 8‐bromo‐cyclic GMP (10 μM), felodipine (1 nM and 10 nM) and ryanodine (3 μM and 10 μM). In addition, removal of Ca2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine.
Phenylephrine‐induced contractions were not further affected by felodipine and 8‐bromo‐cyclic GMP applied concomitantly than by equivalent concentrations of felodipine alone. However, ryanodine and 8‐bromo‐cyclic GMP applied together significantly inhibited phenylephrine‐induced contractions in comparison to ryanodine alone.
These results suggest that phospholipase C‐activated PI hydrolysis in the rat caudal artery is dependent on extracellular Ca2+, mediated, in part, through dihydropyridine‐sensitive Ca2+ channels. Inhibition of contraction by felodipine may be brought about through indirect inhibition of IP3 production and subsequent attenuation of intracellular Ca2+ release. 8‐Bromo‐cyclic GMP does not inhibit PI hydrolysis; it may regulate vascular smooth muscle contraction by inhibition of Ca2+ release from IP3‐mediated intracellular stores, but it is unlikely that 8‐bromo‐cyclic GMP affects ryanodine‐sensitive stores.
Relationships between kallikrein secretion, kallikrein excretion and β‐adrenoceptors in kidney cortical slices from neurogenic hypertensive dogs
Authors: Damase‐Michel Christine , Bompart Guy , Durrieu Geneviève , Montastruc Jean‐Louis , Montastruc Paul , Girolami Jean‐Pierre 
Published: July 2012

Sinoaortic denervation (SAD) in dogs is characterized by an increase in blood pressure and heart rate as well as the development of renal morphological lesions similar to those observed in essential hypertension in human subjects. To assess the effect of SAD on the secretion of kallikrein kinin systems (KKS), we studied the in vitro secretion of kallikrein by renal cortical slices of normal and neurogenic hypertensive dogs (1 and 18 months after SAD). The method using renal cortical slices allowed the study of secretion of kallikrein independently of renal perfusion pressure. The number of renal β‐adrenoceptors was measured by [125I]‐cyanopindolol binding.
SAD was associated with a marked increase in urinary kallikrein excretion at one month and a significant decrease at 18 months when compared with controls. Both changes were statistically significant (P<0.05). Concurrently, a progressive increase in in vitro kalhkrein secretion was observed (+80±10% and +179±48%, 1 and 18 months after SAD, respectively). Moreover, the cortical slices obtained from sinoaortic denervated dogs contained more kalhkrein than the control cortical slices (+ 32 ±16% and +55 ±7%, 1 and 18 months after SAD, respectively).
Renal β‐adrenoceptor number significantly (P<0.05) decreased 18 months after SAD from 18 ±2 to 8 ± 3 fmol mg−1 protein without any change in affinity constant.
Although there was no test of association, because the number of renal β‐adrenoceptors decreased whereas kallikrein secretion increased, the present data could suggest a β‐adrenoceptor‐mediated inhibition of kallikrein secretion. These results show that although the urinary kalhkrein is decreased, the tissue secretory capacities are enhanced. This could suggest a renal compensatory mechanism possibly involved in tissue protection in dogs after SAD, although such a mechanism is not sufficient to reverse hypertension.