bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity to protein kinase C inhibitors of nicardipine‐insensitive component of high K+ contracture in rat and guinea‐pig aorta
Authors: Low A.M. , Loke J.C.P. , Kwan C.Y. , Daniel E.E. 
Published: July 2012

In the rat and guinea‐pig aorta, we observed that the contraction to hypertonically‐added K+, unlike the isotonic K+‐induced contraction, was only partially sensitive to nicardipine (0.1, 1 and 10 μm), an L‐type Ca2+ channel blocker and occurred in Ca2+‐free medium containing 50 μm EGTA. We have characterized this nicarpidine‐insensitive hypertonically‐added K+ contraction.
The contraction induced by an equi‐osmolar concentration of mannitol was similar in size to that evoked by hypertonically‐added K+.
When the tissue was depleted of its internal Ca2+ stores with various agents such as phenylephrine (10 μm), cyclopiazonic acid (30 μm), thapsigargin (1 μm) or ryanodine (30 μm), or by incubation in Ca2+‐free medium over 30 min, little effect was observed on the high K+ contracture in the presence of L‐type Ca2+ channel blockade.
Phentolamine (10 μm) or indomethacin (10 μm) did not reduce the contraction induced by high K+.
Application of a protein kinase C inhibitor, H7 (10, 30 and 100 μm) or calphostin C (1 μm), reduced the high K+ contraction but not that caused by an equi‐osmolar concentration of mannitol.
The data suggest that hypertonic K+‐induced contraction differs from that caused by hypertonicity or depolarization per se and invokes membrane enzyme activation.
Measurement and pharmacokinetic analysis of imipramine and its metabolite by brain microdialysis
Authors: Sato Yuji , Shibanoki Shinji , Sugahara Megumi , Ishikawa Koichi 
Published: July 2012

The feasibility of the brain microdialysis method for direct measurement and pharmacokinetic study of imipramine (Imip) and its metabolite desipramine (DMI) was investigated in the rat brain.
A dialysis tube was inserted into the right striatum of male Wistar rats, which were administered i.p. with 12.5 mg kg−1 Imip. Thirty μl dialysate was collected every 15 min, and the levels of Imip and DMI were measured by high‐performance liquid chromatography with electrochemical detection (h.p.l.c.–e.c.d.). SKF‐525A and aminopyrine were concomitantly administered in order to assess their respective effects on the pharmacokinetics of Imip and DMI in the brain.
The intracerebral half life (t1/2) of Imip was 2.4 ± 0.3 h with Imip alone. Premedication with SKF‐525A, an inhibitor of drug‐metabolizing enzymes, significantly prolonged the t1/2 of Imip, while at the same time production of DMI from Imip was accordingly inhibited. Concomitant administration of aminopyrine did not induce any significant change in the concentrations of Imip, but significantly inhibited the concentrations of DMI through its competitive antagonism in the demethylation pathway.
The present results suggest that the brain microdialysis method reflects the intracerebral pharmacokinetics of Imip and DMI well and may be applicable to further pharmacokinetic investigations of psychotropic agents.
Effects of isocarbacyclin, a stable prostacyclin analogue, on monkey isolated cerebral and peripheral arteries
Authors: Kawai Yasuaki , Ohhashi Toshio 
Published: July 2012

The effects of isocarbacyclin (TEI 7165), a stable prostacyclin analogue, were examined in monkey isolated cerebral and peripheral arteries.
Addition of TEI 7165 (0.1 nm‐10 μm) produced a dose‐dependent relaxation in cerebral arteries pre‐contracted with 1 μm 5‐hydroxytryptamine (5‐HT). High concentrations (more than 1 μm) of TEI 7165 elicited a transient contraction followed by a sustained relaxation.
TEI 7165 also elicited a dose‐dependent relaxation in the peripheral (except popliteal) arteries. The maximum relaxation induced by 10 μm TEI 7165 was greater (P < 0.05) in the mesenteric artery than in the cerebral artery. The negative logarithm of the EC50 value for the mesenteric, 7.6 ± 0.3, was greater (P < 0.05) than that for the cerebral artery, 6.4 ± 0.3. The decreasing order of potency for the TEI 7165‐induced relaxation was as follows: mesenteric > renal > cerebral > coronary > popliteal.
Removal of the endothelium did not significantly affect TEI 7165‐induced relaxations.
The transient contraction produced by high concentrations of TEI 7165 was not observed in cerebral arteries precontracted with 1 nm U46619, a stable analogue of thromboxane A2 (TXA2). Furthermore, the TEI 7165‐induced contraction was markedly suppressed (P < 0.05) by treatment with 10 nm S1452, a TXA2 blocking agent.
These results suggest that TEI 7165 causes an endothelium‐independent relaxation in monkey cerebral and peripheral arteries, and that there is a marked regional difference in the TEI 7165‐induced relaxations. A high concentration of TEI 7165 also produces a transient contraction which is probably through activation of TXA2 (TP‐) receptors.
The differential effects of felodipine and nitrendipine on cerebral dihydropyridine binding ex vivo and the ethanol withdrawal syndrome in mice
Authors: Watson W.P. , Misra A. , Cross A.J. , Green A.R. , Little H.J. 
Published: July 2012

The ability of two dihydropyridine calcium channel antagonists, felodipine and nitrendipine both to displace [3H]‐isradipine binding in CNS tissue measured ex vivo and to protect against the ethanol withdrawal syndrome has been investigated.
Mice were injected with various doses of felodipine or nitrendipine and [3H]‐isradipine binding measured in brain homogenates prepared 0.5, 3 or 5 h later. Inhibition versus dose curves were sigmoid and the dose required to produce 50% inhibition increased linearly with time after administration. Felodipine was approximately 10 times more potent than nitrendipine.
Nitrendipine (50 mg kg−1, i.p.) and felodipine (10 mg kg−1, i.p.) produced around a 75% inhibition of [3H]‐isradipine binding 3 h later. Binding of [3H]‐nitrendipine to cerebral tissues measured after in vivo injection of the ligand was decreased by nitrendipine (50 mg kg−1) and felodipine (10 mg kg−1) to a similar extent.
Nitrendipine (50 mg kg−1) prevented the behavioural signs of ethanol withdrawal as measured by handling induced convulsions, but felodipine (10 mg kg−1 or 2 mg kg−1) did not provide any protection against this effect of ethanol withdrawal. Felodipine (10 mg kg−1, twice daily) during the course of ethanol treatment also failed to attenuate the withdrawal syndrome.
The convulsive response to a mild audiogenic stimulus during ethanol withdrawal was increased following one dose of felodipine (5 mg kg−1, i.p.) but unaffected by nitrendipine.
Injection of Bay K 8644 (60 μg, i.c.v.) produced a significant increase in handling‐induced convulsive behaviour. Felodipine (10 mg kg−1, i.p.) reduced this behaviour both 60 and 120 min later, while nitrendipine (50 mg kg−1) showed a modest reduction only at 120 min.
In contrast, nitrendipine (50 mg kg−1) and felodipine (10 mg kg−1) produced similar effects on the hyperexcitability produced by handling following administration of bicuculline. Hexamethonium (8 mg kg−1) had no effect on this response.
No change was found in [3H]‐isradipine or [125I]‐ω‐conotoxin binding to cerebral tissue prepared from ethanol‐dependent mice.
These results demonstrate that while felodipine and nitrendipine have similar actions on some CNS‐mediated effects (raising seizure thresholds to several convulsant drugs), felodipine, in contrast to nitrendipine, has no effect on the ethanol withdrawal syndrome. Suggested explanations for the results include the possibility that nitrendipine may protect against the ethanol withdrawal syndrome via sites other than dihydropyridine receptors: that felodipine has partial agonist actions at dihydropyridine receptors in the CNS or that felodipine has actions which mask its protective effect in ethanol withdrawal.
Down‐regulation of bombesin binding to guinea‐pig pancreatic acinar cells during homologous desensitization
Authors: Sjödin L. , Gylfe E. 
Published: July 2012

[125I]‐Tyr4‐bombesin exhibited saturable binding to pancreatic acinar cells.
Preincubation of cells at 37°C with 0.03 nM‐1 μm‐bombesin for 10 min followed by acid or neutral washes reduced subsequent binding of [125I]‐Tyr4‐bombesin in a concentration‐dependent manner by up to 90%.
In cell suspensions, bombesin raised the cytoplasmic Ca2+ concentration ([Ca2+]i) and the [Ca2+]i response was reduced by pre‐exposure to the agonist.
In individual superfused cells, bombesin at 1 nM normally caused a large [Ca2+]i transient followed by sustained [Ca2+]i oscillations. The cells exhibited a variable degree of desensitization when subsequently exposed to higher agonist concentrations.
Preincubation with bombesin for 10 min caused a concentration‐related reduction of subsequent amylase responses to bombesin.
Down‐regulation of receptor binding is a rapid phenomenon during bombesin exposure explaining, at least partially, tachyphylaxis of [Ca2+]i and amylase responses.
The imidazoline site involved in control of insulin secretion: characteristics that distinguish it from I1‐ and I2‐sites
Authors: Chan Susan L.F. , Brown Colin. A. , Scarpello Kay E. , Morgan Noel G. 
Published: July 2012

The nature of the binding site mediating the insulin secretagogue activity of certain imidazoline compounds remains unclear and the pharmacology of the I1‐ and I2‐imidazoline sites, described in many tissues, does not correlate with the observed responses to imidazolines in islets. In the present paper, we describe further results which support the concept that the islet imidazoline site may represent a novel subtype of imidazoline receptor.
Culture of rat isolated islets in the presence of imidazoline secretagogues (either efaroxan or phentolamine) resulted in loss of responsiveness on subsequent re‐exposure to these agents. However, culture of islets with either idazoxan or UK 14,304 (imidazoline ligands that do not stimulate insulin secretion) did not lead to any loss of response when the islets were subsequently exposed to efaroxan. By contrast, islets cultured with UK 14,304 (a potent α2‐adrenoceptor agonist), displayed loss of sensitivity to noradrenaline, consistent with down‐regulation of α2‐adrenoceptors.
In order to characterize the imidazoline site further, radioligand binding studies were performed in membranes from RINm5F insulinoma cells using [3H]‐RX821002, an imidazoline insulin secretagogue that does not interact significantly with imidazoline sites in other tissues. [3H]‐RX821002 labelled α2‐adrenoceptors with high affinity (2.01 ± 0.7 nM) but also labelled a second, non‐adrenoceptor site with much lower affinity.
Under conditions of α2‐adrenoceptor blockade (in the presence of adrenaline), efaroxan displaced [3H]‐RX821002 binding to the low affinity site, in a dose‐dependent manner. Competition studies employing additional imidazoline compounds of varying secretagogue activity revealed that the pharmacological profile of the low affinity site correlates well with that observed in secretion experiments.
The results obtained from the down‐regulation experiments with isolated islets and from the radioligand binding studies suggest that the low affinity [3H]‐RX821002 binding site may represent the functional receptor responsible for the secretagogue activity of imidazoline compounds in the endocrine pancreas and that it has a pharmacological profile distinct from those of I1‐ and I2‐sites.
Adaptive changes in 5‐HT1A receptor‐mediated hippocampal inhibition in the alert rat produced by repeated 8‐OH‐DPAT treatment
Authors: Manahan‐Vaughan Denise , Anwyl Roger , Rowan Michael J. 
Published: July 2012

The effect of acute and repeated treatment with 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a 5‐HT1A receptor ligand, on excitatory amino acid‐mediated synaptic transmission was examined in the stratum radiatum CA1 region of the dorsal hippocampus of alert, gently restrained, rats.
Acute administration of 8‐OH‐DPAT transiently reduced the amplitude of the field excitatory postsynaptic potential (e.p.s.p.) in a dose‐dependent (25–75 μg kg−1, i.p.) manner. This effect was blocked by the postsynaptic 5‐HT1A receptor antagonist, MDL 73005EF (2 and 4 mg kg−1, i.p.).
8‐OH‐DPAT (25 μg kg−1, i.p.) administered daily for 7 days produced a gradual reduction in the 24 h pre‐injection baseline field e.p.s.p. amplitude. The reduction reached its lowest level after 7–8 days and was transiently reversed by acute injection of MDL 73005EF (2 mg kg−1, i.p.) on day 8. The field e.p.s.p. baseline amplitude recovered fully 5–8 days after cessation of drug treatment.
8‐OH‐DPAT (25 μg kg−1, i.p.) administered daily for 7 days produced a marked reduction in acute response to 8‐OH‐DPAT (25 and 50 μg kg−1, i.p.) which did not recover until between day 36 and day 80 of the study.
It was concluded that repeated treatment with 8‐OH‐DPAT produced adaptive changes which resulted in a reduction in the dynamic range of 5‐HT1A receptor‐mediated transmission in the hippocampus.
Sodium excretion following central administration of an I1 imidazoline receptor agonist, moxonidine
Authors: Penner S. Brian , Smyth Donald D. 
Published: July 2012

Previously we have shown that an intrarenal infusion of moxonidine, an I1‐imidazoline receptor agonist, resulted in a natriuresis which was inhibited by intravenous idazoxan, a selective imidazoline receptor antagonist. Therefore we examined the effects on renal function of intracerebroventricular (i.c.v.) administration of moxonidine with or without i.c.v. idazoxan.
Seven days after unilateral nephrectomy, Sprague‐Dawley rats had i.c.v. cannulae implanted. Three days later the rats were anaesthetized (pentobarbitone), followed by cannulation of the jugular vein (fluid and drug administration), carotid artery (blood pressure) and the ureter (urine collection).
After a 45 min stabilization period, the effect of moxonidine was investigated by the i.c.v. administration of either isotonic saline or moxonidine (0.1, 0.3 or 1 nmol in isotonic saline) administered in 5 μl over 1 min. All doses of moxonidine resulted in an increase in urine flow with a concomitant increase in sodium excretion without affecting blood pressure. The highest dose of moxonidine (1 nmol) also increased free water clearance.
In a second series of experiments, the effects of idazoxan on the natriuretic response to i.c.v. moxonidine were determined. Moxonidine (0.3 nmol) again increased sodium and water excretion as compared to the i.c.v. saline control animals. Pretreatment with i.c.v. idazoxan (0.3 nmol), at a dose which alone failed to alter sodium and water excretion, completely attenuated the renal response to moxonidine. These results are consistent with central I1‐imidazoline receptors mediating a moxonidine‐induced increase in sodium and water excretion at doses that do not alter blood pressure.
Study of the effector mechanism involved in the production of haemorrhagic necrosis of the small intestine in rat passive anaphylaxis
Authors: Pellón María Isabel , Steil Ana Angelica , Furió Vicente , Crespo Mariano Sánchez 
Published: July 2012

The effector mechanism of intestinal necrosis in rat anaphylaxis was studied following several complementary approaches: (i) the use of monoclonal antibodies (mAb) belonging to different classes (IgG1, IgG2b and IgE anti‐DNP), (ii) the assay of mediators, and (iii) the use of pharmacological tools.
Lethality and haemorrhagic necrosis of the small intestine were observed in IgE‐sensitized rats, whereas IgG mAb produced milder physiological disturbances.
Inhibition of leukotriene biosynthesis reduced the drop of systemic blood pressure (BP) and the extent of protein‐rich plasma exudation but it did not influence the haemorrhagic component of intestinal necrosis.
The antihistamine, pyrilamine, partially diminished the haemorrhagic component of the intestinal necrosis.
The involvement of mediators related to platelet‐activating factor (PAF) was studied by examining the pharmacological effects of these autacoids and of PAF‐receptor antagonists (PCA4248, UR12460 and BB823). PAF induced intestinal lesions similar to those observed in IgE‐sensitized rats and PAF‐receptor antagonists markedly decreased haemorrhage in IgE‐sensitized rats.
PAF levels were transiently increased after dinitrophenol (DNP)‐ bovine serum albumin (BSA) challenge in the small intestine of IgE‐sensitized rats.
These data stress differences in the outcome of anaphylaxis related to the type of receptors for the Fc portion of immunoglobulins that are involved. IgE is the antibody class that elicits the most severe response due to the activation of mast cells via FceRI (surface receptors that bind IgE antibodies with high affinity), and the only one able to produce intestinal haemorrhagic necrosis.
The mast‐cell‐derived mediators PAF/acyl‐PAF and histamine, most probably associated with tumour necrosis factor α/cachectin (TNF‐α), seem to play a central role in the production of the vascular changes required for the extravasation of erythrocytes in the small intestine mucosa.
Modulatory effects of endothelin‐1 on purinergic and adrenergic components of sympathetically‐mediated contractile activity of rabbit saphenous artery
Authors: Mutafova‐Yambolieva Violeta N. , Radomirov Radomir G. 
Published: July 2012

The present study has been performed to evaluate the modulatory effects of endothelin‐1 (ET‐1) on the purinergic and adrenergic components of sympathetically‐mediated contractile responses of endothelium‐free rabbit saphenous artery preparations.
ET‐1 increased the smooth muscle tone, the pD2 value being 7.77 ± 0.05.
Postjunctionally, ET‐1 enhanced the responses to exogenous adenosine 5′‐triphosphate (ATP) and did not influence those to exogenous noradrenaline (NA).
ET‐1 increased the contractile responses to short‐lasting and to long‐lasting electrical field stimulation at a frequency of 5 or 10 Hz, showing a tendency towards decreasing the prazosin‐sensitive component and increasing the mATP‐sensitive component of the contractile responses.
In prazosin‐treated preparations ET‐1 increased the residual mATP‐sensitive responses and this effect was more pronounced after yohimbine.
In mATP‐treated preparations ET‐1 increased the residual electrically‐induced contractions and this increase was abolished after yohimbine.
It is suggested that ET‐1 modulates co‐transmission in the rabbit saphenous artery by potentiating postjunctionally the purinergic component of the contractile responses to both exogenous ATP or electrical stimulation.
Heterogeneity of α1‐adrenoceptor subtypes involved in adrenergic contractions of dog blood vessels
Authors: Kohno Yoko , Saito Hitoshi , Takita Manabu , Kigoshi Shigeru , Muramatsu Ikunobu 
Published: July 2012

We determined the α1‐adrenoceptor subtypes involved in adrenergic contractions of eight different blood vessels isolated from the dog.
Noradrenaline produced concentration‐dependent contractions in all the blood vessels tested, which were competitively inhibited by prazosin, WB4101, HV723 and 5‐methylurapidil. However, there was considerable difference between the vessels with regard to the pKB values for all the antagonists. The α1‐adrenoceptors of dog vertebral and carotid arteries had high affinity for prazosin (pKB > 9.0) but low affinity for WB4101 (< 8.5), 5‐methylurapidil (< 7.5) and HV723 (≤ 8.5). By contrast, HV723 had higher affinity (> 9.0) than prazosin (< 8.3), WB4101 (< 8.7) and 5‐methylurapidil (< 8.2) in the portal vein, mesenteric artery and vein, and renal artery. In the femoral artery and vein, however, the four antagonists showed pKB values in the range 8.0–8.7.
Chloroethylclonidine (10 μm) produced a remarkable reduction of the contractile responses to noradrenaline in the vertebral and carotid arteries as compared with those in the other vessels. Nifedipine inhibited the responses to noradrenaline in all the tissues tested, and had marked effects in the portal vein.
Sympathetic adrenergic contractions induced by transmural electrical stimulation were also inhibited by prazosin and HV723 at different potencies among tissues. The relative potencies of both the antagonists paralleled the relationship in inhibiting the responses to exogenous noradrenaline in each vessel.
According to recent α1‐adrenoceptor subclassification, the present results suggest that the contractions of blood vessels induced by endogenous and exogenous noradrenaline are mediated through different α1‐adrenoceptor subtypes heterogeneously distributed in each vessel; presumably, the α1B subtype in the carotid and vertebral arteries, the α1N subtype in the visceral region and the α1L subtype in the femoral region. Regionally different expression of α1‐adrenoceptor subtypes may be in part associated with the regional heterogeneity of sympathetic responses in the blood vessels.
Characterization of the angiotensin II AT1 receptor subtype involved in DNA synthesis in cultured vascular smooth muscle cells
Authors: Briand V. , Riva L. , Galzin A.M. 
Published: July 2012

This study was undertaken in cultured vascular smooth muscle cells to characterize the angiotensin II (AII) AT1 receptor subtype involved in DNA synthesis because (i) the AII receptor involved in vascular proliferation has previously been characterized in vitro in rat aortic cells and identified as an AT1 subtype and (ii) molecular cloning and biochemical studies have provided evidence for the existence of different AT1 receptor subtypes.
In cultured rat aortic vascular smooth muscle (VSMC), exposure to AII (0.1 to 100 nM) resulted in a concentration‐dependent increase in [3H]‐thymidine incorporation with an EC50 of 1.41 ± 0.51 nM. Maximal stimulation was observed in the presence of 100 nM AII and corresponded to 271 ± 40% of basal [3H]‐thymidine incorporation.
To characterize the AII AT1 receptor subtype involved in this effect, cells were exposed to AII (3 nM) in the absence or presence of increasing concentrations of various AII receptor antagonists. The stimulatory effect of AII (3 nM) on [3H]‐thymidine incorporation in VSMC was antagonized by the non‐selective AT1/AT2 receptor antagonist, [Sar1,Ile8]‐AII (IC50 = 5.6 nM), by the AT1A/AT1B receptor antagonist, losartan (IC50 = 10.5 nM) and the AT1 receptor antagonist, L‐158809 (IC50 = 0.20 nM). The selective AT2 receptor ligand, CGP 42112A, antagonized AII‐induced [3H]‐thymidine incorporation with an IC50 of 6.3 ± 1.3 μm while the AT2/AT1B receptor antagonist, PD 123319, was found to be almost inactive (IC50 > 10 μm).
Under the same experimental conditions, angiotensin III (AIII) was found to be at least 50 times less potent than AII with an apparent EC50 of 81.6 ± 7.7 nM. At the highest concentration tested (10 μm), the effect of AIII corresponded to 327 ± 61% of basal [3H]‐thymidine incorporation.
These results confirm that AII can stimulate DNA synthesis in VSMC through an AT1 receptor. Furthermore, the pharmacological characterization of this AT1 receptor is compatible with the AT1A receptor subtype recently described on cultured mesangial cells since (i) the AT1A/AT1B receptor antagonist losartan is active at nanomolar concentrations, (ii) micromolar concentrations of the AT2/AT1B receptor antagonist PD 123319 are ineffective at antagonizing the AII‐induced [3H]‐thymidine incorporation and (iii) AII is at least 50 times more potent than AIII in stimulating DNA synthesis.