bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of sexual behaviour in the rat by a potent and selective α2‐adrenoceptor antagonist, delequamine (RS‐15385‐197)
Authors: Tallentire D. , McRae G. , Spedding M. , Clark R. , Vickery B. 
Published: July 2012

. The contributions of α2‐adrenoceptors and 5‐HT1A receptors to sexual behaviour in the rat have been re‐evaluated by use of a highly potent and selective α2‐adrenoceptor antagonist, delequamine (RS‐15385‐197), yohimbine, idazoxan and the partial agonist at 5‐HT1A receptors, 8‐hydroxy‐2(di‐n‐propylamino)‐ tetralin (8‐OH‐DPAT).
. In a model where naive male rats were introduced to oestrogen‐progesterone primed, sexually receptive female rats, delequamine (0.4–6.4 mg kg−1, p.o.) dose‐relatedly increased the sexual behaviour score over the entire dose‐range whereas yohimbine was effective at only one dose, 2 mg kg−1, p.o. Idazoxan was active only at 2.5 and 5 mg kg−1, p.o. Yohimbine, but neither delequamine nor idazoxan, decreased ejaculation latency. 8‐OH‐DPAT (0.1 and 0.25 mg kg−1, s.c.) reduced the time, and the number of intromissions to ejaculation without affecting other parameters. A combination of delequamine (0.4 mg kg−1, p.o.) and 8‐OH‐DPAT (0.1 mg kg−1 s.c.) increased the percentage of rats mounting, intromitting and ejaculating, and reduced ejaculation latency and the number of intromissions.
. In orchidectomized, sexually experienced rats exposed to sexually receptive females, delequamine, idazoxan and yohimbine increased the number of rats mounting, and there was a tendency to increase the number of animals intromitting, but no effect on ejaculatory behaviour.
. In ovariectomized female rats brought to low level receptivity by priming with low dose injections of oestradiol benzoate and progesterone, delequamine, at 1.6 and 6.4 mg kg−1 p.o., increased lordosis, while yohimbine, at 2, 4 and 8 mg kg−1 p.o., reduced lordotic responses to sexually experienced males in a dose‐dependent manner. 8‐OH‐DPAT at 0.1, 0.25 mg kg−1, s.c. reduced lordosis in a dose‐dependent manner.
. These findings may be explained on the basis that yohimbine is an α2‐adrenoceptor antagonist with affinity for 5‐HT1A receptors and that the effects of 5‐HT1A receptors may modulate the sexual behaviour responses to α2‐receptor antagonism in some models. Thus, in contrast to yohimbine, the highly‐selective α2‐adrenoceptor antagonist, delequamine, was very effective in increasing the behavioural score in male and female rats over a wide dose‐range.
Two types of ATP‐sensitive potassium channels in rat portal vein smooth muscle cells
Authors: Zhang H‐L. , Bolton T.B. 
Published: July 2012

. Single‐channel recordings were made from single, enzymatically isolated smooth muscle cells of rat portal vein by the patch‐clamp technique.
. Unitary potassium currents were identified through two types of K‐channels with conductances in 60:130 mM K‐gradient of 50 and 22 pS; these are referred to as LK and MK channels respectively.
. The LK channels became extremely active if isolated patches were created into nucleotide‐free solution; activity was inhibited by ATP applied to the inner surface of the patch with a half maximal inhibition (Ki) of 11–23 μm. Channel activity declined and disappeared with time and could be regenerated by a brief application of Mg‐ATP or a nucleoside diphosphate such as UDP (in the presence of Mg). LK channel activity was rarely stimulated by levcromakalim and not by pinacidil (K‐channel openers, KCOs) but was blocked by glibenclamide.
. Activity of MK channels declined if isolated patches were created into nucleotide free solution; activity reappeared if UDP or ATP alone (in the presence of Mg) was applied; pinacidil or levcromakalim in the presence of ATP or UDP further increased channel activity which was blocked by glibenclamide.
. The LK channel inhibited by ATPi is very similar in its conductance and other properties to the KATP channel described in tissues other than smooth muscle, in its conductance and properties the MK channel resembles the KNDP channel we have previous described as present in other smooth muscles and opening in responses to KCOs.
Inhibition by lifarizine of intracellular Ca2+ rises and glutamate exocytosis in depolarized rat cerebrocortical synaptosomes and cultured neurones
Authors: Budd David C. , May Gillian R. , Nicholls David G. , McCormack James G. 
Published: July 2012

. The effects of lifarizine (RS‐87476) on intracellular Ca2+ rises and the release of glutamate from rat cerebrocortical synaptosomes depolarized with 30 mM KCl were investigated by use of entrapped fura 2 and exogenous glutamate dehydrogenase.
. Prior (1 min) addition of lifarizine decreased 30 mM KCl‐induced total glutamate release, with 3 μm and 10μm causing 39% and 72% averaged decreases from controls. The calcium‐dependent component of glutamate release (approx. 40% of total) was similarly decreased by 47% and 74%, whereas the calcium‐independent component was decreased by only 32% and 43% respectively.
. In parallel experiments with fura‐2‐loaded synaptosomes, lifarizine reduced the depolarization‐induced increases in intracellular [Ca2+], suggesting that this is the means by which the decreases in glutamate release are brought about. Lifarizine inhibited both the plateau and the spike phases of the Ca2+ increases suggesting that, in addition to its known sodium channel blocking properties, it may also inhibit more than one class of calcium channel in the synaptosomes.
. Lifarizine at 1 μm and 3 μm also inhibited the rises in intracellular [Ca2+] in rat cultured cortical neurones depolarized with 60 mM KCl.
. These effects of lifarizine on intracellular Ca2+ and glutamate exocytosis may contribute to its neuroprotective action.
Nitric oxide synthase‐cyclo‐oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits
Authors: Lin Jju‐Home , Lin Mao‐Tsun 
Published: July 2012

. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001–10 μ) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h.
. The LPS‐induced febrile response was mimicked by intra‐OVLT injection of the nitric oxide (NO) donors, S‐nitroso‐acetylpenicillamine (SNAP, 1–10 μ), sodium nitroprusside (SNP, 50 μ), or hydroxylamine (10 μ), the cyclic GMP analogue 8‐bromo‐cyclic GMP (8‐Br‐cyclic GMP, 10–100 μ), or prostaglandin E2 (PGE2, 0.2 μ).
. Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 μ), anisomycin (a protein synthesis inhibitor, 100 μ), L‐N5‐(1‐iminoethyl)ornithine (L‐NIO; an irreversible NOS inhibitor, 10–200 μ), aminoguanidine (a specific iNOS inhibitor, 1000 μ), or NG‐methyl‐L‐arginine acetate (L‐NMMA, a NOS inhibitor, 100 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra‐OVLT dose of 1000 μ of NG‐nitro‐L‐arginine methyl ester (L‐NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects.
. Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1–10 μ), 6‐(phenylamino)‐5,8‐quinolinedione (LY‐83583; an inhibitor of soluble guanylate cyclase and NO release, 20 μ), or indomethacin (an inhibitor of cyclo‐oxygenase, COX, 400 μ) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 μ) attenuated the fever induced by intra‐OVLT injection of SNAP.
. The PGE2‐induced fever was potentiated, rather then attenuated, by pretreatment with an intra‐OVLT dose of animoguanidine (1000 μ), L‐NMMA (100 μ), or L‐NIO (200 μ).
. These results suggest that iNOS‐COX pathways in the OVLT represent an important mechanism for modulation of pyrogenic fever in rabbits.
Effects of β‐adrenoceptor antagonists on Ca2+‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes
Authors: Chen Min , Hashizume Hiroko , Abiko Yasushi 
Published: July 2012

The effects of β‐adrenoceptor antagonists including (−)− and (+)‐propranolol, (−)− and (+)‐penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca2+‐overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat.
Fura‐2 was used for measurement of the intracellular calcium concentration ([Ca2+]i). LPC (15 μm) produced a rapid increase in [Ca2+]i from 72±5 to 3042±431 nM which coincided with a decrease in the percentage of rod‐shaped cells from 69±2 to 5±2%.
Preincubation with (−)−propranolol (20 μm), (+)‐propranolol (50 μm), or (−)− or (+)‐penbutolol (20 μm), the lipophilicity of which is higher than other β‐adrenoceptor antagonists, significantly inhibited both the increase in [Ca2+]i and the cell‐shape change induced by 15 μm LPC. The inhibitory effects of the four drugs on the LPC‐induced increase in [Ca2+]i and cell‐shape change were concentration‐dependent. The IC50s of (−)−propranolol, (+)‐propranolol, (−)− and (+)‐penbutolol for the increase in [Ca2+]i were 1.28, 10.50, 0.67 and 0.76 μm, respectively.
Pretreatment with pindolol, timolol, acebutolol, practolol, atenolol or lignocaine did not inhibit the increase in [Ca2+]i and the morphological change induced by LPC.
LPC markedly increased the release of creatine phosphokinase from 9±1 to 45±2% which could be significantly reduced by (−)− or (+)‐propranolol but not by acebutolol or timolol.
The protective effects of (−)− and (+)‐propranolol, (−)− and (+)‐penbutolol against the Ca2+‐overload induced by LPC were not associated with the β‐adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these β‐adrenoceptor antagonists against the Ca2+‐overload induced by LPC.
Respective degree of expression of β1, β2‐ and β3‐adrenoceptors in human brown and white adipose tissues
Authors: Deng Chengjun , Paoloni‐Giacobino Ariane , Kuehne Françoise , Boss Olivier , Revelli Jean‐Pierre , Moinat Madelaine , Cawthorne Michael A. , Muzzin Patrick , Giacobino Jean‐Paul 
Published: July 2012

The possible existence of a β3‐adrenoceptor in human brown and white adipose tissues was investigated by mRNA expression and binding studies.
The relative amounts of β1‐, β2‐ and β3‐adrenoceptor mRNA, as determined by total RNA Northern blot analysis in newborn brown adipose tissue, were 28, 63 and 9% respectively of the total β‐adrenoceptor mRNA.
The β1/β2‐adrenoceptors of human brown adipose tissue plasma membranes were characterized using [3H]‐CGP 12177 as a ligand. Their Kd and Bmax values were 1.9 nM and 156 fmol mg−1 of membrane proteins, respectively. The β3‐adrenoceptor was characterized by use of the new specific radioligand [3H]‐SB 206606. The binding of this ligand was stereospecifically displaced by the active R, R‐ or the inactive S, S‐enantiomer of BRL 37344 up to a concentration of about 10 μm. The Kd and Bmax values of the brown adipose tissue membrane β3‐adrenoceptors were 87 nM and 167 fmol mg−1 of proteins, respectively. A low affinity [3H]‐CGP 12177 binding site population was also detected in these membranes.
In human omental white adipose tissue, no β3‐adrenoceptor mRNA could be detected in total RNA Northern blots and the β1‐ and β2‐adrenoceptor mRNAs represented 9 and 91%, respectively of the total β‐adrenoceptor mRNA, and no specific binding of [3H]‐SB 206606 could be measured.
Characterization of a P2X‐purinoceptor in cultured neurones of the rat dorsal root ganglia
Authors: Robertson S.J. , Rae M.G. , Rowan E.G. , Kennedy C. 
Published: July 2012

The electrophysiological actions of the P2‐purinoceptor agonists, adenosine 5′‐triphosphate (ATP), 2‐methylthioATP (2‐meSATP) and α, β‐methyleneATP (α, β‐meATP) and of uridine 5′‐triphosphate (UTP) were studied under concentration and voltage‐clamp conditions in dissociated neurones of 1–6 day old rat dorsal root ganglia.ATP (10 nM‐100 μm) applied rapidly via a U‐tube perfusion system (equilibration time > 10 ms) activated concentration‐dependent inward currents with a latency to onset of a few ms, an EC50of 719 nM and a Hill slope of 1.47.2‐meSATP (10 nM‐100 μm) and α, μ‐meATP (100 nM‐100 μm) also evoked transient inward currents. The EC50and Hill slopes were 450 nM and 1.58 for 2‐meSATP and 1.95 μmand 1.53 for α, μ‐meATP respectively. There was no significant difference between the maximum currents evoked by the three agonists.As the concentration of ATP increased so the rate of rise and decay of the currents also increased. At 100 and 300 nM ATP the decay of the current was best fitted by a single exponential, but at 1 μmand above two exponentials were required. Log‐log plots of the rise time or time constants of decay versus concentration were linear. Currents evoked by 2‐meSATP and α, μ‐meATP showed a similar concentration‐dependence in their kinetics.Inward currents evoked by ATP, 2‐meSATP and α, μ‐meATP (300 nM) were abolished by the P2‐purinoceptor antagonist, suramin (100 μm).UTP (10 μm) evoked similar transient inward currents, which were sensitive to suramin (100 μm). ATP (10 μm), applied 2 min beforehand, reduced the response to UTP (10 μm) by 80 ± 10%.This study shows that ATP, 2‐meSATP and α, μ‐meATP act via a suramin‐sensitive P2X‐purinoceptor to evoke rapid, transient inward currents in dissociated neurones of rat dorsal root ganglia. The pyrimidine nucleotide, UTP, was also active. It is likely that the agonists were acting at the P2X3‐subtype to produce these effects.
Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus
Authors: Pellegrini‐Giampietro Domenico E. , Torregrossa Serenella Albani , Moroni Flavio 
Published: July 2012

Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD‐coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined.
The mGluR‐selective agonist (1S, 3R)‐1‐aminocyclopentane‐1, 3‐dicarboxylic acid [(1S, 3R)‐ACPD] induced a concentration‐dependent (10–300 μm) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments.
The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S, 3S, 4S)‐α‐(carboxycyclopropyl)‐glycine > (1S, 3R)‐ACPD > L‐cysteine sulphinic acid > L‐aspartate > L‐glutamate. L‐(+)‐2‐Amino‐4‐phosphonobutyric acid and the ionotropic glutamate receptor agonists N‐methyl‐D‐aspartate, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid, and kainate failed to activate PLD. (RS)‐3, 5‐dihydroxyphenylglycine (100–300 μm), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 μm (1S, 3R)‐ACPD.
(+)‐α‐Methyl‐4‐carboxyphenylglycine (0.1‐1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L‐(+)‐2‐Amino‐3‐phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 μm (1S, 3R)‐ACPD‐induced PLC response but produced a robust stimulation of PLD.
12‐O‐Tetradecanoylphorbol 13‐acetic acid and phorbol 12, 13‐dibutyrate (PDBu), activators of protein kinase C, at 1 μm had a stimulatory effect on mGluRs linked to PLD but depressed (1S, 3R)‐ACPD‐induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 μm) reduced PLD activation induced by 1 μm PDBu but not by 100 μm (1S, 3R)‐ACPD.
Our results suggest that PLD‐linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC‐independent mechanism.
Properties of spontaneous depolarizations in circular smooth muscle cells of rabbit urethra
Authors: Hashitani Hikaru , Van Helden Dirk F. , Suzuki Hikaru 
Published: July 2012

. Intracellular microelectrode recordings were made from circular smooth muscle of rabbit urethra.
. The smooth muscle of urethra was spontaneously active exhibiting large, regularly occurring depolarizations, termed slow waves (SWs), 1–3 s in duration, up to 40 mV in amplitude and generated every 3–15 s and small irregularly occurring events (or summations there of) termed spontaneous transient depolarizations (STDs) of < 1 s in duration.
. The SWs and STDs were not sensitive to 10−6 m atropine, 10−6 m phentolamine, 10−5 m guanethidine or 10−6 m tetrodotoxin, indicating that they were myogenic in origin.
. Application of 3 × 10−6 m nifedipine or 5 × 10−5 m GdCl3 did not inhibit the generation of SWs or STDs, indicating that activation of L‐type Ca2+ channels and non‐selective cation channels are not essential for their generation. However, the duration of SWs but not STDs was reduced by nifedipine, indicating L‐type Ca2+ channels contribute to the plateau‐like potential of SWs.
. Application of low chloride solution (6.4 mM), niflumic acid (10−5‐10−4 m) or 4,4′‐diisothiocyanostilbene‐2,2′‐disulphonic acid (DIDS, 10−4‐5 × 10−4 m) inhibited the generation of SWs and STDs, suggesting an involvement of chloride channels.
. Application of nominally Ca2+ free solution, 5 × 10−5 m BAPTA‐AM, 10−5 m cyclopiazonic acid, 10−2 m caffeine or 10−3 m procaine inhibited the generation of SWs and STDs, indicating that Ca2+ released from intracellular stores was required for the generation of SWs and STDs.
. Exogenously applied noradrenaline (10−7‐10−5 m) increased the frequency of SWs through stimulation of α‐adrenoceptors which was inhibited by sodium nitroprusside (SNP, 10−4 m). SNP also reduced the frequency of SWs without altering the membrane potential, an effect mimicked by 8‐bromocyclic GMP (10−3 m) indicating that SNP acted by elevating the production of cyclic GMP.
. It is concluded that smooth muscle cells of the rabbit urethra exhibit SWs and STDs which are likely to be induced by stimulation of Ca2+‐activated chloride channels evoked by release of Ca2+ from intracellular stores.
Action of probucol in arteries from normal and hypercholesterolaemic rabbits
Authors: Del Rio M. , Chulia T. , Ruiz E. , Tejerina T. 
Published: July 2012

. The effect of probucol on the vascular reactivity of different arteries isolated from rabbits was studied as well as its effects on the development of atherosclerosis in a cholesterol‐fed rabbit model.
. Probucol 10−6‐5 × 10−4 m produced a concentration‐dependent inhibition of the contractile responses induced by KCl (80 mM), the sequence for the IC50 was: mesenteric artery (5th branch, 4.8 ± 2.6 × 10−5 m) > aorta (8.2 ± 2.3 × 10−5 m) > femoral artery (> 5 × 10−4 m). The response to noradrenaline was: mesenteric artery (5th branch, 4.2 ± 1.3 × 10−5 m) > aorta (3.2 ± 3.0 × 10−4 m) > femoral (> 5 × 10−4 m).
. In the aorta, probucol (10−5‐10−4 m) shifted the concentration‐response curves to Ca2+ downward and to the right.
. Probucol at 5 × 10−5 m and 5 × 10−4 m showed a reduction in the 45Ca2+ uptake in resting, non‐stimulated aortic rings as well as the uptake induced by both noradrenaline 10−6 m and KCl 80 mM.
. In experiments in vivo, probucol did not affect lipid profiles; however, drug‐treatment significantly decreased the cholesterol content of aortic tissue and the extent of intimal surface covered with atherosclerotic lesions.
. The vascular reactivity was recovered in femoral arteries from rabbits on the atherogenic diet plus probucol.
. It is concluded that the effect of probucol in vascular smooth muscle can be attributed to an inhibition of Ca2+ entry through both potential‐ and receptor‐operated pathways. Moreover our findings suggest that the effects of probucol on movement of calcium in vascular smooth muscle may play an important role in the mechanism of antiatherogenic properties of this drug.
The site of anti‐arthritic action of the K‐opioid, U‐50,488H, in adjuvant arthritis: importance of local administration
Authors: Wilson Jodie L. , Nayanar Vim , Walker Judith S. 
Published: July 2012

. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (K)‐opioid, U‐50,488H (trans‐(±)‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl) cyclohexyl]‐benzene‐acetamide methane sulphonate), possesses anti‐arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, K‐opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti‐arthritic effects in the periphery. Thus, the dose‐effect relationship of a K‐opioid agonist, U‐50,488H was compared after both local and distant administration. Further, we tested whether the anti‐arthritic effects of this drug are stereospecific and receptor‐mediated by use of opioid antagonists.
. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (±)‐U‐50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (±)‐U‐50,488H on radiology and histology varied according to treatment time. Administration of (±)‐U‐50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (±)‐U‐50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose‐dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (±)‐U‐50,488H was approximately fourfold more potent as an ‘anti‐arthritic’ agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 ± 1.6 vs 19.5 ± 0.8 mg kg−1).
. Equivalent doses of the (−)−enantiomer (20 mg kg−1 day−1) and the racemate (±) of U‐50,488H (40 mg kg−1 day−1), elicited a similar attenuation of arthritic parameters while the (+)‐enantiomer exacerbated arthritis, suggesting that the anti‐arthritic activity lies solely with the (−)−enantiomer.
. Both the peripherally selective antagonist, naloxone methiodide, and the K‐selective antagonist, MR2266 ((−)−5, 9α‐diethyl‐2‐(3‐furylmethyl)‐2′‐hydroxy‐6,7‐benzomorphan), were able to reverse fully the peripheral anti‐arthritic effects of U‐50,488H, indicating that it exerts its effects through peripheral K‐opioid receptors.
. Taken together, these results not only confirm our previous findings that demonstrate anti‐arthritic effects of U‐50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral K‐receptors in the arthritic joint. Peripherally acting K‐opioid agonists should lead to new therapies for arthritis.