bluuebunny/crossref_metadata_2025_split huggingface dataset:
UTP induces vascular responses in the isolated and perfused canine epicardial coronary artery via UTP‐preferring P2Y receptors
Authors: Matsumoto Takako , Nakane Tokio , Chiba Shigetoshi 
Published: January 2005

Vasoconstrictor responses of the isolated and perfused canine epicardial coronary artery to uridine 5′‐triphosphate (UTP) were analysed pharmacologically.
At basal perfusion pressure, UTP induced vasoconstriction in a dose‐related manner and the vasoconstriction was sometimes followed by a slight vasodilatation at large doses (more than 10 nmol). The rank order of potency for vasoconstriction was UTP=UDP>ATP>TTPITP>> UMP. At raised perfusion pressure by 20 mm KCl, the vasoconstriction was not changed and a small vasodilatation was induced at large doses. The rank order of potency for vasodilatation was induced at large doses. The rank order of potency for vasodilatation was ATP>>ITPUDP>UTPTTP. The maximal vasodilator response to UTP was much less than that to ATP. UMP did not induce vasodilatation.
The P2X receptor agonist and desensitizing agent α,β‐methylene ATP (1 μm) and the P2 receptor antagonist suramin (100 μm) inhibited the vasoconstrictor responses to ATP but not those to UTP and UDP. The P2 receptor antagonist reactive blue 2 (30 μm) did not inhibit the vascular responses to UTP.
UTP (200 μm) desensitized the vasoconstrictor responses to UTP, but not either the vasodilator responses to UTP or the vasoconstrictor responses to ATP and UDP. UDP (200 μm) did not desensitize the vascular responses to UTP.
Preincubating the UDP stock solution and arterial preparation with hexokinase (10 and 1 uml−1, respectively) did not change the vasoconstrictor responses to UDP.
The Ca channel blocker diltiazem (1 μm) inhibited the vasoconstrictor responses to UTP but not those to ATP and UDP. Incubation in a Ca2+‐free solution containing 1 mm EGTA inhibited the vascular responses to ATP, UTP and UDP.
Removal of the endothelium by an intraluminal injection of saponin (1 mg) inhibited the vasodilator responses to UTP. Indomethacin, a cyclo‐oxygenase inhibitor (1 μm), inhibited the vasodilator responses to UTP, but NG‐nitro‐l‐arginine, a nitric oxide synthase inhibitor (300 μm), did not have an inhibitory effect.
The results suggest that (1) UTP induces vasoconstriction via UTP‐preferring P2Y receptors on the smooth muscle and vasodilatation via receptors different from those mediating the vasoconstriction induced by UTP and mediating the vasodilatation by ATP on the endothelium, through mainly the release of prostacyclin in the canine epicardial coronary artery; (2) UDP induces vasoconstriction via UDP‐preferring P2Y receptors; and (3) L‐type Ca ion channels are involved in the vasoconstriction induced by UTP, but not in that induced by UDP.
Risperidone inhibits 5‐hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5‐hydroxytryptamine
Authors: Hertel Peter , Nomikos George G. , Svensson Torgny H. 
Published: January 2005

The effects of risperidone on brain 5‐hydroxytryptamine (5‐HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN).
Administration of risperidone (25–400 μg kg−1, i.v.) dose‐dependently decreased 5‐HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25–4.0 mg kg−1, i.v.), the putative antipsychotic drug amperozide (0.5–8.0 mg kg−1, i.v.) and the selective α1‐adrenoceptor antagonist prazosin (50–400 μg kg−1, i.v.).
The selective α2‐adrenoceptor antagonist idazoxan (10–80 μg kg−1, i.v.), in contrast, increased the firing rate of 5‐HT neurones in the DRN, whereas the D2 and 5‐HT2A receptor antagonists raclopride (25–200 μg kg−1, i.v.) and MDL 100,907 (50–400 μg kg−1, i.v.), respectively, were without effect. Thus, the α1‐adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5‐HT cell firing.
Pretreatment with the selective 5‐HT1A receptor antagonist WAY 100,635 (5.0 μg kg−1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5‐HT cells induced by risperidone, failed to prevent the prazosin‐induced decrease in 5‐HT cell firing. This finding argues against the notion that α1‐adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells.
The inhibitory effect of risperidone on 5‐HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5‐HT depletor PCPA (p‐chlorophenylalanine; 300 mg kg−1, i.p., day−1 for 3 consecutive days) in comparison with drug naive animals.
Administration of risperidone (2.0 mg kg−1, s.c.) significantly enhanced 5‐HT output in the DRN.
Consequently, the reduction in 5‐HT cell firing by risperidone appears to be related to increased availability of 5‐HT in the somatodendritic region of the neurones leading to an enhanced 5‐HT1A autoreceptor activation and, in turn, to inhibition of firing, and is probably only to a minor extent caused by its α1‐adrenoceptor antagonistic action.
Characterization of β‐adrenoceptors in urinary bladder: comparison between rat and rabbit
Authors: Oshita Masafumi , Hiraoka Yasuko , Watanabe Yoshinari 
Published: January 2005

β‐Adrenoceptor subtypes in rat and rabbit urinary bladder were investigated in functional experiments by use of several agonists and antagonists.
All agonists tested produced concentration‐dependent relaxation, but the relative potencies varied between both species: BRL  37344 (pD2:8.0)>isoprenaline (7.3)>adrenaline (6.7)=noradrenaline (6.6) in rat bladder, and isoprenaline (8.7)=adrenaline (8.5)>noradrenaline (7.7)=BRL  37344 (7.4) in rabbit bladder.
The relaxation response to isoprenaline in rat bladder was relatively resistant to propranolol and ICI  118551, and the slopes of Schild plot for both antagonists were different from unity. The apparent pKB values estimated by single concentrations of propranolol (1, 10 μm) and ICI  118551(10 μm) were 6.6 and 5.4, respectively.
On the other hand, the relaxation response to isoprenaline in rabbit bladder was antagonized by lower concentrations (1 nm–100 nm) of propranolol and ICI  118551 in a competitive manner, resulting in pA2 values of 8.7 and 8.6, respectively.
These results suggest species‐heterogeneity of β‐adrenoceptors in urinary bladder; β3 and β2 subtypes in rat and β2 subtype in rabbit.
Vasorelaxant effects induced by the antiangiogenic drug linomide in aortic and saphenous vein preparations of the rabbit
Authors: Amerini Sandra , Filippi Sandra , Parenti Astrid , Ledda Fabrizio , Ziche Marina 
Published: January 2005

Linomide (N‐phenylmethyl‐1,2‐dihydro‐4‐hydroxyl‐1‐methyl‐2‐oxoquinoline‐3‐carboxamide) inhibits vascular proliferation and has been proposed as an antiangiogenic drug. We have investigated the vascular effect of linomide in rabbit aortic and saphenous vein ring preparations and in rat cultured vascular smooth muscle cells (VSMCs).
Linomide (25–300 μg ml−1) did not alter the basal tone of the preparations. The drug induced a concentration‐dependent relaxant effect in aortic rings with endothelium, preconstricted by noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and by the thromboxane mimetic U46619.
The degree of relaxation induced by linomide was significantly reduced by exposure to the cyclo‐oxygenase inhibitors indomethacin (3 μm) and acetylsalicylic acid (500 μm), and was not influenced by pretreatment with the nitric oxide synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME) (100 μm) in aortic rings with endothelium, preconstricted with NA.
Endothelium removal significantly reduced the relaxant response to linomide in aortic ring preparations.
A concentration‐dependent relaxant response was observed also in rabbit saphenous vein preparations deprived of endothelium and preconstricted either by NA or U46619. The degree of relaxation obtained in a high potassium solution was consistently smaller than that observed in NA‐pretreated venous preparations.
The vasorelaxant effect of linomide was consistently blunted by the adenylate cyclase inhibitor SQ 22536 (50 μm), both in intact aortic rings and in those deprived of endothelium.
In rat cultured vascular smooth muscle cells, linomide (100–200 μg ml−1) induced a significant increase in cyclic AMP levels, which was blocked by exposure to 50 μm SQ 22536.
In endothelium‐deprived aortic ring preparations, the linomide‐induced relaxant effect was greatly reduced in high potassium medium (KCl=25 mm). Pretreatment with the ATP potassium channel inhibitor glibenclamide (3 μm) significantly reduced the linomide‐induced relaxation.
The results show that linomide possesses a vasorelaxant effect which is attributable to both endothelium‐dependent and ‐independent properties. While the former component of the drug's activity is apparently due to the release of a prostanoid from endothelial cells, the endothelium‐independent mechanism involved in linomide relaxation is linked to cyclic AMP accumulation and to ATP‐sensitive potassium channel activation in VSMCs.
Dopamine stimulation of cardiac β‐adrenoceptors: the involvement of sympathetic amine transporters and the effect of SKF38393
Authors: Habuchi Yoshizumi , Tanaka Hideo , Nishio Manabu , Yamamoto Taku , Komori Toshiaki , Morikawa Junichiro , Yoshimura Manabu 
Published: January 2005

Mechanisms underlying β‐adrenoceptor stimulation by dopamine were examined on guinea‐pig Langendorff‐perfused hearts and isolated cells from the right atrium, by using the chronotropic effects and the enhancement of L‐type Ca2+ current (ICa,L) in the presence of prazosin as indicators of β‐adrenoceptor stimulation. Dopamine‐induced overflow of noradrenaline (NA) concentrations was measured by high‐performance liquid chromatography.
Dopamine caused positive chronotropic effects with an EC50 of 2.5 μm and induced NA overflow with a similar EC50 (1.3 μm). The chronotropic effect of dopamine was abolished by bisoprolol (1 μm).
The effects of dopamine were maintained during prolonged application, whereas the effects of tyramine faded with time. Dopamine (3 μm) restored the chronotropic effects and the NA release suppressed by pretreatment with tyramine, suggesting a de novo synthesis of NA during the exposure to dopamine.
Dopamine (3 μm)‐induced NA release was not affected by tetrodotoxin, ω‐conotoxin, rauwolscine, ICI118551 or sulpiride, but was inhibited by desipramine, a NA uptake inhibitor (IC50 ∼1 μm). It was also not affected by GBR12909 and bupropion, dopamine uptake inhibitors in the central nervous system.
SKF38393, a D1 receptor partial agonist, potently inhibited the 3 μm dopamine‐induced release of NA (IC50 ∼0.1 μm). D1 receptors are not involved in the DA‐induced release of NA, since SCH23390 (3 μm), a potent D1 antagonist, inhibited the NA release only slightly, and dihydrexidine (1 μm) and chloro‐APB (1 μm), full D1 agonists, caused no significant NA release.
SKF38393 inhibited tyramine‐induced overflow of NA, and potentiated the field stimulation‐induced NA release. SKF38393 and desipramine retarded the decay of the stimulation‐induced tachycardia in a similar manner. These results indicate that SKF38393 is a potent monoamine transport inhibitor and a useful tool for the functional evaluation of indirectly‐acting sympathomimetic agonists in the heart. In the presence of SKF38393 (10 μm), dopamine at 1 μm showed no chronotropic effect.
Voltage clamp experiments with isolated atrial cells revealed that dopamine is a weak partial agonist. The EC50 for ICa,L stimulation by dopamine was high (13 μm). As a result, dopamine at 1 μm did not affect ICa,L. Bisoprolol abolished the stimulation of ICa,L by dopamine (30 μm), and dihydrexidine (1 μm) did not affect ICa,L.
It was concluded that the cardiac effects of dopamine at clinically relevant concentrations (<1 μm) result almost exclusively from the indirect effect of β adrenoceptor stimulation, involving the release of NA from sympathetic nerve terminals. The roles of the direct stimulation of β adrenoceptors by dopamine at these concentrations and the stimulation of postjunctional D1 receptors seem negligible. The desipramine‐ and SKF38393‐sensitive monoamine transporter mediates the release of NA.
ω‐Conotoxin GVIA‐resistant neurotransmitter release from postganglionic sympathetic nerves in the guinea‐pig vas deferens and its modulation by presynaptic receptors
Authors: Smith Amanda B , Cunnane Tom C 
Published: January 2005

Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea‐pig isolated vas deferens.
Recently, a component of action potential‐evoked release which is insensitive to high concentrations of the selective N‐type calcium channel blocker ω‐conotoxin GVIA termed ‘residual release’ has been described. Under these conditions, release of the neurotransmitter ATP evoked by trains of low frequency stimuli is abolished, but at higher frequencies a substantial component of release is revealed.
‘Residual release’ was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The α2‐adrenoceptor agonist clonidine (30–100 nM) inhibited ‘residual release’, the degree of inhibition being most marked at the beginning of a train.
The α2‐adrenoceptor antagonist yohimbine (1 μM) induced a marked increase in ‘residual release’ which was dependent on both the frequency of stimulation and the number of stimuli in a train.
Prostaglandin E2 (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of ‘residual release’ at all stimulation frequencies examined.
4‐Aminopyridine (100 μM) induced a powerful potential of ‘residual release’ and could reverse the inhibition of ω‐conotoxin GVIA.
‘Residual release’ was modulated through presynaptic α2‐adrenoceptors suggesting that (i) residual release of ATP is subject to α‐autoinhibition through the co‐release of noradrenaline, (ii) noradrenaline release can be triggered by calcium channels other than the N‐type and (iii) when presynaptic receptors are activated, inhibition of transmitter release can occur by mechanisms other than modulation of calcium‐entry through N‐type calcium channels in postganglionic sympathetic nerves. Prostaglandin E2 and neuropeptide Y also modulated neurotransmitter release.

British Journal of Pharmacology (1998) 123, 167–172; doi:10.1038/sj.bjp.0701577
Effects of long‐term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction
Authors: Yamaguchi Fuminari , Sanbe Atsushi , Takeo Satoshi 
Published: January 2005

Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction.
CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end‐diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF.
The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25–1 min with 10−5 M Ca2+ (48–88%) and when preloaded with 10−6 M Ca2+ and then exposed to 0.1–1 mM caffeine (45–93%).
The [3H]‐ryanodine‐binding activity in SR‐enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+‐release channel.
Rats were treated orally with 3 mg kg−1 day−1 trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end‐diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF.
It is concluded that long‐term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.

British Journal of Pharmacology (1998) 123, 326–334; doi:10.1038/sj.bjp.0701592
Effects of a hydroxylated metabolite of the β‐adrenoreceptor antagonist, carvedilol, on post‐ischaemic splanchnic tissue injury
Authors: Christopher Theodore A , Lopez Bernard L , Ma Xin‐Liang , Feuerstein Giora Z , Ruffolo Robert R , Yue Tian‐Li 
Published: January 2005

Reactive oxygen species have been demonstrated to play a critical role in post‐ischaemic tissue injury. The present experiment was designed to evaluate the effects of SB 211475, a hydroxylated metabolite of the new β‐adrenoceptor antagonist, carvedilol, on rat splanchnic ischaemia (SI, 60 min) and reperfusion(R)‐induced shock and tissue injury.
Administration of SB 211475 two min before R attenuated SI/R injury in a dose‐dependent manner. At doses of 0.5 mg kg−1 and 1.0 mg kg−1, SB 211475 exerted significant anti‐shock and endothelial protective effects, characterized by prolonged survival times, increased survival rates, attenuated increases in tissue myeloperoxidase activity and haematocrits, and preserved endothelium‐dependent vasorelaxation.
Administration of 1 mg kg−1 carvedilol attenuated shock‐induced tissue injury and endothelial dysfunction. However, administration of 0.5 mg kg−1 carvedilol had no protective effects on post‐ischaemic tissue injury.
Previous studies have shown that SB 211475 has virtually no β‐blocking activity but possesses more potent antioxidant activity than carvedilol. In the present study, SB 211475 exerted more potent protective effects than the parent compound, suggesting that this metabolite of carvedilol is superior to carvedilol with regard to its protection against post‐ischaemia tissue injury.

British Journal of Pharmacology (1998) 123, 292–298; doi:10.1038/sj.bjp.0701598
Protective effects of mercaptoethylguanidine, a selective inhibitor of inducible nitric oxide synthase, in ligature‐induced periodontitis in the rat
Authors: Lohinai Zsolt , Benedek Péter , Fehér Erzsébet , Györfi Adrienn , Rosivall László , Fazekas Árpád , Salzman Andrew L. , Szabó Csaba 
Published: January 2005

Excessive production of nitric oxide (NO), and the generation of peroxynitrite have been implicated in various proinflammatory conditions. In the present study, using mercaptoethylguanidine (MEG), a selective inhibitor of iNOS and a peroxynitrite scavenger, we investigated the role of iNOS and peroxynitrite in a rat model of periodontitis.
Periodontitis was produced in rat by a ligature of 2/0 braided silk placed around the cervix of the lower left 1st molar. Animals were then divided into two groups: one group of rats was treated with MEG (30 mg kg−1, i.p., 4 times per day for 8 days), animals in the other group received vehicle. At day 8, the gingivomucosal tissue encircling the mandibular 1st molars was removed on both sides from ligated and sham operated animals for inducible nitric oxide synthase (iNOS) activity assay and for immunocytochemistry with anti‐iNOS serum. Plasma extravasation was measured with the Evans blue technique. Alveolar bone loss was measured with a videomicroscopy.
Ligation caused a significant, more than 3 fold increase in the gingival iNOS activity, whereas it did not affect iNOS activity on the contralateral side, when compared to sham‐operated animals. Immunohistochemical analysis revealed iNOS‐positive macrophages, lymphocytes and PMNs in the connective tissue and immunoreactive basal layers of epithelium on side of the ligature, and only a few iNOS‐reactive connective tissue cells on the contralateral side. Ligation significantly increased Evans blue extravasation in gingivomucosal tissue and alveolar bone destruction compared to the contralateral side. MEG treatment significantly reduced the plasma extravasation and bone destruction.
The present results demonstrated that ligature‐induced periodontitis increases local NO production and that MEG treatment protects against the associated extravasation and bone destruction. Based on the present data, we propose that enhanced formation of NO and peroxynitrite plays a significant role in the pathogenesis of periodontitis.

British Journal of Pharmacology (1998) 123, 353–360; doi:10.1038/sj.bjp.0701604
Effects of the Aconitum alkaloid mesaconitine in rat hippocampal slices and the involvement of α‐ and β‐adrenoceptors
Authors: Ameri Angela 
Published: January 2005

The effects of mesaconitine, the main alkaloid contained in Aconiti tuber, were investigated by use of extracellular recordings of stimulus‐evoked population spikes and field excitatory postsynaptic potentials (e.p.s.ps) in the CA1 region of rat hippocampal slices.
At a concentration of 10 nM, mesaconitine evoked excitations, which were manifested as an increase in the amplitude of the orthodromic spike and the appearance of multiple spikes following the first postsynaptic spike, without affecting the magnitude of paired‐pulse facilitation. The increase in spike amplitude was persistent and was not reversed by up to 90 min of washout. At concentrations of 30 and 100 nM, the alkaloid produced a biphasic effect, that is an excitation followed by an inhibition without having any effect upon the field e.p.s.p. At concentrations above 100 nM, mesaconitine suppressed the orthodromic population spike and the field e.p.s.p.
The excitatory effect was also observed when electrical stimulation was stopped completely during the application of mesaconitine (10 nM) and during the first 15 min of washout.
The enhancement of the population spike and the appearance of multiple spikes induced by mesaconitine (10–100 nM) were blocked by pretreatment with the β‐adrenoceptor antagonists propranolol (1 μM) and timolol (1 μM), whereas the inhibitory effect was blocked by the α‐adrenoceptor antagonists yohimbine (1 μM) and phentolamine (10 μM). However, when the β‐adrenoceptor antagonist timolol was added 10 min after the application of mesaconitine, it failed to block the long‐lasting enhancement of the spike amplitude and the appearance of multiple population spikes.
Application of the selective β‐adrenoceptor agonist isoprenaline (500 nM) to the hippocampal slices induced an increase in the amplitude of the orthodromic population spike and elicited 2–3 additional spikes. Mesaconitine (10 nM) did not further potentiate this enhancement of the spike amplitude when added after a 15 min pretreatment with isoprenaline.
Perfusion of forskolin, which directly activates adenylate cyclase, enhanced the population spike. Mesaconitine had no additional effect when applied after pretreatment with forskolin.
It is concluded that the excitatory effects evoked by lower concentrations of the plant alkaloid mesaconitine are mediated by stimulation of β‐adrenoceptors and the consequent activation of intracellular processes which lead to the long‐lasting changes in excitability.

British Journal of Pharmacology (1998) 123, 243–250; doi:10.1038/sj.bjp.0701608