bluuebunny/crossref_metadata_2025_split huggingface dataset:
The pharmacology of fluparoxan: a selective α2‐adrenoceptor antagonist
Authors: Halliday C.A. , Jones B.J. , Skingle M. , Walsh D.M. , Wise H. , Tyers M.B. 
Published: July 2012

This paper describes the pharmacology of the novel α2‐adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti‐depressant. Idazoxan and yohimbine were included in many studies for comparison.
In the rat isolated, field‐stimulated vas deferens and the guinea‐pig isolated, field‐stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the α2‐adrenoceptor agonist UK‐14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the α1‐adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an α2:α1‐adrenoceptor selectivity ratio of greater than 2500.
In the conscious mouse, fluparoxan (0.2–3.0 mg kg−1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine‐induced hypothermia and antinociception. In the rat, UK‐14304‐induced hypothermia (ED50 = 1.4 mg kg−1, p.o. or 0.5 mg kg−1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg−1 p.o. or 1.3 mg kg−1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67–6 mg kg−1, p.o., also prevented UK‐14304‐induced sedation and bradycardia in the dog.
In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 × 10−5 m. It displayed weak affinity for 5‐HT1A (pIC50 = 5.9) and 5‐HT1B (pKi = 5.5) binding sites in rat brain.
We conclude that fluparoxan is a highly selective and potent α2‐adrenoceptor antagonist. The density of rat brain [3H]‐dihydroalprenolol binding sites was reduced by 26% when fluparoxan was administered chronically for 6 days at a dose of 12 mg kg−1 orally twice daily. The down‐regulation of β‐adrenoceptors by fluparoxan is consistent with its antidepressant potential.
α2‐Adrenoceptor blocking profile of SK&F 104078: further evidence for receptor subtypes
Authors: Akers I. , Coates J. , Drew G.M. , Sullivan A.T. 
Published: July 2012

The ability of the putative, selective post‐junctional α2‐adrenoceptor antagonist, SK&F 104078 to antagonize the effects of structurally‐diverse agonists at pre‐junctional α2‐adrenoceptors in the guinea‐pig ileum and rat vas deferens in vitro and in the rat heart in vivo, and at post‐junctional α2‐adrenoceptors in the rabbit ear vein in vitro, was examined. Results obtained with SK&F 104078 were compared with those obtained with yohimbine.
Xylazine and B‐HT933 each caused a concentration‐dependent inhibition of the field‐stimulation‐evoked twitch responses of the guinea‐pig ileum and rat vas deferens. SK&F 104078 did not antagonize either agonist in the guinea‐pig ileum and exerted only minimal blocking activity against xylazine in the rat vas deferens. In contrast, SK&F 104078 competitively antagonized B‐HT933 in the rat vas deferens (pA2 = 6.45). Yohimbine competitively antagonized both agonists in each tissue (pA2 values ranged between 7.46 and 7.88).
In the pithed rat xylazine and B‐HT933, injected intravenously, caused a dose‐dependent reduction in the tachycardia elicited by stimulation of the cardiac preganglionic sympathetic nerves. SK&F 104078 (10 mg kg−1, i.v.) caused a 20–30 fold rightward displacement of the dose‐response curve to xylazine, but did not affect responses to B‐HT933. Yohimbine (1 mg kg−1, i.v.) antagonized both agonists to a similar degree.
In the rabbit ear vein xylazine, B‐HT933, noradrenaline and UK14304 elicted vasoconstrictor responses. Prazosin was without effect, but in contrast, SK&F 104078 was a competitive antagonist of each of the agonists (pA2 values ranged between 6.63 and 6.72). Yohimbine also competitively antagonized each of the agonists in this preparation (pA2 values ranged between 7.81 and 8.07).
SK&F 104078 was also a competitive antagonist (pA2 = 6.20) against noradrenaline at post‐junctional α1‐adrenoceptors in the rabbit aorta.
These data show that SK&F 104078 is a competitive antagonist at post‐junctional α1‐ and α2‐adrenoceptors. Its antagonist potency at pre‐junctional α2‐adrenoceptors is agonist‐ and tissue‐dependent. Yohimbine does not discriminate between pre‐ and post‐junctional α2‐adrenoceptors. The findings are discussed in terms of the possible existence of subclasses of α2‐adrenoceptors.
The involvement of endothelium‐derived relaxing factor in the regulation of renal cortical blood flow in the rat
Authors: Walder Claire E. , Thiemermann Christoph , Vane John R. 
Published: July 2012

In the present study the role of endogenous nitric oxide (NO) was investigated, in the regulation of renal cortical blood flow (RCBF) in vivo in anaesthetized rats under conditions in which prostacyclin involvement had been eliminated.
Infusions of the NO synthesis inhibitor NG‐monomethyl‐l‐arginine (MeArg) at 1 or 3 mg kg−1 min−1, i.v., produced significant decreases in RCBF of 29 ± 7% and 35 ± 5%, respectively. These effects were reversed by co‐infusion of a 3 fold excess of l‐arginine (l‐Arg).
Similarly, intravenous infusion of Nω‐nitro‐l‐arginine methyl ester (NO2Arg) at 30 or 300 μg kg−1 min−1 attenuated RCBF by 21 ± 4% or 53 ± 4%, respectively, and these effects were reversed by l‐Arg (3 or 10 mg kg−1 min−1, i.v.). Most importantly, a low dose of NO2Arg (30 μg kg−1 min−1, i.v.), while having no pressor effect, considerably reduced RCBF, indicating that basal release of NO is important for the maintenance of renal cortical blood flow.
MeArg (3 mg kg−1 min−1, i.v.) or NO2Arg (300 μg kg−1 min−1, i.v.) inhibited endothelium‐dependent acetylcholine (ACh, 10 μg kg−1 min−1, i.v. for 3 min) increases in RCBF in an l‐Arg reversible manner, but did not affect endothelium‐independent (dopamine 10 μg kg−1 min−1, i.v., for 3 min) increases. Endothelin‐1 (1 nmol kg−1, i.v.), when given as a control for the vasoconstrictor effects of MeArg and NO2Arg, produced a slight inhibition of the ACh‐induced increase in RCBF, but this effect was significantly weaker than that produced by MeArg or NO2Arg.
Our findings suggest that MeArg and NO2Arg inhibit basal and ACh‐stimulated release of NO in the renal cortical vasculature. Thus, endogenous NO formation may play an important role in the local regulation of renal cortical blood flow.
Facilitation of amphetamine‐induced hypothermia in mice by GABA agonists and CCK‐8
Authors: Boschi Gabrielle , Launay Nicole , Rips Richard 
Published: July 2012

Amphetamine‐induced hypothermia in mice is facilitated by dopaminergic stimulation and 5‐hydroxytryptaminergic inhibition. The present study was designed to investigate: (a) the involvement of other neuronal systems, such as the γ‐aminobutyric acid (GABA), the opioid and the cholecystokinin (CCK‐8) systems; (b) the possible contribution of hydroxylated metabolites of amphetamine to the hypothermia; (c) the capacity of dopamine itself to induce hypothermia and its mechanisms, in order to clarify the resistance of amphetamine‐induced hypothermia to certain neuroleptics.
Pretreatment with the GABA antagonists, bicuculline and picrotoxin, did not inhibit amphetamine‐induced hypothermia. The GABAB agonist, baclofen (2.5 mg kg−1, i.p.) potentiated this hypothermia, whereas the GABAA agonist, muscimol, did not. γ‐Butyrolactone (GBL) (40 mg kg−1, i.p.) and the neuropeptide CCK‐8 (0.04 mg kg−1, i.p.) also induced potentiation. The opioid antagonist, naloxone, was without effect.
Dopamine itself (3, 9, 16 and 27 μg, i.c.v.) induced less hypothermia than the same doses of amphetamine. Sulpiride did not block dopamine‐induced hypothermia, but pimozide (4 mg kg−1, i.p.), cis(z)flupentixol (0.25 mg kg−1, i.p.) and haloperidol (5 μg, i.c.v.) did. The direct dopamine receptor agonist, apomorphine, did not alter the hypothermia. Neither the 5‐hydroxytryptamine (5‐HT) receptor blocker, cyproheptadine, nor the inhibitor of 5‐HT synthesis, p‐chlorophenylalanine (PCPA), modified dopamine‐induced hypothermia. Fluoxetine, an inhibitor of 5‐HT. reuptake, had no effect, whereas quipazine (6 mg kg−1, i.p.), a 5‐HT agonist, totally prevented the hypothermia. Hypothermia was unaffected by pretreatment with CCK‐8.
These data indicate that the hypothermia induced by amphetamine involves not only dopaminergic and 5‐hydroxytryptaminergic systems which are functionally antagonistic, but is also facilitated by direct or indirect GABA and CCK‐8 receptor stimulation. This facilitation could result, in part, from modulation of dopaminergic neurotransmission. This may explain the apparent resistance of amphetamine‐induced hypothermia to some neuroleptics, while dopamine‐induced hypothermia is not resistant. The possible action of hydroxylated metabolites of amphetamine may also help to explain these differences.
Involvement of capsaicin‐sensitive nerves in the bronchomotor effects of arachidonic acid and melittin: a possible role for lipoxin A4
Authors: Manzini Stefano , Meini Stefania 
Published: July 2012

Functional studies have been performed to evaluate the potential involvement of capsaicin‐sensitive nerves in the bronchomotor responses evoked by lipid mediators produced from the metabolic breakdown of arachidonic acid (AA) in the guinea‐pig bronchus.
In the presence of indomethacin, the exogenous administration of AA (0.01–1 mm) produced a concentration‐dependent contractile response in guinea‐pig isolated bronchial rings. AA‐induced contractions were augmented by epithelium‐removal and by thiorphan (10 μm) an inhibitor of tachykinin breakdown. A sustained downward and rightward displacement of the complete concentration‐response curve to AA was observed after in vitro capsaicin desensitization.
BWA4C (1 μm), a selective inhibitor of 5‐lipoxygenase, shifted the AA concentration‐response curve to the right. In the presence of this inhibitor, capsaicin desensitization did not have any further inhibitory action.
A potent, concentration‐dependent and capsaicin‐sensitive bronchoconstrictor effect was also observed with the polypeptide, melittin (10 nm–1 μm), an activator of phospholipase A2, which therefore should generate endogenous AA.
In vitro capsaicin‐desensitization produced a significant reduction of the bronchomotor responses evoked by lipoxin A4 (1–6 μm), but not of those elicited by other lipoxygenases products such as leukotriene D4 (1–100 nm) or by 15‐hydroxyeicosatetraenoic acid (15‐HETE, 1–6 μm).
These findings indicate that lipoxin A4 but not leukotriene D4 or 15‐HETE, might be one of the lipoxygenase mediators of excitatory effects of AA on capsaicin‐sensitive sensory nerves.
Investigation into the 5‐hydroxytryptamine receptor mediating smooth muscle relaxation in the rat oesophagus
Authors: Reeves J.J. , Bunce K.T. , Humphrey P.P.A. 
Published: July 2012

An investigation has been made into the 5‐hydroxytryptamine (5‐HT) receptor mediating relaxation of rat oesophagus in preparations precontracted with carbachol.
In tissues treated with pargyline (100 μm) and in the presence of corticosterone (30 μm) and cocaine (30 μm) the potency of 5‐HT and 5‐methoxytyramine (5‐MeOT) was not changed but the maximum response to these agonists was reduced. Thus there was no evidence of metabolism and/or uptake through an amine depleting mechanism.
The relaxant concentration‐effect curves to 5‐HT were shifted to the left in a concentration‐related manner by isobutylmethylxanthine (1 and 10 μm), suggesting the involvement of adenosine 3′:5′‐cyclic monophosphate in these responses.
5‐HT produced concentration‐related relaxations of rat oesophagus with an EC50 value of 0.24 μm. Several indole agonists were tested and the following rank order of potency of key agonists obtained: 5‐HT > α‐methyl‐5‐hydroxytryptamine = 5‐carboxamidotryptamine (5‐CT) > 5‐MeOT. In contrast, 2‐methyl‐5‐hydroxytryptamine, sumatriptan and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin were weak or inactive.
The substituted benzamides, metoclopramide, cisapride, renzapride and R,S‐zacopride acted as partial agonists, producing 60–70% of the 5‐HT maximum.
The relaxation responses to 5‐HT were neither inhibited by antagonists selective for 5‐HT1 or 5‐HT2 receptors nor by the 5‐HT3 receptor antagonists, ondansetron, granisetron or MDL 72222.
The relaxation responses induced by 5‐HT, 5‐CT, 5‐MeOT and renzapride were selectively inhibited by high concentrations of ICS 205–930 with pKB values of approximately 6.
The 5‐HT receptor mediating relaxation in rat oesophagus cannot be designated 5‐HT1, 5‐HT2 or 5‐HT3 under the current 5‐HT classification, but the observed effects are consistent with stimulation of the putative 5‐HT4 receptor.
The role of endogenous thromboxane in contractions to U46619, oxygen, 5‐HT and 5‐CT in the human isolated umbilical artery
Authors: Templeton A.G.B. , McGrath J.C. , Whittle M.J. 
Published: July 2012

The effects of selective thromboxane antagonists and a thromboxane synthase inhibitor on the contraction to 9,11‐dideoxy‐11α,9α‐epoxymethano‐prostaglandin F2α (U46619) and oxygen in the human umbilical artery (HUA) were examined. The effect of the antagonists on contractions to both 5‐hydroxytryptamine (5‐HT) and 5‐carboxamidotryptamine (5‐CT) were also examined.
U46619 (0.3 nm–10 μm) contracted the HUA. This contraction was antagonized by two selective thromboxane receptor antagonists EP092 (10 nm–1 μm) and GR32191B (10 nm–1 μm). The contraction was not affected by the selective thromboxane synthase inhibitor, dazoxiben (10 nm–1 μm).
When the oxygen tension was increased from 16 mmHg to 120 mmHg, the HUA transiently contracted. Both thromboxane antagonists inhibited this contraction in a concentration‐dependent manner with 1 μm almost completely abolishing the response (the oxygen‐induced contraction of the control preparation normally increases with a second exposure to 120 mmHg oxygen).
In low (16 mmHg) oxygen, responses to both 5‐HT and 5‐CT were unaffected by both thromboxane receptor antagonists at concentrations up to 1 μm. In high oxygen (120 mmHg) responses to both 5‐HT and 5‐CT were biphasic in nature, with an additional initial high sensitivity phase, which was abolished by a cyclo‐oxygenase inhibitor. In high oxygen, EP092 and GR32191B blocked this initial phase in a concentration‐dependent manner, returning sensitivity to 5‐HT and 5‐CT to that seen in low oxygen.
The thromboxane synthase inhibitor, dazoxiben, at concentrations greater than 10 nm inhibited the contraction to 120 mmHg oxygen and at 1 μm, dazoxiben almost abolished the response. In low oxygen, the response to 5‐HT was unaffected by dazoxiben at concentrations up to 10 μm. In high oxygen, the initial phase of the contraction to 5‐HT was inhibited by concentrations greater than 10 nm, with no effect on the maximum response.
The results show that thromboxane receptor antagonism or blockade of thromboxane synthesis selectively attenuates oxygen‐induced contractions and those responses to 5‐HT and 5‐CT which are dependent on high oxygen for their expression. This suggests that the contractions caused by high oxygen tension, and the enhancement of the contractile effects of low concentrations of 5‐HT and 5‐CT in the presence of high oxygen tension are mediated by endogenously released thromboxane A2.
Mechanisms of the coronary vascular effects of platelet‐activating factor in the rat perfused heart
Authors: Hu Weimin , Kinnaird Anne A. A. , Man Ricky Y.K. 
Published: July 2012

In a previous study it was demonstrated that bolus injections of platelet‐activating factor (PAF) in the rat perfused heart resulted in coronary vasodilatation, vasoconstriction or the combination of both, depending on the amount of PAF that was injected. In the present study, the mechanisms of these coronary vascular effects of PAF in the rat perfused heart were investigated.
Pretreatment of the rat perfused heart with the PAF antagonists FR‐900452 or BN‐52021 did not affect the vasodilator effect of PAF but eliminated the vasoconstrictor effect of PAF. FR‐900452 had no effect on the vasoconstrictor response to leukotriene C4 (LTC4) or LTD4.
The cyclo‐oxygenase inhibitor, indomethacin, did not modify the coronary vascular effects of PAF. However L‐649,923 (a leukotriene antagonist) and MK‐886 (a leukotriene synthesis inhibitor) eliminated both the vasodilator and vasoconstrictor effects of PAF.
When leukotrienes were administered by bolus injection in the rat perfused heart, LTB4 produced vasodilatation while LTC4 and LTD4 produced vasoconstriction. L‐649,923 blocked both the vasodilator and vasoconstrictor effects of the leukotrienes tested.
The results suggest that lipoxygenase products are responsible for both the vasodilator and vasoconstrictor actions of PAF in the coronary vasculature of the rat perfused heart while the cyclo‐oxygenase products do not play a significant role. The ineffectiveness of PAF antagonists in blocking the vasodilatation produced by PAF is compatible with the concept that there may be multiple PAF receptors.
Termination of digitalis‐induced ventricular tachycardias by clonidine involves central α2‐adrenoceptors in cats
Authors: Chen Shih‐Ann , Liu Ren‐Hon , Ting Tso‐Hui , Chang Mau‐Song , Chiang B. N. , Kuo Jon‐Son 
Published: July 2012

Effects of intravenous (i.v.) and intravertebral arterial (i.a.) administration of the α2‐adrenoceptor agonist, clonidine (Clon) and its antagonist, yohimbine (Yoh, 0.5 mg kg−1, i.v.; 0.05 mg kg−1, i.a.), on ventricular tachycardia (VT) induced by intravenous acetylstrophanthidin (AS) were studied in cats anaesthetized with intraperitoneal chloralose.
AS dose‐dependently produced cardiac arrhythmias including complete atrioventricular conduction block (118 ± 14 μg kg−1, i.v.), junctional tachycardia (128 ± 20 μg kg−1, i.v.), multiform ventricular premature beats (157 ± 21 μg kg−1, i.v.) and sustained VT (220 ± 23 μg kg−1, i.v.).
Doses of Clon (i.v.) required for termination of VT following i.v. Yoh (62.9 ± 5.2 μg kg−1) or i.a. Yoh (88.5 ± 16.3 μg kg−1) were higher than those for termination of VT without Yoh administration (28.3 ± 6.2 μg kg−1). Doses of Clon (i.a.) required for termination of VT without or with i.a. Yoh administration were 5.8 ± 1.0 or 14.8 ± 3.7 μg kg−1, respectively, and they were significantly different.
These experiments demonstrate that either i.v. or i.a. Yoh antagonizes the antiarrhythmic effect of Clon on AS‐induced VT. Since small doses of Clon administered i.a. act predominantly on the central nervous system, we suggest that its antiarrhythmic effect is likely to be on central α2‐adrenoceptors in the central nervous system.
Lack of effect of zaprinast on methacholine‐induced contraction and inositol 1,4,5‐trisphosphate accumulation in bovine tracheal smooth muscle
Authors: Chilvers Edwin R. , Giembycz Mark A. , Challiss R.A. John , Barnes Peter J. , Nahorski Stefan R. 
Published: July 2012

The effects of zaprinast (M&B 22948), a selective guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor, and sodium nitroprusside on cyclic GMP content, phosphoinositide hydrolysis and airway smooth muscle tone were examined in flurbiprofen pretreated bovine tracheal smooth muscle (BTSM).
Anion‐exchange chromatography of the soluble fraction of BTSM homogenates resolved three peaks of Ca2+/calmodulin‐independent phosphodiesterase (PDE) activity that corresponded to type la (cyclic GMP‐specific, zaprinast‐inhibitable), type II (cyclic GMP‐stimulated) and type IV (Ro 20 1724‐inhibitable) PDE isoenzymes. Zaprinast caused a selective inhibition of the type Ia PDE isoenzyme (IC50 0.94 μm) with respect to the type II and IV (IC50 s 93 μm and 197 μm respectively) isoenzymes.
Pretreatment of BTSM strips with zaprinast (10 μm) for 20min affected neither the initial rate of force development, nor the resultant magnitude of contraction induced by methacholine (10 μm). In addition, zaprinast (10 μm; 20 min) did not affect the cumulative concentration‐response relationship induced by methacholine. In contrast, sodium nitroprusside (300 μm) either alone, or in combination with zaprinast (10 μm), significantly attenuated tone induced by low, but not high concentrations of methacholine. This resulted in a non‐parallel, rightwards shift of the methacholine concentration‐response curves (nitroprusside: 4.0 fold; nitroprusside/zaprinast: 4.8 fold at the EC50 values), without a reduction in the maximum tone generated.
In BTSM slices, zaprinast (10 or 100 μm) did not influence basal or methacholine (10 μm)‐stimulated cyclic GMP accumulation or inositol 1,4,5‐trisphosphate (Ins(1,4,5)P3) mass accumulation over a 60s incubation period, although it did significantly increase cyclic GMP content over longer (30 min) stimulation periods.
In [3H]‐inositol prelabelled BTSM slices, stimulated in the presence of 5 mm LiCl, methacholine (10 μm) caused a marked increase in total [3H]‐inositol phosphate accumulation. This effect was not inhibited by zaprinast (10 μm), sodium nitroprusside (300 μm) or a combination of these drugs despite these agents markedly increasing tissue cyclic GMP content.
These findings demonstrate that despite zaprinast being a potent and selective inhibitor of the type Ia PDE isoenzyme in a cell‐free system, this drug only increases cyclic GMP content in BTSM following prolonged agonist‐stimulation. This may explain its lack of inhibitory effect on methacholine‐induced tone. The inability of drugs which increase tissue cyclic GMP content and exhibit anti‐spasmogenic activity to inhibit methacholine‐stimulated Ins(1,4,5)P3 formation suggests that, unlike vascular smooth muscle, cyclic GMP‐dependent mechanisms do not regulate receptor‐mediated phosphoinositide hydrolysis in BTSM.
Subclassification of the presynaptic α2‐autoreceptors in rabbit brain cortex
Authors: Limberger Norbert , Späth Leni , Starke Klaus 
Published: July 2012

α2‐Adrenoceptor binding sites have been subclassified into α2A sites of which a main characteristic is very low affinity for prazosin, and α2B sites with relatively high affinity for prazosin. The presynaptic α2‐autoreceptors in rabbit brain cortex were studied in order to classify them in terms of α2A and α2B. Release of [3H]‐noradrenaline in cortical slices was elicited by trains of 4 pulses delivered at 100 Hz.
Clonidine caused concentration‐dependent inhibition of the stimulation‐evoked overflow of tritium, with an EC50 of 7.5 nm and a maximal inhibition by 96%.
The following α‐adrenoceptor antagonists shifted the concentration‐response curve of clonidine to the right (antagonist‐receptor dissociation constants KD in brackets): yohimbine (14 nm), 2‐[2H‐(1‐methyl‐1,3‐dihydroisoindole)methyl]‐4,5‐dihydroimidazole (BRL 44408; 15 nm) and 1,2‐dimethyl‐2,3,9,13b‐tetrahydro‐1H‐dibenzo[c,f]imidazo[1,5‐a]azepine (BRL 41992; 630 nm). Prazosin 1 μm and 2‐[2‐[4‐(o‐methoxyphenyl)piperazine‐1‐yl]‐ethyl]‐4,4‐dimethyl‐1,3(2H,4H)‐isoquinolinedione (AR‐C 239) μm failed to antagonize the effect of clonidine. Higher concentrations of prazosin and AR‐C 239 greatly accelerated the basal efflux of tritium.
The method used permits the functional determination of antagonist affinities undistorted by endogenous α2‐autoinhibition. A comparison with affinities derived from radioligand binding experiments indicates that the presynaptic α2‐autoreceptors in rabbit brain cortex are markedly different from the α2B‐subtype and probably belong to the prazosin‐insensitive α2A‐subtype.