bluuebunny/crossref_metadata_2025_split huggingface dataset:
S 15535, a benzodioxopiperazine acting as presynaptic agonist and postsynaptic 5‐HT1A receptor antagonist, prevents the impairment of spatial learning caused by intrahippocampal scopolamine
Authors: Carli Mirjana , Balducci Claudia , Millan Mark J , Bonalumi Pierenrico , Samanin Rosario 
Published: January 2005

The effect of S 15535 (4‐benzodioxan‐5‐yl)1‐(indan‐2‐yl)piperazine), an agonist at presynaptic and antagonist at postsynaptic 5‐HT1A receptors, on the impairment of spatial learning caused by intrahippocampal scopolamine in a two‐platform spatial discrimination task was studied.
Scopolamine (4.0 μg μl−1), injected bilaterally into the CA1 region of the dorsal hippocampus 10 min before each training session, impaired choice accuracy with no effect on choice latency and errors of omission.
Administered subcutaneously 30 min before each training session, S 15535 1.0 (but not 0.3) mg kg−1 did not modify choice accuracy but prevented its impairment by intrahippocampal scopolamine.
WAY 100635, a 5‐HT1A receptor antagonist, injected into the dorsal raphe at 1.0 μg 0.5 μl−1 5 min before scopolamine, had no effect on choice accuracy and latency or errors of omission and did not modify the effect of scopolamine but completely antagonized the effect of S 15535 (1.0 mg kg−1) on scopolamine‐induced impairment of choice accuracy.
The results confirm a previous report (Carli et al., 1998) that stimulation of presynaptic 5‐HT1A receptors in the dorsal raphe counteracts the deficit caused by intrahippocampal scopolamine, probably by facilitating the transfer of facilitatory information from the entorhinal cortex to the hippocampus.
Drugs that stimulate action on presynaptic 5‐HT1A receptors, such as S 15535 and other partial 5‐HT1A receptors agonists, may be useful in the symptomatic treatment of human memory disturbances associated with loss of cholinergic innervation to the hippocampus.

British Journal of Pharmacology (1999) 128, 1207–1214; doi:10.1038/sj.bjp.0702915
Non‐adrenergic binding of [3H]atipamezole in rat kidney–regional distribution and comparison to α2‐adrenoceptors
Authors: Sjöholm Birgitta , Lähdesmäki Janne , Pyykkö Kaija , Hillilä Maarit , Scheinin Mika 
Published: January 2005

Atipamezole (4‐(2‐ethyl‐2,3‐dihydro‐1H‐inden‐2‐yl)‐1H‐imidazole) was first introduced as a potent and specific α2‐adrenoceptor antagonist, but in some tissues [3H]atipamezole identifies an additional population of binding sites, distinct from both classical α2‐adrenoceptors and I1‐ and I2‐imidazoline receptors identified with [3H]para‐aminoclonidine or [3H]idazoxan.
In the present study we have characterized [3H]atipamezole binding sites in rat kidney by receptor autoradiography and membrane binding assays and determined whether they are pharmacologically identical with the previously described binding sites for [3H]para‐aminoclonidine and [3H]idazoxan. [3H]RX821002 and [3H]rauwolscine were used to compare the regional distribution of α2‐adrenoceptors to that of non‐adrenergic binding sites of [3H]atipamezole.
Comparative autoradiographic experiments demonstrated the differential localisation of [3H]atipamezole, [3H]RX821002 and [3H]rauwolscine binding sites in rat kidney. The pattern of distribution of non‐adrenergic [3H]atipamezole binding sites is clearly distinct from that of α2‐adrenoceptors.
The non‐adrenergic binding of [3H]atipamezole in rat kidney does not fall into any of the previously identified three classes of imidazoline receptors studied with [3H]para‐aminoclonidine, [3H]idazoxan and [3H]RX821002.
Atipamezole had no inhibitory effect on MAO‐A or MAO‐B activity in renal membranes, which speaks against the involvement of MAOs in the observed radioligand binding.

British Journal of Pharmacology (1999) 128, 1215–1222; doi:10.1038/sj.bjp.0702917
Desensitization and resensitization of β1‐ and putative β4‐adrenoceptor mediated responses occur in parallel in a rat model of cardiac failure
Authors: Kompa Andrew R , Summers Roger J 
Published: January 2005

Cardiostimulant effects of the non‐conventional partial agonist, CGP 12177A, are mediated by a receptor distinct from the β3‐adrenoceptor and termed the putative β4‐adrenoceptor. Using a rat model of cardiac failure, induced by myocardial infarction (MI), we compared the desensitization and resensitization of responses to CGP 12177A with those to isoprenaline and RO 363 in left (LA) and right atria (RA). We also examined the ability of β‐adrenoceptor antagonists to block responses to CGP 12177A.
MI reduced the maximum inotropic response to isoprenaline by 48% (sham 4.1±0.6 mN, n=10; MI 2.1±0.4 mN, n=8, P<0.02), RO 363 by 61% (sham 4.2±0.5 mN, n=10; MI 1.8±0.3 mN, n=8, P<0.005) and CGP 12177A by 49% (sham 1.4±0.1 mN, n=5; MI 0.7±0.2 mN, n=7, P<0.05) in electrically stimulated LA. MI also reduced the sensitivity to isoprenaline (pEC50: sham 8.79±0.08, n=10; MI 8.30±0.10, n=8; P=0.001) and RO 363 (pEC50: sham 8.69±0.07, n=10; MI 8.33±0.10, n=8; P<0.01). The maximum chronotropic responses to isoprenaline, RO 363 and CGP 12177A in RA were unaffected.
Pertussis toxin treatment (10 μg kg−1, i.p.) restored the maximum inotropic response and sensitivity to isoprenaline (sham 3.5±0.5 mN, n=9; MI 3.2±0.6 mN, n=11, P=0.702) and CGP 12177A (sham 1.6±0.3 mN, n=6; MI 1.9±0.4 mN, n=7, P=0.537) in MI animals to levels similar to those in the sham group.
CGP 20712A (pKB: LA 6.7±0.2, n=6; RA 7.1±0.1, n=4), ICI 118,551 (pKB: LA 6.4±0.1, n=5; RA 6.3±0.1, n=6), propranolol (pKB: LA 6.6±0.1, n=5; RA 6.8±0.1, n=6) and bupranolol (pKB: LA 7.2±0.1, n=6; RA 7.7±0.1, n=8), showed moderate affinity for the putative β4‐adrenoceptor.
Desensitization after MI and resensitization (after pertussis toxin treatment) to isoprenaline and CGP 12177A therefore occur in parallel, suggesting that the β1‐ and putative β4‐adrenoceptor use the same signalling pathway. Antagonist affinity studies confirmed that drugs acting at β1‐adrenoceptors also interact with putative β4‐adrenoceptors with approximately 100 times lower affinity. We suggest that CGP 12177A produces its cardiac effects by interacting with a low affinity state of the β1‐adrenoceptor.

British Journal of Pharmacology (1999) 128, 1399–1406; doi:10.1038/sj.bjp.0702920
Release of nitric oxide from endothelial cells stimulated by YC‐1, an activator of soluble guanylyl cyclase
Authors: Wohlfart Paulus , Malinski Tadeusz , Ruetten Hartmut , Schindler Ursula , Linz Wolfgang , Schoenafinger Karl , Strobel Hartmut , Wiemer Gabriele 
Published: January 2005

In this study we examined the endothelium‐dependent effect of YC‐1–a benzyl indazole derivative which directly activates soluble guanylyl cyclase (sGC)–on vascular relaxation and nitric oxide (NO) and guanosine‐3′,5′‐cyclic monophosphate (cyclic GMP) in endothelial cells.
In preconstricted rat aortic rings with intact endothelium, YC‐1 produced a concentration‐dependent relaxation. However, the concentration response curve was shifted rightward to higher concentrations of YC‐1, when (i) the aortas were pre‐treated with L‐NG‐nitroarginine methylester (L‐NAME) or (ii) the endothelium was removed.
Incubation of bovine aortic endothelial cells (BAEC) with YC‐1 produced a concentration‐dependent NO synthesis and release as assessed using a porphyrinic microsensor. Pre‐incubating cells with L‐NAME or with 8‐bromo‐cyclic GMP decreased this effect indicating that the YC‐1 stimulation of NO synthesis is due to an activation of nitric oxide synthase, but not to an elevation of cyclic GMP. No direct effect of YC‐1 on recombinant endothelial constitutive NO synthase activity was observed.
The YC‐1 stimulated NO release was reduced by 90%, when extracellular free calcium was diminished.
In human umbilical vein endothelial cells (HUVEC), YC‐1 stimulated intracellular cyclic GMP production in a concentration‐ and time‐dependent manner. Stimulation of cyclic GMP was greater with a maximum concentration of YC‐1 compared to calcium ionophore A23187. Similar effects were observed in BAEC and rat microvascular coronary endothelial cells (RMCEC).
When HUVEC and RMCEC were pre‐treated with L‐NG‐nitroarginine (L‐NOARG), the maximum YC‐1 stimulated cyclic GMP increase was reduced by 50%.
These results indicate, that beside being a direct activator of sGC, YC‐1 stimulates a NO‐synthesis and release in endothelial cells which is independent of elevation of cyclic GMP but strictly dependent on extracellular calcium. The underlying mechanism needs to be determined further.

British Journal of Pharmacology (1999) 128, 1316–1322; doi:10.1038/sj.bjp.0702921
Continued morphine modulation of calcium channel currents in acutely isolated locus coeruleus neurons from morphine‐dependent rats
Authors: Connor Mark , Borgland Stephanie L , Christie Macdonald J 
Published: January 2005

The actions of the opioid agonists morphine and methionine‐enkephalin (met‐enkephalin) on the calcium channel currents (IBa) of acutely isolated locus coeruleus (LC) neurons from morphine‐dependent and vehicle‐treated rats were examined using whole cell patch clamp techniques.
In LC neurons maintained in 5 μM morphine, co‐superfusion of naloxone (1 μM) or the μ‐opioid receptor antagonist CTAP (D‐Phe‐Cys‐Tyr‐D‐Trp‐Arg‐Thr‐Pen‐Thr‐NH2 1 μM) with morphine resulted in a significant increase in the amplitude of IBa. The increases in IBa were not different in neurons from morphine‐dependent or vehicle rats. The increase in IBa was mimicked by washing off morphine, but not by co‐superfusion of the κ‐receptor antagonist norbinaltorphimine (300 nM) or the δ‐receptor antagonist ICI‐174864 (1 μM).
In spontaneously withdrawn LC neurons from morphine‐dependent rats, met‐enkephalin (pD2 7.1, maximum inhibition 49%) and morphine (pD2 6.5, maximum inhibition 33%), inhibited IBa in all cells. In cells from vehicle rats the pD2 for met‐enkephalin was 7.3, maximum inhibition 52%, while the pD2 for morphine was 6.6 and the maximum inhibition 43% (P<0.05 versus cells from morphine‐dependent rats).
IBa in LC neurons was mostly comprised of ω‐conotoxin GVIA‐ (N‐type) and ω‐agatoxin IVA‐ (P/Q‐type) sensitive components, with lesser amounts of nimodipine‐sensitive current and current resistant to all three blockers. Neither the density of IBa nor the proportion of any of the components of IBa differed between neurons from morphine‐dependent or vehicle‐treated rats.
This study demonstrates that in morphine‐dependent rats, morphine and met‐enkephalin modulation of somatic IBa in LC neurons displays modest tolerance compared with untreated rats. Further, chronic morphine treatment does not alter the type or density of IBa in LC neurons. These results provide more evidence that functional μ‐opioid receptor coupling is not dramatically altered in the LC in morphine‐dependent rats.

British Journal of Pharmacology (1999) 128, 1561–1569; doi:10.1038/sj.bjp.0702922
Vasodilator effects of sodium nitroprusside, levcromakalim and their combination in isolated rat aorta
Authors: Pérez‐Vizcaíno Francisco , Cogolludo Angel L , Zaragozá‐Arnáez Francisco , Fajardo Susana , Ibarra Manuel , López‐López J G , Tamargo Juan 
Published: January 2005

The endothelial modulation of the relaxant responses to the nitric oxide (NO) donor sodium nitroprusside (SNP) and the KATP channel opener levcromakalim (LEM) and the interactions between these agents were analysed in isolated rat aorta.
LEM‐induced relaxation was unchanged by endothelium removal or by the presence of L‐NAME (10−4 M) or ODQ (10−6 M). In contrast, in KCl‐ (25 mM), but not in noradrenaline‐ (NA, 10−6 M) contracted arteries, SNP‐induced relaxation was augmented by endothelium removal but not by L‐NAME, indomethacin, glibenclamide nor charybdotoxin plus apamin.
The isobolographic analysis of the interactions between exogenously activated KATP channels and cyclic GMP using mixtures of SNP and LEM revealed that there were no interactions between both drugs at the proportions at which both drugs were active. However, the points for the SNP : LEM mixtures in proportions 10 : 1 and 1 : 10,000 (i.e. at concentrations at which LEM and SNP were inactive, respectively) fell significantly above the line of additivity indicating that there were negative interactions between both drugs at these selected proportions (about 5‐ and 2 fold inhibition, respectively). The former interaction was sensitive to glibenclamide, whereas the latter was insensitive ODQ. The magnitude of the 10 : 1 SNP : LEM interaction was smaller in endothelium‐intact arteries and was absent in arteries stimulated by NA.
In conclusion, the relaxations induced by LEM and SNP were additive. However, the presence of endothelium and low concentrations of LEM inhibited SNP‐induced relaxation. Both inhibitory effects were not additive and were only observed in KCl‐ and not in NA‐contracted aortae.

British Journal of Pharmacology (1999) 128, 1419–1426; doi:10.1038/sj.bjp.0702924
Effects of inhibitors of the activity of poly (ADP‐ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock
Authors: McDonald Michelle C , Filipe Helder Mota , Thiemermann Christoph 
Published: January 2005

Poly (ADP‐ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the effects of the PARS inhibitors 3‐aminobenzamide (3‐AB), nicotinamide and 1,5‐dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat.
Haemorrhage (sufficient to lower mean arterial blood pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to 66±4 mmHg (control, n=13). This circulatory failure was not affected by administration (5 min prior to resuscitation) of 3‐AB (10 mg kg−1 i.v., n=7), nicotinamide (10 mg kg−1 i.v., n=6) or ISO (3 mg kg−1 i.v., n=6).
Haemorrhage and resuscitation also resulted in rises in the serum levels of urea and creatinine. This renal dysfunction was attenuated by 3‐AB and nicotinamide, but not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO (n=6) also attenuated the renal dysfunction caused by haemorrhage and resuscitation, its vehicle (10% DMSO, n=4) had the same effect.
Haemorrhagic shock resulted in enhanced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, indicating the development of hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock also resulted in an increase in the serum levels of creatine kinase (CK) indicating the development of neuromuscular injury. This was attenuated by 3‐AB and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its vehicle had the same effect.
Thus, activation of PARS contributes to the organ injury and dysfunction caused by haemorrhage and resuscitation in the rat.

British Journal of Pharmacology (1999) 128, 1339–1345; doi:10.1038/sj.bjp.0702928
Endothelin alters the reactivity of vasa vasorum: mechanisms and implications for conduit vessel physiology and pathophysiology
Authors: Scotland Ramona , Vallance Patrick , Ahluwalia Amrita 
Published: January 2005

The walls of certain large blood vessels are nourished by the vasa vasorum, a network of microvessels that penetrate the adventitia and media of the vessel wall. The purpose of this study was to characterize endothelin‐1 (ET‐1)‐mediated contraction of vasa and to investigate whether threshold concentrations of ET‐1 alters the sensitivity to constrictors. Arterial vasa were dissected from the walls of porcine thoracic aorta and mounted in a tension myograph.
ET‐1 and ETB‐selective agonist, sarafotoxin 6c (S6c), produced concentration‐dependent contraction. ETA receptor antagonist, BQ123 (10 μM), caused a biphasic rightward shift of ET‐1 response curves. ETB receptor antagonist, BQ788 (1 μM), produced a rightward shift of response curves to ET‐1 and S6c of 5‐ and 80 fold respectively.
ET‐1 responses were abolished in Ca2+‐free PSS but unaffected by selective depletion of intracellular Ca2+ stores. Nifedipine (10 μM), an L‐type Ca2+ channel blocker, attenuated ET‐1 responses by 44%. Inhibition of receptor‐operated Ca2+ channels or non‐selective cation entry using SKF 96365 (30 μM) and Ni2+ (1 mM) respectively, attenuated ET‐1 contractions by 60%.
ET‐1 (1–3 nM) enhanced responses to noradrenaline (NA) (4 fold) but not to thromboxane A2‐mimetic, whilst K+ (10–20 mM) sensitized vasa to both types of constrictor.
Therefore, ET‐1‐induced contraction of isolated vasa is mediated by ETA and ETB receptors and involves Ca2+ influx through L‐type and non‐L‐type Ca2+ channels. Furthermore elevation of basal tone of vasa vasorum alters the profile of contractile reactivity. These results suggest that ET‐1 may be an important regulator of vasa vasorum reactivity.

British Journal of Pharmacology (1999) 128, 1229–1234; doi:10.1038/sj.bjp.0702930
Effects of antisense oligonucleotides on brain delta‐opioid receptor density and on SNC80‐induced locomotor stimulation and colonic transit inhibition in rats
Authors: Negri Lucia , Broccardo Maria , Lattanzi Roberta , Melchiorri Pietro 
Published: January 2005

To reduce the density of δ‐opioid receptor protein, five antisense phosphorothioate oligodeoxynucleotides (aODN), targeting the three exons of rat δ‐opioid receptor mRNA (DOR), were injected twice daily for 4 days or continuously infused for 7 days into brain lateral ventricles (i.c.v.) of Sprague‐Dawley rats. Rats acting as controls were infused or injected with a mismatch sequence (mODN) of each aODN. The density of opioid receptors in rat brain membranes was measured by saturation binding experiments using selective ligands for δ, μ and κ opioid receptors.
aODNs injected twice a day for 4 days left rat brain δ‐opioid receptor density unchanged. The ODN targeting the DOR nucleotide sequence 280–299 (aODN280–299, exon 2), decreased brain δ‐opioid receptor density significantly more than aODNs targeting exon 1 (aODN239–258), exon 2 (aODN361–380), or exon 3 (aODN741–760) (to 52% vs 79, 72, and 68%). None of the aODNs to the DOR changed the brain density of μ‐ or k‐opioid receptors.
When in a novel environment (but not when kept in their home cages), the locomotor activity of aODN280–299 treated rats was significantly lower than that of saline or mODN treated rats. The δ‐opioid agonist SNC80 (5 mg kg−1, s.c.) significantly and potently stimulated locomotion and delayed colonic propulsion in saline‐ and mODN‐infused rats, but left motor behaviour and colonic transit of δ‐knockdown rats unchanged.
The baseline nociceptive threshold and the antinociceptive response to morphine were unchanged in δ‐knockdown rats.

British Journal of Pharmacology (1999) 128, 1554–1560; doi:10.1038/sj.bjp.0702931
Pharmacological characterization of antagonists of the C5a receptor
Authors: Paczkowski Natalii J , Finch Angela M , Whitmore Jacqueline B , Short Anna J , Wong Allan K , Monk Peter N , Cain Stuart A , Fairlie David P , Taylor Stephen M 
Published: January 2005

Potent and highly selective small molecule antagonists have recently been developed by us for C5a receptors (C5aR) on human polymorphonuclear leukocytes (PMN). In this study we compared a new cyclic antagonist, F‐[OPdChaWR], with an acyclic derivative, MeFKPdChaWr, for their capacities to bind to C5aR on human PMN and human umbilical artery membranes. We also compared their inhibition of myeloperoxidase (MPO) secretion from human PMNs and their inhibition of human umbilical artery contraction induced by human recombinant C5a.
In both PMNs and umbilical artery, the cyclic and acyclic C5a antagonists displayed insurmountable antagonism against C5a. There were differences in selectivities for the C5aR with F‐[OPdChaWR] (pKb 8.64±0.21) being 30 times more potent than MeFKPdChaWr (pKb 7.16±0.11, P<0.05) in PMNs, but of similar potency (pKb 8.19±0.38 vs pKb 8.28±0.29, respectively) in umbilical artery. This trend was also reflected in their relative binding affinities, both antagonists having similar affinities (−logIC50 values) for C5aR in umbilical artery membranes (F‐[OPdChaWR], 7.00±0.46; MeFKPdChaWr, 7.23±0.17), whereas in PMN membranes the C5aR affinity of the cycle F‐[OPdChaWR] (7.05±0.06) was four times higher than that of acyclic MeFKPdChaWr (6.43±0.24, P<0.05).
In summary, the results reveal that these antagonists are insurmountable in nature against C5a for C5aR on at least two human cell types, and the differences in relative receptor binding affinities and antagonistic potencies against C5a are consistent with differences in receptors within these cell types. The nature of these differences is yet to be elucidated.

British Journal of Pharmacology (1999) 128, 1461–1466; doi:10.1038/sj.bjp.0702938
The adrenergic receptor agonist, clonidine, potentiates the anti‐parkinsonian action of the selective κ‐opioid receptor agonist, enadoline, in the monoamine‐depleted rat
Authors: Hill M P , Brotchie J M 
Published: January 2005

The treatment of Parkinson's disease relies predominantly upon dopamine replacement therapy, usually with l‐dihydroxyphenylalanine (L‐DOPA). However, side‐effects of long‐term treatment, such as L‐DOPA‐induced dyskinesias can be more debilitating than the disease itself. Non‐dopaminergic treatment strategies might therefore be advantageous.
The aim of this study was to investigate the potential anti‐parkinsonian efficacy of the κ‐opioid receptor agonist, enadoline, and the α‐adrenoreceptor agonist, clonidine, both alone or in combination, in the reserpine‐treated rat model of Parkinson's disease.
Rats were treated with reserpine (3 mg kg−1), and experiments carried out 18 h later, at which time they exhibited profound akinesia (normal animals 1251±228 mobile counts h−1, reserpine‐treated animals 9±2 mobile counts h−1). Both enadoline and clonidine increased locomotion in reserpine‐treated rats in a dose‐dependent manner. The maximum locomotor‐stimulating effect of enadoline alone was seen at a dose of 0.2 mg kg−1 (208±63 mobile counts h−1). The maximum effect of clonidine was seen at a dose of 2 mg kg−1 (536±184 mobile counts h−1).
Co‐administration of enadoline (0.1 mg kg−1) and clonidine (0.01–0.1 mg kg−1) at sub‐threshold doses, synergistically increased locomotion.
The synergistic stimulation of locomotion in the reserpine‐treated rat involved activation of κ‐opioid receptors and a combination of both α1 and α2‐adrenoreceptors.
The results presented suggest a need for further studies on the potential of stimulating κ‐opioid and/or α‐adrenoreceptors as a therapy for Parkinson's disease. Furthermore, the studies may offer potential mechanistic explanations of the ability of α2‐adrenergic receptor antagonist to reduce L‐DOPA‐induced dyskinesia in Parkinson's disease.

British Journal of Pharmacology (1999) 128, 1577–1585; doi:10.1038/sj.bjp.0702943