bluuebunny/crossref_metadata_2025_split huggingface dataset:
A neuromodulatory role for neuronal nitric oxide in the rabbit renal artery
Authors: Vials Amanda J , Crowe Rahima , Burnstock Geoffrey 
Published: August 2006

The effects of the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME) on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline were examined in the rabbit isolated renal artery with and without an intact endothelium. In addition, the effect of removing the endothelium from the renal artery on vasoconstrictor responses to transmural electrical nerve stimulation and noradrenaline was also investigated. Immunohistofluorescence techniques were carried out to determine if there were any nitrergic nerves supplying the renal artery.
The vasoconstriction produced in response to transmural electrical nerve stimulation (2–64 Hz) was significantly enhanced in the presence of L‐NAME (3×10−6, 10−5, 3×10−5 and 10−4 M).
L‐NAME (3×10−6, 10−5, 3×10−5 and 10−4 M) did not significantly affect the maximum vasoconstriction produced in response to noradrenaline. However, the noradrenaline dose‐response curve was significantly shifted to the left by the addition of L‐NAME (3×10−6, 10−5, 3×10−5 and 10−4 M).
The increase in the amplitude of the vasoconstriction, produced in response to transmural electrical nerve stimulation (16 Hz) and noradrenaline (10−5 M) in the presence of L‐NAME (10−5 M) was not observed when L‐arginine (10−3 M) was added in addition to L‐NAME (10−5 M).
Removing the endothelium did not significantly affect the response to transmural electrical nerve stimulation (1–64 Hz). The maximum vasoconstriction in response to noradrenaline was also unaffected by the removal of the endothelium. The pD2 value for noradrenaline obtained from vessels with no endothelium was significantly greater than the pD2 value obtained from vessels with an intact endothelium (5.90±0.11 and 5.16±0.03, respectively).
On renal artery segments with no endothelium L‐NAME (3×10−5 M) significantly enhanced the response to transmural electrical nerve stimulation (2–64 Hz). L‐NAME did not affect the maximum response to noradrenaline. However, there was a significant shift to the right of the noradrenaline dose‐response curve in the presence of L‐NAME (3×10−5 M).
Both nitric oxide synthase‐containing and NADPH‐diaphorase stained nerves were located on the adventitial‐medial border of the rabbit renal artery.
The present study has suggested a presynaptic inhibitory action for nitric oxide (probably derived from identified perivascular nitrergic nerves), on perivascular sympathetic vasoconstrictor nerve mediated responses of the rabbit renal artery. In contrast, the enhancement of the response to noradrenaline by L‐NAME can be attributed to inhibition of the synthesis of endothelium‐derived nitric oxide.

British Journal of Pharmacology (1997) 121, 213–220; doi:10.1038/sj.bjp.0701141
Interactions between imidazoline compounds and sulphonylureas in the regulation of insulin secretion
Authors: Mourtada Mirna , Brown Colin A. , Smith Stephen A. , Piercy Valerie , Chan Susan L. F. , Morgan Noel G. 
Published: August 2006

Imidazoline α2‐antagonist drugs such as efaroxan have been shown to increase the insulin secretory response to sulphonylureas from rat pancreatic B‐cells. We have investigated whether this reflects binding to an islet imidazoline receptor or whether α2‐adrenoceptor antagonism is involved.
Administration of (±)‐efaroxan or glibenclamide to Wistar rats was associated with a transient increase in plasma insulin. When both drugs were administered together, the resultant increase in insulin levels was much greater than that obtained with either drug alone.
Use of the resolved enantiomers of efaroxan revealed that the ability of the compound to enhance the insulin secretory response to glibenclamide resided only in the α2‐selective‐(+)‐enantiomer; the imidazoline receptor‐selective‐(−)‐enantiomer was ineffective.
In vitro, (+)‐efaroxan increased the insulin secretory response to glibenclamide in rat freshly isolated and cultured islets of Langerhans, whereas (−)‐efaroxan was inactive. By contrast, (+)‐efaroxan did not potentiate glucose‐induced insulin secretion but (−)‐efaroxan induced a marked increase in insulin secretion from islets incubated in the presence of 6 mM glucose.
Incubation of rat islets under conditions designed to minimize the extent of α2‐adrenoceptor signalling (by receptor blockade with phenoxybenzamine; receptor down‐regulation or treatment with pertussis toxin) abolished the capacity of (+)‐and (±)‐efaroxan to enhance the insulin secretory response to glibenclamide. However, these manoeuvres did not alter the ability of (±)‐efaroxan to potentiate glucose‐induced insulin secretion.
The results indicate that the enantiomers of efaroxan exert differential effects on insulin secretion which may result from binding to effector sites having opposite stereoselectivity. Binding of (−)‐efaroxan (presumably to imidazoline receptors) results in potentiation of glucose‐induced insulin secretion, whereas interaction of (+)‐efaroxan with a second site leads to selective enhancement of sulphonylurea‐induced insulin release.

British Journal of Pharmacology (1997) 121, 799–805; doi:10.1038/sj.bjp.0701172
Effect of calpain inhibitor I, an inhibitor of the proteolysis of IκB, on the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat
Authors: Ruetten Hartmut , Thiemermann Christoph 
Published: August 2006

We compared the effects of calpain inhibitor I (inhibitor of the proteolysis of IκB and, hence, of the activation of nuclear factor κB (NFκB)) and dexamethasone on (i) the circulatory failure, (ii) multiple organ dysfunction and (iii) induction of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclo‐oxygenase (COX‐2) in anaesthetized rats with endotoxic shock.
Injection of lipopolysaccharide (LPS, E. coli, 10 mg kg−1, i.v.) resulted in hypotension and a reduction of the pressor responses elicited by noradrenaline. This circulatory dysfunction was attenuated by pretreatment of LPS‐rats with calpain inhibitor I (10 mg kg−1, i.v., 2 h before LPS) or dexamethasone (1 mg kg−1, i.v.).
Endotoxaemia also caused rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) (hepatocellular injury), bilirubin and γ‐glutamyl transferase (γGT) (liver dysfunction), (iii) lipase (pancreatic injury) and (iv) lactate. Calpain inhibitor I and dexamethasone attenuated the liver injury, the pancreatic injury, the lactic acidosis as well as the hypoglycaemia caused by LPS. Dexamethasone, but not calpain inhibitor I, reduced the renal dysfunction caused by LPS.
Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX‐2 protein and activity in lung and liver, which was attenuated in LPS‐rats pretreated with calpain inhibitor I or dexamethasone.
Thus, calpain inhibitor I and dexamethasone attenuate (i) the circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury, lactic acidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX‐2 protein and activity in rats with endotoxic shock. We propose that prevention of the activation of NF‐κB in vivo may be useful in the therapy of circulatory shock or of disorders associated with local or systemic inflammation.

British Journal of Pharmacology (1997) 121, 695–704; doi:10.1038/sj.bjp.0701180
Interaction of a new bis‐indol derivative, KAR‐2 with tubulin and its antimitotic activity
Authors: Orosz Ferenc , Kovács János , Löw Péter , Vértessy Beáta G , Urbányi Zoltán , Ács Tibor , Keve Tibor , Ovádi Judit 
Published: August 2006

KAR‐2 (3″‐(β‐chloroethyl)‐2″,4″‐dioxo‐3,5″‐spiro‐oxazolidino‐4‐deacetoxy‐vinblastine), is a bis‐indol derivative; catharantine is coupled with the vindoline moiety which contains a substituted oxazolidino group. Our binding studies showed that KAR‐2 exhibited high affinity for bovine purified brain tubulin (Kd=3 μM) and it inhibited microtubule assembly at a concentration of 10 nM.
Anti‐microtubular activity of KAR‐2 was highly dependent on the ultrastructure of microtubules: while the single tubules were sensitive, the tubules cross‐linked by phosphofructokinase (ATP: D‐fructose‐6‐phosphate‐1‐phosphotransferase, EC 2.7.1.11) exhibited significant resistance against KAR‐2.
The cytoplasmic microtubules of Chinese hamster ovary mammalian and Sf9 insect cells were damaged by 1 μg ml−1 KAR‐2, as observed by indirect immunofluorescence and transmission electron microscopy. Scanning electron microscopy revealed intensive surface blebbing on both types of cells in the presence of KAR‐2.
KAR‐2 was effective in the mouse leukaemia P338 test in vivo without significant toxicity. Studies on a primary cerebro‐cortical culture of rat brain and differentiated PC12 cells indicated that the toxicity of KAR‐2 was significantly lower than that of vinblastine. The additional property of KAR‐2 that distinguishes it from bis‐indol derivatives is the lack of anti‐calmodulin activity.
Evidence that antipsychotic drugs are inverse agonists at D2 dopamine receptors
Authors: Hall David A. , Strange Philip G. 
Published: August 2006

The effects of a number of D2‐like dopamine receptor antagonists have been determined on forskolin‐stimulated cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing the human D2short dopamine receptor (CHO‐D2S cells).
Dopamine inhibited the effect of forskolin (as expected for a D2 receptor). However, all of the antagonists tested, apart from UH232 and (−)‐butaclamol, were able to increase cyclic AMP accumulation above the forskolin control level. (+)‐Butaclamol elicited a similar stimulation of forskolin‐stimulated cyclic AMP accumulation in a CHO cell line expressing human D2long dopamine receptors whereas it exhibited no stimulating effect on forskolin‐stimulated cyclic AMP accumulation in untransfected CHO‐K1 cells.
There was a strong correlation between the EC50 values of these compounds for potentiation of cyclic AMP accumulation and their Ki values from radioligand binding experiments in CHO‐D2S cells.
The effects of both (+)‐butaclamol and dopamine in CHO‐D2S cells were inhibited by pre‐treatment with pertussis toxin indicating a role for Gi/Go proteins.
UH232 did not significantly affect forskolin‐stimulated cyclic AMP accumulation but this substance was able to inhibit the effects of both dopamine and (+)‐butaclamol in a concentration‐dependent manner. Thus the effects of (+)‐butaclamol on forskolin‐stimulated cyclic AMP accumulation are mediated directly via the D2 receptor rather than by reversal of the effects of an endogenous agonist.
These data suggest that the D2 dopamine receptor antagonists tested here, many of which are used clinically as antipsychotic drugs, are in fact inverse agonists at human D2 dopamine receptors.

British Journal of Pharmacology (1997) 121, 731–736; doi:10.1038/sj.bjp.0701196
Pharmacological characterization of the vanilloid receptor in the rat dorsal spinal cord
Authors: Wardle Kay A , Ranson Jennie , Sanger Gareth J 
Published: August 2006

In the present study a novel 96‐well plate assay system was used to characterize pharmacologically the vanilloid receptor in the dorsal spinal cord of the rat. When activated, this receptor stimulates release of calcitonin gene‐related peptide (CGRP) from the central terminals of the afferent nerves.
Capsaicin, resiniferatoxin (RTX) and olvanil each evoked a concentration‐dependent increase in CGRP release with pEC50 values of 6.55±0.07, 7.90±0.24 and 6.19±0.15 respectively. RTX and olvanil were partial agonists with respect to capsaicin. All concentration‐effect curves were bell‐shaped.
The vanilloid receptor antagonist, capsazepine (10 μM) had no effect on basal peptide release but inhibited the CGRP release evoked by all 3 agonists to a similar extent. These results suggest that the antagonistic effects of capsazepine were agonist‐independent.
The capsaicin‐sensitive cation channel blocker, ruthenium red (10 μM) had no effect on basal CGRP release, but antagonized the peptide release evoked by capsaicin, olvanil and RTX.
The pharmacology of the vanilloid receptor in the rat dorsal spinal cord is not identical to that previously found in other systems. The reason for these differences is unclear, but the possibility of multiple classes of receptor cannot at this stage be ruled out.
Modulation of synovial blood flow by the calcitonin gene‐related peptide (CGRP) receptor antagonist, CGRP(8–37)
Authors: McMurdo Lorraine , Lockhart J C , Ferrell W R 
Published: August 2006

The effect of the calcitonin gene‐related peptide (CGRP) receptor antagonist, CGRP(8–37) on blood flow in the knee joint of the anaesthetized rat was investigated.
Synovial blood flow in both exposed and intact, skin‐covered knees was measured by laser Doppler perfusion imaging.
Topical application of CGRP(8–37) caused a dose‐dependent fall in synovial blood flow in the exposed knee joint of the rat. At low (1.5nmol) doses of CGRP(8–37) there was no significant effect on synovial blood flow. In rats treated with 7.5nmol CGRP(8–37) there was a fall in synovial blood flow (maximum effect at 10min: −28.8±4.6%; n=7), which returned to resting levels within 30min. The highest dose (15nmol) of antagonist used in this study caused a marked (maximum at 10min: −35.6±9.3%; n=8), and prolonged (up to 30min) fall in blood flow.
Ten days after surgical denervation, CGRP(8–37) (15nmol, topical) had no significant effect on blood flow in the rat exposed knee joint (change in flux at 10min: −5.1±3.6%; n=4). This suggests that CGRP(8–37) acts selectively to antagonize the actions of a neurally derived product, probably CGRP, on the rat synovial vasculature.
In skin‐covered knee joints, intra‐articular injection of CGRP(8–37) (15nmol; bolus) elicited a significant fall in synovial blood flow (maximum effect at 10min: −15.5±5.8%; n=6).
CGRP (0.01, 0.1 or 1.0nmol; topical) caused a dose‐dependent increase in exposed knee joint blood flow, which was attenuated by co‐administration of 1.5nmol CGRP(8–37). For example, 1nmol CGRP elicited a peak increase in flux at 10min of 94.7±31.8% (n=8) and 28.8±8.9% (n=7) in the absence and presence of CGRP(8–37), respectively. The vasodilator responses induced by acetylcholine (ACh) (10nmol, topical; n=4–5) or sodium nitroprusside (SNP) (10nmol, topical; n=4–5) were unaltered in the presence of CGRP(8–37) (1.5nmol, topical).
Thus, the CGRP receptor antagonist CGRP(8–37) elicits vasoconstriction in the rat synovium. This suggests that the endogenous, basal release of CGRP may play a physiological role in the regulation of blood flow in the rat knee joint.
Inhibition of muscarinic K+ current in guinea‐pig atrial myocytes by PD 81,723, an allosteric enhancer of adenosine binding to A1 receptors
Authors: Brandts B , Bünemann M , Hluchy J , Sabin G V , Pott L 
Published: August 2006

PD 81,723 has been shown to enhance binding of adenosine to A1 receptors by stabilizing G protein‐receptor coupling (‘allosteric enhancement’). Evidence has been provided that in the perfused hearts and isolated atria PD 81,723 causes a sensitization to adenosine via this mechanism.
We have studied the effect of PD 81,723 in guinea‐pig isolated atrial myocytes by use of whole‐cell measurement of the muscarinic K+ current (IK(ACh)) activated by different Gi‐coupled receptors (A1, M2, sphingolipid). PD 81,273 caused inhibition of IK(ACh) (IC50≃5μm) activated by either of the three receptors. Receptor‐independent IK(ACh) in cells loaded with GTP‐γ‐S and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to PD 81,723. At no combination of concentrations of adenosine and PD 81,723 could an enhancing effect be detected.
The compound was active from the outside only. Loading of the cells with PD 81,723 (50μm) via the patch pipette did not affect either IK(ACh) or its sensitivity to adenosine. We suggest that PD 81,723 acts as an inhibitor of inward rectifying K+ channels; this is supported by the finding that ventricular IK1, which shares a large degree of homology with the proteins (GIRK1/GIRK4) forming IK(ACh) but is not G protein‐gated, was also blocked by this compound.
It is concluded that the functional effects of PD 81,723 described in the literature are not mediated by the A1 adenosine receptor‐Gi‐IK(ACh) pathway.
Regulation of bradykinin B2‐receptor expression by oestrogen
Authors: Madeddu Paolo , Emanueli Costanza , Varoni Maria Vittoria , Demontis Maria Piera , Anania Vittorio , Gorioso Nicola , Chao Julie 
Published: August 2006

Tissue kallikrein is overexpressed in the kidney of female rats, this sexual dimorphism being associated with a greater effect of early blockade of bradykinin B2‐receptors on female blood pressure phenotype. We evaluated the effect of ovariectomy and oestradiol benzoate (50 μg kg−1 every two days for two weeks) on the vasodepressor response to intra‐arterial injection of bradykinin (150–900 ng kg−1) and on the expression of bradykinin B2‐receptors.
Ovariectomy reduced the magnitude of the vasodepressor response to bradykinin and unmasked a secondary vasopressor effect. Oestrogen replacement restored the vasodepressor response to bradykinin in ovariectomized rats.
The vasodepressor responses to sodium nitroprusside (3–18 μg kg−1), acetylcholine (30–600 ng kg−1), desArg9‐bradykinin (150–900 ng kg−1) or prostaglandin E2 (30–600 ng kg−1) were significantly reduced by ovariectomy. Oestrogen restored to normal the responses to desArg9‐bradykinin, acetylcholine and prostaglandin E2, but not that to sodium nitroprusside.
B2‐receptor mRNA levels were decreased by ovariectomy in the aorta and kidney and they were restored to normal levels by oestrogen. Neither ovariectomy nor oestradiol affected receptor expression in the heart and uterus.
These results indicate that oestrogen regulates B2‐receptor gene expression and function. Since kinins exert a cardiovascular protective action, reduction in their vasodilator activity after menopause might contribute to the increased risk of pathological cardiovascular events. Conversely, the cardioprotective effects of oestrogen replacement might be, at least in part, mediated by activation of the kallikrein‐kinin system.

British Journal of Pharmacology (1997) 121, 1763–1769; doi:10.1038/sj.bjp.0701255
Effects of captopril, losartan, and nifedipine on cell hypertrophy of cultured vascular smooth muscle from hypertensive Ren‐2 transgenic rats
Authors: Peiró Concepción , Llergo José L , Angulo Javier , López‐Novoa José M , Rodríguez‐López Ana , Rodríguez‐Mañas Leocadio , Sánchez‐Ferrer Carlos F 
Published: August 2006

We hypothesized that tissular renin‐angotensin system (RAS) induces vascular hypertrophy in hypertensive Ren‐2 transgenic rats (TGR; strain name TGR(mRen2)L27). This assumption was tested in cell cultures of vascular smooth muscle (VSMC) from both hypertensive TGR and control normotensive Sprague‐Dawley (SD) rats. Planar cell surface area, protein synthesis, and protein content per cell were studied, the role for locally produced angiotensin II (AII) was evaluated and the possible pharmacological interference by different drugs was analysed.
By use of radioimmunoassay techniques, AII could be determined in TGR cultures (10.25±0.12 pg per 107 cells) while it could not be detected in SD ones.
Under serum‐free conditions, VSMC from hypertensive TGR were hypertrophic when compared to SD VSMC, as they presented a higher protein content per cell (335±18 and 288±7 pg per cell respectively; P<0.05) and increased mean planar cell surface area, as determined by image analysis (4,074±238 and 4,764±204 μm2, respectively; P<0.05).
When exogenously added to cultured SD and TGR VSMC, AII (100 pM to 1 μM) promoted protein synthesis and protein content in a concentration‐dependent manner without affecting DNA synthesis. Maximal effects were observed at 100 nM. At this concentration, AII effectively increased planar cell surface area in both SD and TGR cultures by ∼20%.
Treatment of TGR cultures, in the absence of exogenous AII, with the angiotensin‐converting enzyme inhibitor captopril or the angiotensin AT1 receptors antagonist losartan (100 nM to 10 μM) reduced planar cell surface area in a concentration‐dependent manner. In addition, both captopril and losartan (10 μM), decreased protein synthesis by ∼15%.
Treatment of SD VSMC, in the absence of exogenous AII, with both captopril and losartan had no effect either on planar cell surface area or protein synthesis.
Treatment with the Ca2+ antagonist nifedipine (100 nM to 10 μM) reduced cell size in both SD and TGR cultures. Maximal cell reduction reached by nifedipine averaged 906±58 and 1,292±57 μm2, in SD and TGR, respectively (P<0.05). In addition, nifedipine, nitrendipine and nisoldipine (all at 10 μM) decreased protein synthesis in both cell types by 15–25%.
We concluded that cultured VSMC from TGR are hypertrophic in comparison with those from SD. This cell hypertrophy can be the consequence of the expression of the transgene Ren‐2 that activates a tissular RAS and locally produces AII, which acts in a paracrine, autocrine, or intracrine manner. Cell hypertrophy in TGR cultures could be selectively reduced by RAS blockade, while nifedipine decreased cell size and protein synthesis in both hypertrophic and non hypertrophic cells.