bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for VIP1/PACAP receptors in the afferent pathway mediating surgery‐induced fundic relaxation in the rat
Authors: Boeckxstaens G E , Hollmann M , Heisterkamp S H , Robberecht P , De Jonge W J , Van Den Wijngaard R M J G J , Tytgat G N J , Blommaart P J E 
Published: January 2005

We previously reported activation of an inhibitory adrenergic and a non‐adrenergic non‐cholinergic (NANC) pathway during abdominal surgery relaxing the rat gastric fundus. In the present study, we investigated the possible role of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) in the NANC part of the surgery‐induced fundic relaxation.
The effect of the NO biosynthesis inhibitor NG‐nitro‐L‐arginine (L‐NOARG), the non‐selective VIP receptor antagonist [D‐p‐Cl‐Phe6,Leu17]‐VIP and the selective VIP1 receptor antagonist [Acetyl‐His1,D‐Phe2,Lys15,Arg16,Leu17]‐VIP was investigated on the non‐adrenergic fundic relaxation induced by manipulation of the small intestine followed by resection of the caecum.
Guanethidine partly reduced the manipulation‐induced fundic relaxation. Addition of L‐NOARG reduced this non‐adrenergic component, whereas the non‐selective VIP receptor antagonist had no significant effect. Combination of L‐NOARG and the non‐selective VIP antagonist however further reduced the relaxation to manipulation.
The selective VIP1 receptor antagonist reduced the mean and maximal relaxation induced by abdominal surgery in the presence of guanethidine. When combined with L‐NOARG, the relaxation of the gastric fundus was almost completely abolished. The VIP1 receptor antagonist alone had no significant effect on the mean and maximal relaxation, but enhanced recovery of fundic tone.
In conclusion, as VIP1 receptors are not present in the rat gastric fundus, these results suggest that the NANC inhibitory pathway activated during abdominal surgery involves VIP1 receptors, most likely in the afferent limb. The inhibitory neurotransmitters released at the level of the gastric fundus smooth muscle are NO and a substance different from VIP.

British Journal of Pharmacology (2000) 131, 705–710; doi:10.1038/sj.bjp.0703625
Characterization of prostanoid receptors mediating contraction of the gastric fundus and ileum: studies using mice deficient in prostanoid receptors
Authors: Okada Yuji , Hara Akiyoshi , Ma Hong , Xiao Chun‐Yang , Takahata Osamu , Kohgo Yutaka , Narumiya Shuh , Ushikubi Fumitaka 
Published: January 2005

Receptors mediating prostanoid‐induced contractions of longitudinal sections of gastric fundus and ileum were characterized by using tissues obtained from mice deficient in each type and subtype of prostanoid receptors.
The fundus and ileum from mice deficient in either EP3 (EP3−/− mice), EP1 (EP1−/− mice) and FP (FP−/− mice) all showed decreased contraction to PGE2 compared to the tissues from wild‐type mice, whereas contraction of the fundus slightly increased in EP4−/− mice.
17‐phenyl‐PGE2 also showed decreased contraction of the fundus from EP3−/−, EP1−/− and FP−/− mice. Sulprostone showed decreased contraction of the fundus from EP3−/− and FP−/− mice, and decreased contraction of the ileum to this compound was seen in tissues from EP3−/−, EP1−/− and FP−/− mice. In DP−/− mice, sulprostone showed increased contraction.
DI‐004 and AE‐248 caused the small but concentration‐dependent contraction of both tissues, and these contractions were abolished in tissues obtained from EP1−/− and EP3−/− mice, respectively, but not affected in other mice.
Contractions of both fundus and ileum to PGF2α was absent at lower concentrations (10−9 to 10−7 M), and suppressed at higher concentrations (10−6 to 10−5 M) of the agonist in the FP−/− mice. Suppression of the contractions at the higher PGF2α concentrations was also seen in the fundus from EP3−/−, EP1−/− and TP−/− mice and in the ileum from EP3−/− and TP−/− mice.
Contraction of the fundus to PGD2 was significantly enhanced in DP−/− mice, and contractions of the fundus and ileum to this PG decreased in FP−/− and EP3−/− mice.
Contractions of both tissues to I‐BOP was absent at 10−9 to 10−7 M and much suppressed at higher concentrations in TP−/− mice. Slight suppression to this agonist was also observed in the tissues from EP3−/− mice.
PGI2 induced small relaxation of both tissues from wild‐type mice. These relaxation reactions were much potentiated in EP3−/− mice. On the other hand, significant contraction to PGI2 was observed in both tissues obtained from IP−/− mice.
These results show that contractions of the fundus and ileum induced by each prostanoid agonist are mediated by actions of this agonist on multiple types of prostanoid receptors and in some cases modified by its action on relaxant receptors.

British Journal of Pharmacology (2000) 131, 745–755; doi:10.1038/sj.bjp.0703627
Pharmacological evaluation of the role of cytochrome P450 in intracellular calcium signalling in rat pancreatic acinar cells
Authors: Bruce Jason I E , Elliott Austin C 
Published: January 2005

We have investigated whether the cytochrome P450 system is involved in Ca2+ signalling in rat pancreatic acinar cells. Intracellular free [Ca2+] ([Ca2+]i) was measured in collagenase‐isolated cells using fura‐2 microspectrofluorimetry and imaging.
The imidazole P450 inhibitor ketoconazole (5–50 μM) inhibited [Ca2+]i oscillations induced by cholecystokinin octapeptide (CCK). However, ketoconazole also raised baseline [Ca2+]i when applied in the absence of CCK. These effects were mimicked by 5–50 μM SKF96365, an imidazole widely used as an inhibitor of Ca2+ entry.
The non‐imidazole P450 inhibitor proadifen (SKF525A) inhibited CCK‐induced [Ca2+]i oscillations at a concentration of 10–50 μM. Proadifen alone caused intracellular Ca2+ release at 25 or 50 μM, but not at 10 μM.
Octadecynoic acid and 1‐aminobenzotriazole, structurally‐unrelated non‐imidazole P450 inhibitors, did not alter baseline [Ca2+]i or CCK‐evoked oscillations.
We compared cumulative CCK dose‐response relationship in control cells and in cells where P450 had been induced by prior injection of animals with β‐naphthoflavone. Only minor differences were apparent, with induced cells showing some decrease in responsiveness at moderate and higher concentration of CCK (30 pM–3 nM).
Direct assessment of depletion‐activated Ca2+ entry showed no clear differences between control and induced cells.
In conclusion, we could find no compelling evidence for a role of P450 in controlling Ca2+ signalling generally, or Ca2+ entry in particular, in pancreatic acinar cells. Induction of P450 is therefore probably toxic to acinar cells via a Ca2+‐independent mechanism.

British Journal of Pharmacology (2000) 131, 761–771; doi:10.1038/sj.bjp.0703631
Sub‐family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP‐specific phosphodiesterases
Authors: Baillie George S , MacKenzie Simon J , McPhee Ian , Houslay Miles D 
Published: January 2005

Expressed in intact cells and in vitro, PDE4B and PDE4C isoenzymes of cyclic nucleotide phosphodiesterase (PDE), in common with PDE4D isoenzymes, are shown to provide substrates for C‐terminal catalytic unit phosphorylation by the extracellular signal‐regulated kinase Erk2 (p42MAPK).
In contrast, PDE4A isoenzymes do not provide substrates for C‐terminal catalytic unit phosphorylation by Erk2.
Mutant PDE4 enzymes were generated to show that Erk2 phosphorylation occurs at a single, cognate serine residue located within the C‐terminal portion of the PDE4 catalytic unit.
PDE4 long‐form isoenzymes were markedly inhibited by Erk2 phosphorylation.
The short‐form PDE4B2 isoenzyme was activated by Erk2 phosphorylation.
These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.
Epidermal growth factor (EGF) challenge caused diametrically opposed changes in cyclic AMP levels in COS1 cells transfected to express the long PDE4B1 isoenzyme compared to cells expressing the short PDE4B2 isoenzyme.
We suggest that PDE4 enzymes may provide a pivotal point for integrating cyclic AMP and Erk signal transduction in cells with 4 genes encoding enzymes that are either insensitive to Erk2 action or may either be activated or inhibited. This indicates that PDE4 isoenzymes have distinct functional roles, giving credence to the notion that distinct therapeutic benefits may accrue using either PDE4 subfamily or isoenzyme‐selective inhibitors.

British Journal of Pharmacology (2000) 131, 811–819; doi:10.1038/sj.bjp.0703636
Adenosine A1 receptor stimulation inhibits α1‐adrenergic activation of the cardiac sarcolemmal Na+/H+ exchanger
Authors: Avkiran Metin , Yokoyama Hiroyuki 
Published: January 2005

Sarcolemmal Na+/H+ exchanger (NHE) activity is increased by stimulation of Gq protein‐coupled receptors (GqPCRs), but the roles of other GPCRs are largely unknown. We determined the effects of N‐[(1S,trans)‐2‐hydroxycyclopentyl]adenosine (GR79236), a selective agonist of the GiPCR adenosine A1 receptor, on sarcolemmal NHE activity in adult rat ventricular myocytes (n=8–10 per group). NHE activity was indexed by the H+ efflux rate after intracellular acidification, measured by microepifluorescence. GR79236 alone (0.01–10 μM) had no effect on NHE activity. However, co‐administration of GR79236 inhibited, in a concentration‐dependent manner, the stimulation of NHE activity by the α1‐adrenoceptor agonist phenylephrine (10 μM). The inhibitory effect of GR79236 (10 μM) was abolished by (1) the selective A1 antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (0.1 μM), confirming an A1 receptor‐mediated action, and (2) pre‐treatment with pertussis toxin (5 μg ml−1 for 60 min), indicating a Gi protein‐mediated mechanism. Our data suggest the existence of inhibitory crosstalk between the GiPCR adenosine A1 receptor and the GqPCR α1‐adrenoceptor in the regulation of sarcolemmal NHE activity.British Journal of Pharmacology (2000) 131, 659–662; doi:10.1038/sj.bjp.0703647
Inhibition of neuroeffector transmission in human vas deferens by sildenafil
Authors: Medina Pascual , Segarra Gloria , Torondel Belén , Chuan Pascual , Domenech Cristina , Vila José M , Lluch Salvador 
Published: January 2005

Sildenafil (0.1–30 μM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1–100 μM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1–100 μM) had no effect on neurogenic contractions. The inhibition induced by sildenafil was not modified by the inhibitor of guanylate cyclase 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxaline‐1‐one (ODQ) (1–30 μM) but it was abolished by the K+ channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 μM) and charybdotoxin (0.1 μM). Sildenafil, zaprinast and SNP did not affect the contractions induced by noradrenaline. SNP (10 μM) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10 μM) and zaprinast (100 μM). ODQ (10 μM) inhibited the increase in cyclic GMP. Sildenafil inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large‐conductance Ca2+‐activated K+ channels.British Journal of Pharmacology (2000) 131, 871–874; doi:10.1038/sj.bjp.0703657
Levamisole induced apoptosis in cultured vascular endothelial cells
Authors: Artwohl Michaela , Hölzenbein Thomas , Wagner Ludwig , Freudenthaler Angelika , Waldhäusl Werner , Baumgartner‐Parzer Sabina M 
Published: January 2005

To better understand the anticancer activity of Levamisole (LMS), which serves as an adjuvant in colon cancer therapy in combination with 5‐Fluorouracil, this study analyses LMS' ability to induce apoptosis and growth arrest in cultured human micro‐ and macrovascular endothelial cells (ECs) and fibroblasts.
Cells exposed (24 h) to Levamisole (range: 0.5–2 mmol l−1) alone or in combination with antioxidants (10 mmol l−1 glutathione or 5 mmol l−1 N‐Acetylcysteine or 0.1 mmol l−1 Tocopherol) were evaluated for apoptosis (3H‐thymidine assays, in situ staining), mRNA/protein expression (Northern/Western blot), and proliferation (3H‐thymidine incorporation).
Levamisole dose‐dependently increased apoptosis in ECs to 230% (HUVECs‐human umbilical vein ECs), 525% (adult human venous ECs) and 600% (human uterine microvascular ECs) but not in fibroblasts compared to control cells (set as 100%).
Levamisole increased in ECs integrin‐dependent matrix adhesion, inhibited proliferation (−70%), reduced expression of survival factors such as clusterin (−30%), endothelin‐1 (−43%), bcl‐2 (−34%), endothelial NO‐synthase (−32%) and pRb (Retinoblastoma protein: −89%), and increased that of growth arrest/death signals such as p21 (+73%) and bak (+50%).
LMS (2 mmol l−1)‐induced apoptosis was inhibited by glutathione (−50%) and N‐Acetylcysteine (−36%), which also counteracted reduction by Levamisole of pRb expression, suggesting reactive oxygen species and pRb play a role in these processes.
The ability of LMS to selectively induce apoptosis and growth arrest in endothelial cells potentially hints at vascular targeting to contribute to Levamisole's anticancer activity.

British Journal of Pharmacology (2000) 131, 1577–1583; doi:10.1038/sj.bjp.0703660
Modulation of histamine H2 receptor signalling by G‐protein‐coupled receptor kinase 2 and 3
Authors: Rodriguez‐Pena Maria Sol , Timmerman Henk , Leurs Rob 
Published: January 2005

To evaluate the role of G‐protein‐coupled receptor kinases (GRK) in the desensitization of the histamine H2 receptor, the H2 receptor was transiently cotransfected with GRK2, 3, 5 or 6 in COS‐7 cells and the cyclic AMP levels in response to histamine were studied.
Coexpression of the H2 receptor with GRK2 and 3 significantly decreased both the basal cyclic AMP levels and the cyclic AMP response to 100 μM histamine. Moreover, preincubation with 100 μM histamine desensitized the H2 receptor response to 53±8%. Coexpression of GRK2 and 3 increased the H2 receptor desensitization to 27±4% and 24±4% respectively. No effect on either cyclic AMP response or desensitization was found when GRK5, GRK6 or dominant negative mutants of GRK2 or 3 (GRK2K220R and GRK3K220R) were coexpressed.
To study the role of the C‐terminal tail in the GRK‐mediated desensitization of the H2 receptor, three truncations of C‐tail were constructed: H2T295, H2T307 and H2T341. H2T307 and 341 H2T341 expressed and responded normally to 100 μM histamine. The interaction of the H2 receptor with GRK2 and 3 was also not altered upon truncation of the C‐terminal tail.
These findings strongly suggest a role of GRK2 and 3 in the desensitization of the H2 receptor. Furthermore, the finding that C‐terminal truncations of the H2 receptor did not abolish the effect of GRK2 and 3 suggests that the C‐terminus is not involved in the GRK mediated desensitization of the histamine H2 receptor.

British Journal of Pharmacology (2000) 131, 1707–1715; doi:10.1038/sj.bjp.0703676
Differential vasoconstrictor activity of human urotensin‐II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey
Authors: Douglas Stephen A , Sulpizio Anthony C , Piercy Valerie , Sarau Henry M , Ames Robert S , Aiyar Nambi V , Ohlstein Eliot H , Willette Robert N 
Published: January 2005

Urotensin‐II (U‐II) and its G‐protein‐coupled receptor, GPR14, are expressed within mammalian cardiac and peripheral vascular tissue and, as such, may regulate mammalian cardiovascular function. The present study details the vasoconstrictor profile of this cyclic undecapeptide in different vascular tissues isolated from a diverse range of mammalian species (rats, mice, dogs, pigs, marmosets and cynomolgus monkeys).
The vasoconstrictor activity of human U‐II was dependent upon the anatomical origin of the vessel studied and the species from which it was isolated. In the rat, constrictor responses were most pronounced in thoracic aortae and carotid arteries: −log[EC50]s 9.09±0.19 and 8.84±0.21, Rmaxs 143±21 and 67±26% 60 mM KCl, respectively (compared, for example, to −log[EC50] 7.90±0.11 and Rmax 142±12% 60 mM KCl for endothelin‐1 [ET‐1] in thoracic aortae). Responses were, however, absent in mice aortae (−log[EC50] <6.50). These findings were further contrasted by the observation that U‐II was a ‘coronary‐selective’ spasmogen in the dog (−log[EC50] 9.46±0.11, Rmax 109±23% 60 mM KCl in LCX coronary artery), yet exhibited a broad spectrum of vasoconstrictor activity in arterial tissue from Old World monkeys (−log[EC50]s range from 8.96±0.15 to 9.92±0.13, Rmaxs from 43±16 to 527±135% 60 mM KCl). Interestingly, significant differences in reproducibility and vasoconstrictor efficacy were seen in tissue from pigs and New World primates (vessels which responded to noradrenaline, phenylephrine, KCl or ET‐1 consistently).
Thus, human U‐II is a potent, efficacious vasoconstrictor of a variety of mammalian vascular tissues. Although significant species/anatomical variations exist, the data support the hypothesis that U‐II influences the physiological regulation of mammalian cardiovascular function.

British Journal of Pharmacology (2000) 131, 1262–1274; doi:10.1038/sj.bjp.0703690
Chamber‐specific alterations of noradrenaline uptake (uptake1) in right ventricles of monocrotaline‐treated rats
Authors: Leineweber Kirsten , Seyfarth Torsten , Brodde Otto‐Erich 
Published: January 2005

In rats a single injection of the alkaloid monocrotaline (60 mg MCT kg−1 body weight, i.p.) caused right ventricular hypertrophy and heart failure. The aim of this study was to find out whether, in these MCT‐treated rats, the cardiac neuronal noradrenaline uptake (uptake1) might undergo chamber‐specific alterations.
For this purpose we assessed in right and left ventricular slices, uptake1 activity (by [3H]‐noradrenaline accumulation), and in right and left ventricular membranes, uptake1 carrier protein density (by [3H]‐nisoxetine binding).
Uptake1‐inhibitors blocked [3H]‐noradrenaline accumulation in ventricular slices and [3H]‐nisoxetine binding in ventricular membranes with the order of potency: desipramine>nisoxetine>>cocaineGBR 12909, indicating that with both approaches noradrenaline uptake1 was determined.
In right ventricular slices of MCT‐treated rats uptake1 activity was significantly lower than in control rats (84.7±8.2 vs 145.1±6.2 pmol noradrenaline mg−1 tissue 15 min−1; P<0.05). This was accompanied by a significant decrease in the density of [3H]‐nisoxetine binding sites (73.7±14.4 vs 125.9±9.1 fmol mg−1 protein; P<0.05).
In left ventricular slices of MCT‐treated rats uptake1 activity was not significantly altered (131.2±10.5 vs 116.1±5.2 pmol noradrenaline mg−1 tissue 15 min−1); similarly, also the density of [3H]‐nisoxetine binding sites was unchanged (108±9.7 vs 123±7.7 fmol mg−1 protein).
We conclude that in MCT‐treated rats with right ventricular hypertrophy and heart failure uptake1 activity is chamber‐specifically reduced possibly due to a decrease in carrier protein density.

British Journal of Pharmacology (2000) 131, 1438–1444; doi:10.1038/sj.bjp.0703698
Pertussis toxin‐sensitive Gi‐proteins and intracellular calcium sensitivity of vasoconstriction in the intact rat tail artery
Authors: Spitzbarth‐Régrigny E , Petitcolin M ‐A , Bueb J ‐L , Tschirhart E J , Atkinson J , Capdeville‐Atkinson C 
Published: January 2005

We studied the involvement of pertussis toxin (PTX)‐sensitive G‐proteins in the sensitivity of arterial constriction to intracellular calcium ([Ca2+]i) mobilization.
Vasoconstriction was measured in vitro in perfused, de‐endothelialized rat tail arteries loaed with the calcium‐sensitive dye, fura‐2 and treated or not with PTX (30–1000 ng ml−1). Arteries were stimulated with noradrenaline (NA, 0.1–100 μM) or KCl (15–120 mM).
KCl elicited a smaller vasoconstrictor response (Emax=94±8 mmHg) than NA (Emax=198±9 mmHg) although [Ca2+]i mobilization was similar (Emax=123±8 and 135±7 nM for KCl and NA, respectively). PTX (1000 ng ml−1) had no effect on [Ca2+]i mobilization but lowered NA‐ (but not KCl‐) induced vasoconstriction (Emax=118±7 mmHg).
Gi/o‐proteins were revealed by immunoblotting with anti‐Giα and anti‐Goα antibodies in membranes prepared from de‐endothelialized tail arteries. [α32P]‐ADP‐ribosylation of G‐proteins by PTX (1000 ng ml−1) was demonstrated in the intact rat tail artery (pixels in the absence of PTX: 3150, presence: 25053).
In conclusion, we suggest that smooth muscle cells possess a PTX‐sensitive Gi‐protein‐mediated intracellular pathway which amplifies [Ca2+]i sensitivity of contraction in the presence of agonists such as NA.

British Journal of Pharmacology (2000) 131, 1337–1344; doi:10.1038/sj.bjp.0703703
Effects of castration on contraction and α1‐adrenoceptor expression in rat prostate
Authors: Homma Yukio , Hamada Kozo , Nakayama Yasuhisa , Tsujimoto Gozoh , Kawabe Kazuki 
Published: January 2005

The prostate function is regulated by androgens and α‐adrenergic activity. Clinically, antiandrogens and/or α1‐adrenergic antagonists are commonly used to treat symptomatic prostatic hypertrophy. To elucidate the effects of androgen deprivation on prostate contractility via α1‐adrenoceptor, the characteristics and expression of α1‐adrenoceptors were examined in castrated rats.
Isolated prostate strips from intact and castrated rats were subjected to a phenylephrine stimulated contraction. Prazosin (10 nM), [3H]‐prazosin and phenoxybenzamine (3–300 nM) were used for inhibition assay, receptor characterization and partial alkylation of α‐adrenoceptor, respectively. The mRNA content of three subtypes of α‐adrenoceptors was determined by reverse transcription combined with polymerase chain reaction (RT–PCR).
Contractile response to phenylephrine increased in castrated rats, which could be explained by a relative increase of the stromal component. A lowered contraction potency was also noted in castrated rats. Receptor binding assay indicated minimal changes in the affinity or density of α1‐adrenoceptor. Escalating alkylation of the α1‐adrenoceptor population resulted in a rightward shift in the contraction‐response curves before depressing maximal contractile force, and the suppression was detected at lower doses in castrated rats. RT–PCR study confirmed the expression of three types of α1‐adrenoceptor, α1a, α1b and α1d‐adrenoceptors, in intact rat prostate, and revealed that α1a‐adrenoceptor, but not α1b or α1d‐adrenoceptors, was down‐regulated in castrates.
The results show that androgen deprivation suppressed α1‐adrenergic contractility of rat prostate strips, and the suppression was associated with down‐regulation of receptor reserve for the α1a‐adreneroceptor population expressed in intact rat prostate.

British Journal of Pharmacology (2000) 131, 1454–1460; doi:10.1038/sj.bjp.0703706