bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of central melanocortin receptors by MT‐II increases cavernosal pressure in rabbits by the neuronal release of NO
Authors: Vemulapalli Rao , Kurowski Stan , Salisbury Brian , Parker Eric , Davis Harry 
Published: January 2005

Melanotan‐II had been reported to cause penile erections in men with erectile dysfunction. In the present study, we investigated the mechanisms by which systemic administration of MT‐II increases intracavernosal pressure in anaesthetized rabbits.
MT‐II (10 μM) had no effect on electrical field stimulation‐evoked relaxations of rabbit corpus cavernosal strips in vitro.
Intravenous injection of MT‐II (66 and 133 μg kg−1 elicited dose‐related increases in cavernosal pressure. SHU 9119 (3 μg kg−1, i.v.), a non‐selective antagonist of MC3 and MC4 receptors did not significantly affect either cavernosal pressure or systemic blood pressure but abolished the MT‐II‐induced increases in cavernosal pressure. SHU 9119 also inhibited the depressor response produced by MT‐II.
Intracavernosal injection 100 μl of the cocktail containing phentolamine mesylate (1 mg ml−1), papaverine (20 mg ml−1) and PGE1 (20 μg ml−1) increased the cavernosal pressure by about 4 fold.
The role of NO‐cyclic GMP dependent pathway to MT‐II‐induced increases in cavernosal pressure was investigated by bilateral transection of the pudendal nerves and by inhibition of NO synthase with L‐NAME (20 mg kg−1, i.v. over 30 min). Ablation of the pudendal nerves or pretreatment with L‐NAME abolished the MT‐II‐induced increases in intracavernosal pressure in anaesthetized rabbits.
The data suggest that activation of central melanocortin receptors by MT‐II increases cavernosal pressure by the neuronal release of NO.

British Journal of Pharmacology (2001) 134, 1705–1710; doi:10.1038/sj.bjp.0704437
Cardioselectivity of the sulphonylurea HMR 1098: studies on native and recombinant cardiac and pancreatic KATP channels
Authors: Manning Fox Jocelyn E , Kanji Hussein D , French Robert J , Light Peter E 
Published: January 2005

In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP‐sensitive potassium (KATP) channels from cardiac ventricular myocytes, the INS‐1 β‐cell line and from recombinant KATP channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,ΔC26. Recombinant channels were expressed in tsA201 or COS‐1 cells.
The effects of HMR 1098 on single channel and whole‐cell currents were recorded using the patch‐clamp technique.
At the single channel level, using excised inside‐out membrane patches, HMR 1098 inhibited KATP channels from ventricular cells and INS‐1 cells with IC50s of 0.88 and 720 μM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 KATP channels. HMR 1098 inhibition of SUR2A/Kir6.2 KATP channels was unaffected by the presence of internal ADP.
In whole‐cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/Kir6.2 currents with IC50s of 2.1 and 860 μM respectively. HMR 1098 was without effect on currents either from the Kir6.2,ΔC26 truncation mutant or from Kir2.1.
Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac KATP channels, showing a 400–800‐fold selectivity over β‐cell KATP channels. The non‐aromatic substitutions in the sulphonylurea moiety greatly increase the cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative.

British Journal of Pharmacology (2002) 135, 480–488; doi:10.1038/sj.bjp.0704455
Role of tachykinin NK receptors on the local and remote injuries following ischaemia and reperfusion of the superior mesenteric artery in the rat
Authors: Souza Danielle G , Mendonça Vanessa A , Castro Maria Salete de A , Poole Steve , Teixeira Mauro M 
Published: January 2005

Neuropeptides acting on tachykinin NK receptors play an important role in the amplification of inflammatory responses. We have assessed the effects of tachykinin NK receptor blockade on the injuries following intestinal ischaemia and reperfusion (I/R) in rats.
The tachykinin NK1 receptor antagonist SR140333 dose‐dependently (0.05 to 0.5 mg kg−1) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. A structurally‐distinct NK1 receptor antagonist, CP99,994, but not tachykinin NK2 or NK3 receptor antagonists also suppressed mild I/R injury.
Neonatal pretreatment with capsaicin effectively depleted sensory neurons and abrogated the injuries following mild I/R.
Treatment with SR140333 (0.5 mg kg−1) significantly reversed severe reperfusion‐induced local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and blood neutropaenia, but did not prevent the lethality associated with severe I/R.
Post‐ischaemic treatment with SR140333 significantly inhibited the elevations of TNF‐α in the intestine and lung, but not serum, following severe I/R. The increase in the concentrations of IL‐10 in the lung and serum were also suppressed.
Post‐ischaemic blockade of tachykinin NK1 receptors markedly inhibited the local and remote injuries, but not lethality, following reperfusion of the SMA in rats. Neuropeptides, possibly substance P, released from sensory nerves appear to account for the activation of these tachykinin NK1 receptors. Antagonists of the tachykinin NK1 receptor may be useful adjuncts in the treatment of the injuries which occur following reperfusion of an ischaemic vascular territory.

British Journal of Pharmacology (2002) 135, 303–312; doi:10.1038/sj.bjp.0704464
Contribution of cytochrome P450 metabolites to bradykinin‐induced vasodilation in endothelial NO synthase deficient mouse hearts
Authors: Ding Zhaoping , Gödecke Axel , Schrader Jürgen 
Published: January 2005

We have characterized the contribution of endothelial nitric oxide synthase (eNOS), cyclo‐oxygenase (COX) and cytochrome P450 (CYP450) to the bradykinin (BK)‐ induced vasodilation in isolated hearts from wildtype (WT) and eNOS deficient mice (eNOS−/−).
The endothelium‐dependent vasodilation by bradykinin (BK, 1 μM) was significantly lower in eNOS−/− hearts than that in WT hearts (+247% and +325% of basal flow, respectively), while there was no difference in the endothelium‐independent vasodilation by adenosine.
In WT hearts, the BK‐induced vasodilation was markedly attenuated following inhibition of NOS with ETU (10 μM) but not after COX inhibition with diclofenac (3 μM) (P<0.01). In line with this finding, Bk did not increase the cardiac prostacyclin release as measured by ELISA for 6‐keto‐PGF1α in the coronary venous effluent. In eNOS−/− hearts, the flow response to BK was insensitive to both NOS and COX inhibition.
The NOS/COX‐independent vasodilatory factor which remained under L‐NMMA+DF application was almost completely eliminated by either clotrimazole (3 μM), miconazole (0.5 μM) or 17‐ODYA (1 μM), suggesting that it was a metabolite of CPY450 enzymes. Sulfaphenazole (10 μM), a CYP450 2C inhibitor, exerted only a minimal inhibitory effect.
In eNOS−/− hearts the effect of CYP450 inhibitors on the BK response was significantly more pronounced than in WT hearts, indicating an enhanced contribution of CYP450 enzymes.
These findings suggest that in isolated mouse hearts the BK‐induced vasodilation is mediated by NO and CYP450 metabolites but not by prostaglandins. The CYP450 dependent vasodilator was was functionally up‐regulated in eNOS−/− hearts and thus likely to compensate for the loss of eNOS in the coronary circulation.

British Journal of Pharmacology (2002) 135, 631–638; doi:10.1038/sj.bjp.0704472
Different glucocorticoids vary in their genomic and non‐genomic mechanism of action in A549 cells
Authors: Croxtall Jamie D , Van Hal Peter Th W , Choudhury Qam , Gilroy Derek W , Flower Rod J 
Published: January 2005

We have examined the effects of 12 glucocorticoids as inhibitors of A549 cell growth.
Other than cortisone and prednisone, all the glucocorticoids inhibited cell growth and this was strongly correlated (r=0.91) with inhibition of prostaglandin (PG)E2 formation.
The molecular mechanism by which the active steroids prevented PGE2 synthesis was examined and three groups were identified. Group A drugs did not inhibit arachidonic acid release but inhibited the induction of COX2. Group B drugs were not able to inhibit the induction of COX2 but inhibited arachidonic acid release through suppression of cPLA2 activation. Group C drugs were apparently able to bring about both effects.
The inhibitory actions of all steroids was dependent upon glucocorticoid receptor occupation since RU486 reversed their effects. However, group A acted through the NF‐κB pathway to inhibit COX2 as the response was blocked by the inhibitor geldanamycin which prevents dissociation of GR and the effect was blocked by APDC, the NF‐κB inhibitor. On the other hand, the group B drugs were not inhibited by NF‐κB inhibitors or geldanamycin but their effect was abolished by the src inhibitor PP2. Group C drugs depended on both pathways.
In terms of PGE2 generation, there is clear evidence of two entirely separate mechanisms of glucocorticoid action, one of which correlates with NF‐κB mediated genomic actions whilst the other, depends upon rapid effects on a cell signalling system which does not require dissociation of GR. The implications for these findings are discussed.

British Journal of Pharmacology (2002) 135, 511–519; doi:10.1038/sj.bjp.0704474
Functional characterization of an endogenous Xenopus oocyte adenosine receptor
Authors: Kobayashi Toru , Ikeda Kazutaka , Kumanishi Toshiro 
Published: January 2005

To investigate the effects of adenosine on endogenous Xenopus oocyte receptors, we analysed defolliculated oocytes injected with mRNAs for the G protein‐activated inwardly rectifying K+ (GIRK) channels.
In oocytes injected with mRNAs for either GIRK1/GIRK2 or GIRK1/GIRK4 subunits, application of adenosine or ATP reversibly induced inward K+ currents, although ATP was less potent than adenosine. The responses were attenuated by caffeine, a non‐selective adenosine receptor antagonist. Furthermore, in uninjected oocytes from the same donor, adenosine produced no significant current.
The endogenous receptor was activated by two selective A1 adenosine receptor agonists, N6‐cyclopentyladenosine (CPA) and N6‐cyclohexyladenosine (CHA), and antagonized by a selective A1 adenosine receptor antagonist, 1,3‐dipropyl‐8‐cyclopenylxanthine (DPCPX) at moderate nanomolar concentrations, but insensitive to micromolar concentrations of selective A2A and A3 adenosine receptor agonists, 2‐[p‐(2‐carbonyl‐ethyl)‐phenylethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS21680) and N6‐(3‐iodobenzyl)‐5′‐(N‐methylcarbamoyl)adenosine (IB‐MECA), respectively. However, the pharmacological characteristics of the receptor were different from those of the cloned Xenopus A1 adenosine receptor and previously proposed adenosine receptors.
The adenosine‐induced GIRK currents were abolished by injection of pertussis toxin and CPA inhibited forskolin‐stimulated cyclic AMP accumulation.
We conclude that an adenosine receptor on the Xenopus oocyte membrane can activate GIRK channels and inhibit adenylyl cyclase via Gi/o proteins. Moreover, our results suggest the existence of an endogenous adenosine receptor with the unique pharmacological characteristics. As the receptor was activated by nanomolar concentrations of adenosine, which is a normal constituent of extracellular fluid, the receptor may be involved in some effects through the Gi/o protein signalling pathways in ovarian physiology.

British Journal of Pharmacology (2002) 135, 313–322; doi:10.1038/sj.bjp.0704475
Nucleotide‐mediated relaxation in guinea‐pig aorta: selective inhibition by MRS2179
Authors: Kaiser Robert A , Buxton Iain L O 
Published: January 2005

The vasodilatory effects of nucleotides in the guinea‐pig thoracic aorta were examined to determine the relationship between molecular expression and function of P2Y receptors.
In aortic rings precontracted with norepinephrine, vasodilatory responses to purine nucleotides exhibited a rank‐order of potency of 2‐methylthio‐ATP>ADP>ATP. Responses to UTP, but not UDP suggested a functional role for P2Y4 but not P2Y6 receptors.
Aortic endothelial cells express at least four P2Y receptors; P2Y1, P2Y2, P2Y4 and P2Y6. In primary culture, these cells exhibit desensitizing transient calcium responses characteristic of P2Y1, P2Y2 and P2Y4, but not P2Y6 receptors. UDP had no effect on endothelial cell calcium.
The pyrimidinergic receptor agonist UTP is capable of eliciting robust vasodilation in aortic rings and causing calcium responses in cultured guineapig aortic endothelial cells. These responses are equivalent to the maximum responses observed to ATP and ADP.
Measurement of intracellular calcium release in response to ATP and 2‐methylthio‐ATP were similar, however only the 2‐methylthio‐ATP response was sensitive to the P2Y1 antagonist N6‐methyl‐2′‐deoxyadenosine‐3′,5′‐bisphosphate (MRS2179). In aortic rings, vasodilatory responses to 2‐methylthio‐ATP, ATP and ADP were all blocked by pre‐incubation of tissues with MRS2179.
MRS2179 pretreatment had no effect of the ability of UTP to cause relaxation of norepinephrine responses in aortic rings or the ability of UTP to cause calcium release in aortic endothelial cells.
We demonstrate robust effects of purine and pyrimidine nucleotides in guineapig aorta and provide functional and biochemical evidence that MRS2179 is a selective P2Y1 antagonist.

British Journal of Pharmacology (2001) 135, 537–545; doi:10.1038/sj.bjp.0704476
Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes – functional importance of phosphodiesterase 4
Authors: Tenor Hermann , Hedbom Erik , Häuselmann Hans‐Jörg , Schudt Christian , Hatzelmann Armin 
Published: January 2005

We studied whether selective inhibitors of cyclic nucleotide hydrolysing phosphodiesterase (PDE) isoenzymes influence IL‐1β‐induced nitric oxide (NO) release from human articular chondrocytes. In addition, the pattern of PDE isoenzymes contributing to cyclic nucleotide hydrolysis in human chondrocytes was characterized.
Chondrocytes were isolated from human osteoarthritic cartilage and cultured in alginate beads. IL‐1β‐induced chondrocyte products (nitric oxide and prostaglandin E2) were measured in culture supernatants after 48 h incubation time. PDE activities were assessed in chondrocyte lysates. Inducible nitric oxide synthase (iNOS) and PDE4A‐D proteins were detected by immunoblotting.
The selective PDE4 inhibitors Piclamilast and Roflumilast partially attenuated IL‐1β‐induced NO production whereas selective inhibitors of PDE2 (EHNA), PDE3 (Motapizone) or PDE5 (Sildenafil) were inactive. Indomethacin reversed the reduction of IL‐1β‐induced NO by PDE4 inhibitors. It was shown that autocrine prostaglandin E2 (PGE2) enabled PDE4 inhibitors to reduce IL‐1β‐induced NO in this experimental setting.
Major PDE4 and PDE1 activities were identified in chondrocyte lysates whereas only minor activities of PDE2, 3 and 5 were found. IL‐1β and cyclic AMP‐mimetics upregulated PDE4 activity and this was associated with an augmentation of PDE4B2 protein.
Based on the view that nitric oxide contributes to cartilage degradation in osteoarthritis our study suggests that PDE4 inhibitors may have chondroprotective effects.

British Journal of Pharmacology (2002) 135, 609–618; doi:10.1038/sj.bjp.0704480
Characterization of the non‐nitrergic NANC relaxation responses in the rabbit vaginal wall
Authors: Ziessen Tom , Moncada Salvador , Cellek Selim 
Published: January 2005

Electrical field stimulation (EFS)‐induced non‐adrenergic non‐cholinergic (NANC) relaxation responses in the rabbit vaginal wall were investigated.
These NANC responses were partially inhibited with the nitric oxide synthase (NOS) inhibitors NG‐nitro‐L‐arginine methyl ester (L‐NAME; 500 μM), NG‐nitro‐L‐arginine (300 μM) or N‐iminoethyl‐L‐ornithine (500 μM) or the selective soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ, 10 μM). Application of L‐NAME and ODQ concomitantly did not increase the degree of inhibition.
L‐NAME or ODQ were observed to be more effective at low frequencies. The resistant part of the responses was more pronounced at higher frequencies and was completely inhibited by tetrodotoxin (1 μM).
Exogenous application of the peptides vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP‐27 and PACAP‐38), peptide histidine methionine (PHM), peptide histidine valine (PHV), helospectin‐I or ‐II induced a relaxation response. Calcitonin gene‐related peptide or substance P did not cause any relaxation.
The peptidase α‐chymotrypsin (type II; 2 units ml−1) did not affect non‐nitrergic NANC responses, although it did inhibit relaxation responses elicited by exogenous VIP, PACAP‐27, PACAP‐38, PHM, PHV, helospectin‐I or ‐II.
K+ channel inhibitors apamin (1 μM) or charybdotoxin (100 nM) when used alone or in conjunction did not affect non‐nitrergic NANC responses.
The non‐nitrergic NANC responses were not associated with any increase in intracellular cyclic adenosine‐3′, 5′‐monophosphate (cyclic AMP) or cyclic guanosine‐3′, 5′‐monophosphate (cyclic GMP) concentrations. The peptide‐induced relaxations were all associated with increases in cyclic AMP concentrations.
These results suggest that a neuronal factor elicits non‐nitrergic NANC responses in the rabbit vaginal wall. The identity of this factor remains to be established.

British Journal of Pharmacology (2002) 135, 546–554; doi:10.1038/sj.bjp.0704481
Uraemic toxins induce proximal tubular injury via organic anion transporter 1‐mediated uptake
Authors: Motojima Masaru , Hosokawa Atsuko , Yamato Hideyuki , Muraki Takamura , Yoshioka Toshimasa 
Published: January 2005

A direct effect of uraemic toxins in promoting progression of chronic renal disease has not been established. In this study, we investigated the toxic effects of organic anions which characteristically appeared in the patients with progressive renal disease on renal proximal tubular cells expressing human organic anion transporter (hOAT) 1.
A renal proximal tubular cell line, opossum kidney (OK) cells, was transformed with hOAT1. Among the organic anions examined, hippuric acid, para‐hydroxyhippuric acid, ortho‐hydroxyhippuric acid, indoxyl sulphate and indoleacetic acid showed a high affinity for hOAT1 expressed in the OK cells. Indoxyl sulphate and indoleacetic acid concentration‐dependently inhibited proliferation of the hOAT1‐transformed cells. The h.p.l.c. analysis demonstrated that cellular uptake of these organic anions was significantly elevated in hOAT1‐transformed cells.
These organic anions also concentration‐dependently stimulated cellular free radical production. The degrees of inhibition of cell proliferation and the stimulation of free radical production induced by the organic anions were significantly higher in the hOAT1‐transformed cells than vector‐transformed cells. The stimulatory effect of indoxyl sulphate on free radical production was abolished by anti‐oxidants and probenecid.
Less free radical production was observed in the hOAT1‐transformed cells treated with p‐hydroxyhippuric acid, o‐hydroxyhippuric acid compared with indoxyl sulphate and indoleacetic acid. Hippuric acid had little effect on free radical production.
Organic anions present in the serum of patients with progressive renal disease may cause proximal tubular injury via hOAT1‐mediated uptake. The mechanism of cellular toxicity by these uraemic toxins involves free radical production. Thus, some uraemic toxins may directly promote progression of chronic renal disease.

British Journal of Pharmacology (2002) 135, 555–563; doi:10.1038/sj.bjp.0704482
Pharmacological actions of a novel NO‐independent guanylyl cyclase stimulator, BAY 41‐8543: in vitro studies
Authors: Stasch Johannes‐Peter , Alonso‐Alija Cristina , Apeler Heiner , Dembowsky Klaus , Feurer Achim , Minuth Torsten , Perzborn Elisabeth , Schramm Matthias , Straub Alexander 
Published: January 2005

BAY 41‐8543 is a novel, highly specific and so far the most potent NO‐independent stimulator of sGC. Here we report the effects of BAY 41‐8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation.
BAY 41‐8543 stimulates the recombinant sGC concentration‐dependently from 0.0001 μM to 100 μM up to 92‐fold. In combination, BAY 41‐8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41‐8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO.
In vitro, BAY 41‐8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC50‐values in the nM range.
In the rat heart Langendorff preparation, BAY 41‐8543 potently reduces coronary perfusion pressure from 10−9 to 10−6 g ml−1 without any effect on left ventricular pressure and heart rate.
BAY 41‐8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate‐tolerant rats.
BAY 41‐8543 is a potent inhibitor of collagen‐mediated aggregation in washed human platelets (IC50=0.09 μM). In plasma, BAY 41‐8543 inhibits collagen‐mediated aggregation better than ADP‐induced aggregation, but has no effect on the thrombin pathway. BAY 41‐8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations.
These results suggest that BAY 41‐8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases.

British Journal of Pharmacology (2002) 135, 333–343; doi:10.1038/sj.bjp.0704484
Evidence of a role for NK1 and CGRP receptors in mediating neurogenic vasodilatation in the mouse ear
Authors: Grant Andrew D , Gerard Norma P , Brain Susan D 
Published: January 2005

The aims of this study were to develop a technique to measure blood flow in the mouse ear and to investigate the nature of the vasodilator mediator(s) involved in the response to capsaicin.
The response to capsaicin, applied topically, was investigated in anaesthetized CD1 or Sv129+C57BL/6 wild‐type (+/+) or NK1 receptor knockout mice (−/−). Blood flow was assessed by laser Doppler flowmetry and oedema formation by 125I‐albumin accumulation.
Capsaicin induced significant increases in blood flow (0.2–200 μg in 20 μl) and oedema (2–200 μg in 20 μl). The oedema response was absent in NK1−/− mice and NK1+/+mice treated with the selective NK1 receptor antagonist SR140333 (480 nmol kg−1) as expected. Furthermore, the capsaicin‐evoked increase in blood flow was significantly potentiated in the knockout mice (203% of wild‐type response, P<0.05) and wild‐type mice treated with SR140333 (201%, P<0.05).
The CGRP receptor antagonist CGRP8–37 (400 nmol kg−1) had no effect on capsaicin‐induced blood flow in NK1+/+mice but abolished the increased blood flow to capsaicin in NK1−/−, and NK1+/+wild‐type mice pre‐treated with SR140333.
The results indicate that neurogenic vasodilatation can be measured in the mouse ear. The capsaicin‐induced increased blood flow involves activation of, and possible interactions between, both NK1 and CGRP1 receptors.

British Journal of Pharmacology (2002) 135, 356–362; doi:10.1038/sj.bjp.0704485