bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effects of cyclic AMP elevating agents on lipopolysaccharide (LPS)‐induced microvascular permeability change in mouse skin
Authors: Irie Kaoru , Fujii Emiko , Ishida Hiroyasu , Wada Keiji , Suganuma Taiyo , Nishikori Tomohiro , Yoshioka Toshimasa , Muraki Takamura 
Published: January 2005

Anti‐inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)‐induced microvascular permeability change.
Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 μg site−1) from Salmonella typhimurium.
Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS‐induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg−1), milrinone (5 – 10 mg kg−1), rolipram (0.5 – 10 mg kg−1) and zaprinast (5 – 10 mg kg−1). The dye leakage was also inhibited by β‐adrenoceptor agonists, including isoproterenol (0.5 – 5 mg kg−1) and salbutamol (0.05 – 5 mg kg−1), an adenylate cyclase activator, forskolin (5 mg kg−1), and a cell permeable cyclic AMP analogue, 8‐bromo‐cyclic AMP (8‐Br‐cAMP, 10 mg kg−1).
LPS caused a transient increase in serum TNF‐α level peaking at 1 h after the injection. This increase in serum TNF‐α was completely blocked by a pretreatment with pentoxifylline (160 mg kg−1), milrinone (5 mg kg−1), rolipram (1 mg kg−1), zaprinast (10 mg kg−1), salbutamol (0.5 mg kg−1), forskolin (1 mg kg−1) and 8‐Br‐cAMP (10 mg kg−1).
LPS caused an increase in serum IL‐1α level peaking at 3 h after injection. This increase in serum IL‐1α was not significantly suppressed by the cyclic AMP elevating agents.
Our study suggests that cyclic AMP elevating agents attenuate LPS‐induced microvascular permeability change by suppressing TNF‐α up regulation.

British Journal of Pharmacology (2001) 133, 237–242; doi:10.1038/sj.bjp.0704073
Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia
Authors: Ma Jianya , Qiu Jianhua , Hirt Lorenz , Dalkara Turgay , Moskowitz Michael A 
Published: January 2005

We tested the hypothesis that combined use of trophic factors and caspase inhibitors increases brain resistance to ischaemia in mice.
Intracerebroventricular administration of bFGF (>10 ng) 30 min after MCA occlusion decreased infarct size and neurological deficit in a dose‐dependent manner following 2 h ischemia and reperfusion (20 h).
Combined administration of the subthreshold doses of bFGF (3 ng) and caspase inhibitors (z‐VAD.FMK, 27 ng or z‐DEVD.FMK, 80 mg) reduced infarct volume by 60%, and reduced neurological deficit.
Treatment with a subthreshold dose of bFGF (3 ng) extended the therapeutic window for z‐DEVD.FMK (480 ng) from 1 to 3 h after reperfusion.
Caspase‐3 activity in the ischaemic brain was increased 30 min and 2 h after reperfusion but, was significantly reduced in bFGF‐treated animals by 29 and 16%, respectively. Caspase‐3 activity was not reduced by a direct bFGF effect because addition of bFGF (10 nM – 2 μM) did not decrease recombinant caspase‐3 activity, in vitro.
Our data show that combining caspase inhibitors and bFGF lengthens the treatment window for the second treatment, plus lowers the dosage requirements for neuroprotection. These findings are important because low doses of caspase inhibitors or bFGF reduce the possibility of side effects plus extend the short treatment window for ischaemic stroke.

British Journal of Pharmacology (2001) 133, 345–350; doi:10.1038/sj.bjp.0704075
Mechanisms of leukotriene D4‐induced constriction in human small bronchioles
Authors: Snetkov V A , Hapgood K J , McVicker C G , Lee T H , Ward J P T 
Published: January 2005

We examined the mechanisms underlying leukotriene D4‐ (LTD4) induced constriction of human small (300 – 500 μm i.d.) bronchioles, and the effect of LTD4 on ion currents and Ca2+ transients in smooth muscle cells (SMC) isolated from these bronchioles.
LTD4 caused a concentration‐dependent bronchoconstriction with an EC50=0.58±0.05 nM (n=7) which was not easily reversible upon washout. This bronchoconstriction was entirely dependent on extracellular Ca2+.
Blockade of L‐type Ca2+ channels with nifedipine (10 μM) reduced LTD4 response by 39±2% (n=8), whilst La3+, Gd3+ and SK&F 96,365 abolished LTD4‐induced bronchoconstriction completely and reversibly, suggesting the majority of Ca2+ entry was via non‐selective cation channels.
Antagonists of PI‐PLC (U73,122 and ET‐18‐OCH3), PLD (propranolol) and PKC (cheleretrine and Ro31‐8220) were without any effect on LTD4‐induced bronchoconstriction, whilst the PC‐PLC inhibitor D609 caused complete relaxation. Inhibition of protein tyrosine kinase with tyrphostin A23 (100 μM) caused about 50% relaxation, although the inactive analogue tyrphostin A1 was without effect.
In freshly isolated SMC from human small bronchioles LTD4 caused a slow increase of intracellular Ca2+ concentration, with a consequent rise of the activity of large conductance Ca2+‐dependent K+ channels and the amplitude of depolarization‐induced outward whole‐cell current. Again, no effect of LTD4 could be observed in the absence of extracellular Ca2+.
We conclude that LTD4 causes constriction of these small bronchioles primarily by activating Ca2+ entry via non‐voltage gated channels, possibly by a PC‐PLC mediated pathway.

British Journal of Pharmacology (2001) 133, 243–252; doi:10.1038/sj.bjp.0704076
Detection of receptor ligands by monitoring selective stabilization of aRenillaluciferase‐tagged, constitutively active mutant, G‐protein‐coupled receptor
Authors: Ramsay Douglas , Bevan Nicola , Rees Stephen , Milligan Graeme 
Published: January 2005

The wild‐type β2‐adrenoceptor and a constitutively active mutant of this receptor were C‐terminally tagged with luciferase from the sea pansyRenilla reniformis.C‐terminal addition ofRenillaluciferase did not substantially alter the levels of expression of either form of the receptor, the elevated constitutive activity of the mutant β2‐adrenoceptor nor the capacity of isoprenaline to elevate cyclic AMP levels in intact cells expressing these constructs.Treatment of cells expressing constitutively active mutant β2‐adrenoceptor‐Renillaluciferase with antagonist/inverse agonist ligands resulted in upregulation of levels of this polypeptide which could be monitored by the elevated luciferase activity.The pEC50for ligand‐induced luciferase upregulation and ligand affinity to bind the receptor were highly correlated.Similar upregulation could be observed following sustained treatment with agonist ligands.These effects were only observed at a constitutively active mutant of the β2‐adrenoceptor. Co‐expression of the wild‐type β2‐adrenoceptor C‐terminally tagged with the luciferase fromPhotinus pyralisdid not result in ligand‐induced upregulation of the levels of activity of this luciferase.Co‐expression of the constitutively active mutant β2‐adrenoceptor‐Renillaluciferase and an equivalent mutant of the α1b‐adrenoceptor C‐terminally tagged with green fluorescent protein allowed pharmacological selectivity of adrenoceptor antagonists to be demonstrated.This approach offers a sensitive and convenient means, which is amenable to high throughput analysis, to monitor ligand binding to a constitutively active mutant receptor.As no prior knowledge of receptor ligands is required this approach may be suitable to identify ligands at orphan G protein‐coupled receptors.British Journal of Pharmacology(2001)133, 315–323; doi:10.1038/sj.bjp.0704077
The broad‐spectrum anti‐emetic activity of AS‐8112, a novel dopamine D2, D3 and 5‐HT3 receptors antagonist
Authors: Yoshikawa Takashi , Yoshida Naoyuki , Oka Makoto 
Published: January 2005

The anti‐emetic and pharmacological profile of AS‐8112 ((R)‐5‐bromo‐N‐(1‐ethyl‐4‐methylhexahydro‐1H‐1,4‐diazepin‐6‐yl)‐2‐methoxy‐6‐methylamino‐3‐pyridinecarboxamide·2 fumarate), a novel and potent dopamine D2, D3 and 5‐hydroxytryptamine‐3 (5‐HT3) receptors ligand, was investigated in the present study.
In guinea‐pig isolated colon, AS‐8112 produced a rightward shift of the concentration‐response curves of 2‐methyl‐5HT, a 5‐HT3 receptor agonist (pA2 value of 7.04). Other 5‐HT3 receptor antagonists also produced such a shift in the following antagonistic‐potency order: granisetron> ondansetron=AS‐8112>>metoclopramide.
In mice, AS‐8112 (1.0 – 3.0 mg kg−1 s.c.) potently inhibited hypothermia induced by the dopamine D3 receptor agonist; R(+)‐7‐OH‐DPAT (R(+)‐7‐hydroxy‐2‐(N,N‐di‐n‐propylamino)tetraline) (0.3 mg kg−1 s.c.). Domperidone and haloperidol, which have affinity for dopamine D3 receptor, also inhibited R(+)‐7‐OH‐DPAT‐induced hypothermia.
In ferrets or dogs, AS‐8112 dose‐dependently inhibited emesis induced by R(+)‐7‐OH‐DPAT, apomorphine, morphine or cisplatin with ID50 values of 2.22 μg kg−1 s.c., 10.5 μg kg−1 s.c., 14.2 μg kg−1 i.v. and 17.6 μg kg−1 i.v., respectively. Moreover, oral administration of AS‐8112 significantly inhibited emesis induced by these emetogens. AS‐8112 (0.3 mg kg−1 i.v.) significantly inhibited emesis induced by cyclophosphamide and doxorubicin.
In conclusion, AS‐8112 is a potent dopamine D2, D3 and 5‐HT3 receptors antagonist, and a novel anti‐emetic agent with a broad‐spectrum of anti‐emetic activity. These results suggest that this compound is worthy of clinical investigation.

British Journal of Pharmacology (2001) 133, 253–260; doi:10.1038/sj.bjp.0704078
Influence of the 5‐HT2C receptor antagonist SB242,084 on behaviour produced by the 5‐HT2 agonist Ro60‐0175 and the indirect 5‐HT agonist dexfenfluramine
Authors: Higgins G A , Ouagazzal A M , Grottick A J 
Published: January 2005

Ro60‐0175 has been described as a selective agonist at the 5‐HT2C receptor, yet it has only 10‐ fold higher affinity at the 5‐HT2C compared to the 5‐HT2A subtype, and equivalent affinity for the 5‐HT2B receptor.
The selective 5‐HT2C receptor antagonist SB242,084 (0.5 mg kg−1 i.p.), blocked the hypoactivity and penile grooming induced by Ro60‐0175 (1 mg kg−1 s.c.). The combination of SB242,084 (0.5 mg kg−1 i.p.) and Ro60‐0175 (3 – 10 mg kg−1) produced a completely different pattern of behaviours including wet‐dog shakes, hyperactivity and back muscle contractions. These latter effects were blocked by the selective 5‐HT2A receptor antagonist MDL100,907 (0.5 mg kg−1 i.p.), but not the 5‐HT2B receptor antagonist SB215,505 (3 mg kg−1 p.o.).
The indirect 5‐HT releaser/reuptake inhibitor dexfenfluramine (1 – 10 mg kg−1 i.p.) produced a mild increase in locomotor activity, penile grooming, and occasional back muscle contractions and wet‐dog shakes. Pre‐treatment with SB242,084 (0.5 mg kg−1), blocked the incidence of penile grooming, and markedly potentiated both the dexfenfluramine‐induced hyperactivity, the incidence of back muscle contractions, and to a lesser extent wet‐dog shakes. Some toxicity was also evident in animals treated with dexfenfluramine (10 mg kg−1)/SB242,084 (0.5 mg kg−1), but not in any other treatment groups.
The hyperactivity and toxicity produced by the dexfenfluramine (10 mg kg−1)/SB242,084 (0.5 mg kg−1) combination was replicated in a further study, and hyperthermia was also recorded. Both hyperthermia and toxicity were blocked by MDL100,907 (0.5 mg kg−1) but not SB215,505 (3 mg kg−1). An attenuation of the hyperlocomotor response was also observed following MDL100,907.
These findings suggest that 5‐HT2C receptor activation can inhibit the expression of behaviours mediated through other 5‐HT receptor subtypes.

British Journal of Pharmacology (2001) 133, 459–466; doi:10.1038/sj.bjp.0704082
Effect of 1‐week treatment with erythropoietin on the vascular endothelial function in anaesthetized rabbits
Authors: Noguchi Katsuhiko , Yamashiro Satoshi , Matsuzaki Toshihiro , Sakanashi Mayuko , Nakasone Junko , Miyagi Kanako , Sakanashi Matao 
Published: January 2005

Chronic administration of erythropoietin (EPO) is often associated with hypertension in animals and humans. The aim of this study was to estimate whether 1‐week treatment with EPO can affect the vascular endothelial function.
Rabbits were given with EPO (400 iu kg−1 s.c.) or saline each other day for 1 week. Hypotensive responses to intravenously given acetylcholine (ACh), endothelium‐independent nitric oxide donors (NOC7, nitroprusside and nitroglycerin) and prostaglandin I2 were tested before and after administration of NG‐nitro‐L‐arginine methyl ester (L‐NAME), a specific nitric oxide synthase inhibitor, under pentobarbitone anaesthesia.
Blood haemoglobin concentration in EPO group was significantly higher than that in control group, whereas baseline values of aortic pressure, heart rate and femoral vascular resistance were similar. The dose of ACh (172 ng kg−1) requiring for a 15 mmHg hypotension from the baseline in EPO group was apparently higher than that (55 ng kg−1) in control group. On the contrary, hypotensive responses to NOC7, nitroprusside, nitroglycerin and prostaglandin I2 were comparable between two groups. The extent of ACh‐induced hypotension did not correlate with haemoglobin concentration.
L‐NAME significantly inhibited the ACh‐induced vasodilating response in control group but did not in EPO group.
In another set of rabbits, the same treatment with EPO also decreased vasodilating responses to carbachol, bradykinin and substance P besides ACh as compared with control group.
These results indicate that 1‐week treatment with EPO selectively attenuates depressor responses to endothelium‐dependent vasodilators in anaesthetized rabbits, most likely due to inhibition of endothelial nitric oxide synthase.

British Journal of Pharmacology (2001) 133, 395–405; doi:10.1038/sj.bjp.0704083
The vascular activity of some isoflavone metabolites: implications for a cardioprotective role
Authors: Chin‐Dusting Jaye P F , Fisher Lisa J , Lewis Tamara V , Piekarska Anna , Nestel Paul J , Husband Alan 
Published: January 2005

Legume‐derived isoflavones such as genistein, diadzein and equol have been associated with a reduction in risk of cardiovascular disease. In the current study, we explore the vascular activity of several isoflavone metabolites namely dihydrodaidzein, cis and trans‐tetrahydrodaidzein and dehydroequol for potential cardioprotective properties.
Rat isolated aortic rings were used. 17β‐oestradiol, equol, and all four of the metabolites studied significantly antagonized contractile responses to noradrenaline.
The direct vasodilatory action of these compounds were examined and in contrast to 17β‐oestradiol, the vasodilatory effect of which was demonstrated to be endothelium independent, the dilatory action of all four compounds could be inhibited by endothelium denudation.
Further, the dilatory action of both dihydrodaidzein and cis‐tetrahydrodaidzein were inhibited by the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine (NOLA), by the soluble guanylate cyclase inhibitor, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) and by 40 mM KCl. Dilatory responses to dehydroequol and trans‐tetrahydrodaidzein, on the other hand, were inhibited by 40 mM KCL but not by NOLA nor ODQ.
Finally, we examined the protective potential of these compounds in inhibiting endothelium damage by oxidized low density lipoprotein (ox‐LDL). Trans‐tetrahydrodaidzein was at least 10 fold more potent than 17β‐oestradiol in protecting against ox‐LDL induced damage.
We conclude that the isoflavone metabolites, dihydrodaidzein, cis‐ and trans‐tetrahydrodaidzein and dehydroequol, may potentially represent a novel series of cardioprotective therapeutics.

British Journal of Pharmacology (2001) 133, 595–605; doi:10.1038/sj.bjp.0704088
Inhibition of nitric oxide synthase abrogates lipopolysaccharides‐induced up‐regulation of L‐arginine uptake in rat alveolar macrophages
Authors: Hammermann Rainer , Stichnote Christina , Closs Ellen Ildicho , Nawrath Hermann , Racké Kurt 
Published: January 2005

It was tested whether the inducible nitric oxide synthase (iNOS) pathway might be involved in lipopolysaccharides‐(LPS)‐induced up‐regulation of L‐arginine transport in rat alveolar macrophages (AMΦ).
AMΦ were cultured in absence or presence of LPS. Nitrite accumulation was determined in culture media and cells were used to study [3H]‐L‐arginine uptake or to isolate RNA for RT – PCR.
Culture in presence of LPS (1 μg ml−1, 20 h) caused 11 fold increase of nitrite accumulation and 2.5 fold increase of [3H]‐L‐arginine uptake.
The inducible NO synthase (iNOS) inhibitor 2‐amino‐5,6‐dihydro‐6‐methyl‐4H‐1,3‐thiazine (AMT) present alone during culture had only marginal effects on [3H]‐L‐arginine uptake. However, AMT present during culture additionally to LPS, suppressed LPS‐induced nitrite accumulation and LPS‐stimulated [3H]‐L‐arginine uptake in the same concentration‐dependent manner. AMT present only for the last 30 min of the culture period had similar effects on [3H]‐L‐arginine uptake. AMT present only during the uptake period also inhibited LPS‐stimulated [3H]‐L‐arginine uptake, but with lower potency.
The inhibitory effect of AMT could not be opposed by the NO releasing compound DETA NONOate.
LPS caused an up‐regulation of the mRNA for the cationic amino acid transporter CAT‐2B, and this effect was not affected by AMT.
AMT (100 μM) did not affect L‐arginine transport studied by electrophysiological techniques in Xenopus laevis oocytes expressing either the human cationic amino acid transporter hCAT‐1 or hCAT‐2B.
In conclusion, iNOS inhibition in rat AMΦ abolished LPS‐activated L‐arginine uptake. This effect appears to be caused by reduced flow of L‐arginine through the iNOS pathway.

British Journal of Pharmacology (2001) 133, 379–386; doi:10.1038/sj.bjp.0704091
Characterization of EP receptor subtypes responsible for prostaglandin E2‐induced pain responses by use of EP1 and EP3 receptor knockout mice
Authors: Minami Toshiaki , Nakano Hiroyuki , Kobayashi Takuya , Sugimoto Yukihiko , Ushikubi Fumitaka , Ichikawa Atsushi , Narumiya Shuh , Ito Seiji 
Published: January 2005

Prostaglandin E2 (PGE2) is known to be the principal pro‐inflammatory prostanoid and play an important role in nociception. To identify PGE receptor (EP) subtypes that mediate pain responses to noxious and innocuous stimuli, we studied them by use of EP1 and EP3 knockout (EP1−/− and EP3−/−) mice.
PGE2 could induce mechanical allodynia in EP1+/+, EP3+/+ and EP3−/− mice, but not in EP1−/− mice. N‐methyl‐D‐aspartate (NMDA), the substrate of nitric oxide (NO) synthase L‐arginine, or the NO donor sodium nitroprusside administered intrathecal (i.t.) could induce allodynia in EP3−/− and EP1−/− mice. Activation of EP1 receptors appears to be upstream, rather than downstream, of NMDA receptor activation and NO production in the PGE2‐induced allodynia.
Although PGE2 produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 μg kg−1 in EP3+/+ mice, it showed a monophasic hyperalgesic action at 5 ng kg−1 or higher doses in EP3−/− mice. The selective EP3 agonist, ONO‐AE‐248, induced hyperalgesia at 500 pg kg−1 in EP3+/+ mice, but not in EP3−/− mice.
Saline‐injected EP1−/− mice showed hyperalgesia, which was reversed by i.t. PGE2 in a dose‐dependent manner.
There was no significant difference in the formalin‐induced behaviours between EP1−/− or EP3−/− mice and the cognate wild‐type mice.
These results demonstrate that spinal EP1 receptors are involved in the PGE2‐induced allodynia and that spinal EP3 receptors are involved in the hyperalgesia induced by low doses of PGE2. However, the formalin‐induced pain cannot be ascribed to a single EP receptor subtype EP1 or EP3.

British Journal of Pharmacology (2001) 133, 438–444; doi:10.1038/sj.bjp.0704092
Dexamethasone inhibits TNF‐α‐induced apoptosis and IAP protein downregulation in MCF‐7 cells
Authors: Messmer Udo K , Pereda‐Fernandez Carmen , Manderscheid Markus , Pfeilschifter Josef 
Published: January 2005

Exposure of human mammary carcinoma cell line MCF‐7 to TNF‐α leads to apoptotic cell death within 24 h. In search for apoptosis‐preventing signals, we identified glucocorticoids as potent death‐preventing compounds. Ten nM dexamethasone provided a significant protective effect whereas 100 nM dexamethasone roughly blocked 80 – 90% of TNF‐α‐induced apoptosis.
Surprisingly, dexamethasone exerted a protective effect even when supplied several hours after TNF‐α. This points to a powerful inhibition of even advanced apoptotic processes by dexamethasone.
To further pinpoint the anti‐apoptotic glucocorticoid action, we investigated the expression levels of several members of the inhibitors of apoptosis (IAPs) family of proteins in response to TNF‐α and dexamethasone. IAP proteins directly block caspase protease activities including caspase‐3, caspase‐7, and caspase‐9. Exposure of MCF‐7 cells to TNF caused an extensive downregulation of cIAP1, cIAP2, and XIAP protein levels. The decline of the IAP protein levels temporally paralleled the appearance of apoptotic DNA fragments which started 12 – 14 h following TNF‐α addition and maximal effects were seen within 24 h.
Coincubation of cells with TNF‐α and dexamethasone potently blocked cIAP1, cIAP2, and XIAP downregulation.
TNF‐α‐mediated IAP protein downregulation was not affected by proteasome inhibitors like lactacystin, ALLN or ALLM, whereas it was blocked by the broad‐spectrum caspase inhibitor Z‐VAD‐fmk which also prevented TNF‐α‐induced apoptotic cell death. These data suggest that inhibition of IAP downregulation mediated by a caspase proteolytic activity constitutes the anti‐apoptotic action of glucocorticoids in MCF‐7 carcinoma cells.

British Journal of Pharmacology (2001) 133, 467–476; doi:10.1038/sj.bjp.0704093
Cyclic AMP elevating agents and nitric oxide modulate angiotensin II‐induced leukocyte‐endothelial cell interactions in vivo
Authors: Alvarez Angeles , Piqueras Laura , Blazquez Maria‐Amparo , Sanz Maria‐Jesus 
Published: January 2005

Angiotensin (Ang‐II) is a key molecule in the development of cardiac ischaemic disorders and displays proinflammatory activity in vivo. Since intracellular cyclic nucleotides elevating agents have proved to be effective modulators of leukocyte recruitment, we have evaluated their effect on Ang‐II‐induced leukocyte‐endothelial cell interactions in vivo using intravital microscopy within the rat mesenteric microcirculation.
Pretreatment with iloprost significantly inhibited (1 nM) Ang‐II‐induced increase in leukocyte rolling flux, adhesion and emigration at 60 min by 96, 92 and 90% respectively, and returned leukocyte rolling velocity to basal levels. Pretreatment with salbutamol or co‐superfusion with forskolin exerted similar effects.
When theophylline was administered, leukocyte rolling flux, adhesion and emigration elicited by Ang‐II were significantly attenuated by 81, 89 and 71% respectively. Rolipram administration caused similar reduction of Ang‐II‐induced leukocyte responses.
Co‐superfusion of Ang‐II with the NO‐donor, spermine‐NO, or 8‐Br‐cyclic GMP, or pretreatment with a transdermal nytroglycerin patch, resulted in a significant reduction of the leukocyte‐endothelial cell interactions elicited by Ang‐II.
Salbutamol preadministration did not modify leukocyte‐endothelial cell interactions elicited by either L‐NAME or L‐NAME+Ang‐II, indicating that the inhibitory leukocyte effects caused by cyclic AMP‐elevating agents are mediated through NO release.
In conclusion, we have provided evidence that cyclic AMP elevating agents and NO donors, are potent inhibitors of Ang‐II‐induced leukocyte‐endothelial cell interactions. Thus, they could constitute a powerful therapeutical tool in the control of the leukocyte recruitment characteristic of the vascular lesions that occur in cardiovascular disease states where Ang‐II plays a critical role.

British Journal of Pharmacology (2001) 133, 485–494; doi:10.1038/sj.bjp.0704096