bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells
Authors: Chen Jiann‐Jong , Wang Paulus S , Chien Eileen‐Jea , Wang Shyi‐Wu 
Published: January 2005

Digoxin (10−7 – 10−5 M) or digitoxin (10−7 – 10−5 M) decreased the basal and human chorionic gonadotropin (hCG)‐stimulated release of progesterone from rat granulosa cells.
Digoxin (10−5 M) or digitoxin (10−5 M) attenuated the stimulatory effects of forskolin and 8‐bromo‐cyclic 3′ : 5′‐adenosine monophosphate (8‐Br‐cAMP) on progesterone release from rat granulosa cells.
Digoxin (10−5 M) or digitoxin (10−5 M) inhibited cytochrome P450 side chain cleavage enzyme (cytochrome P450scc) activity (conversion of 25‐hydroxyl cholesterol to pregnenolone) in rat granulosa cells but did not influence the activity of 3β‐hydroxysteroid dehydrogenase (3β‐HSD).
Neither progesterone production nor P450scc activity in rat granulosa cells was altered by the administration of ouabain.
Digoxin (10−5 M) or digitoxin (10−5 M), but not ouabain, decreased the expression of P450scc and steroidogenic acute regulatory (StAR) protein in rat granulosa cells.
The present results suggest that digoxin and digitoxin decrease the progesterone release by granulosa cells via a Na+,K+‐ATPase‐independent mechanism involving the inhibition of post‐cyclic AMP pathway, cytochrome P450scc and StAR protein functions.

British Journal of Pharmacology (2001) 132, 1761–1768; doi:10.1038/sj.bjp.0703974
Mitogenic effect of oxidized low‐density lipoprotein on vascular smooth muscle cells mediated by activation of Ras/Raf/MEK/MAPK pathway
Authors: Yang Chuen‐Mao , Chien Chin‐Sung , Hsiao Li‐Der , Pan Shiow‐Lin , Wang Chuan‐Chawn , Chiu Chi‐Tso , Lin Chih‐Chung 
Published: January 2005

It has been demonstrated that oxidized low‐density lipoprotein (OX‐LDL) is a risk factor in atherosclerosis by stimulating vascular smooth muscle cell (VSMC) proliferation. However, the mechanisms of OX‐LDL‐induced cell proliferation are not completely understood. Therefore, we investigated the effect of OX‐LDL on cell proliferation associated with mitogen‐activated protein kinase (MAPK) activation in rat cultured VSMCs.
Both native‐LDL (N‐LDL) and OX‐LDL induced a time‐ and concentration‐dependent incorporation of [3H]‐thymidine in VSMCs.
OX‐LDL induced time‐ and concentration‐dependent phosphorylation of p42/p44 MAPK. Pretreatment of these cells with pertussis toxin or U73122 attenuated the OX‐LDL‐induced responses.
Pretreatment with PMA for 24 h, preincubation with a PKC inhibitor staurosporine or the tyrosine kinase inhibitors, genistein and herbimycin A for 1 h, substantially reduced [3H]‐thymidine incorporation and p42/p44 MAPK phosphorylation induced by OX‐LDL.
Removal of Ca2+ by BAPTA/AM or depletion of the internal Ca2+ pool by thapsigargin significantly inhibited OX‐LDL‐induced [3H]‐thymidine incorporation and p42/p44 MAPK phosphorylation.
OX‐LDL‐induced [3H]‐thymidine incorporation and p42/p44 MAPK phosphorylation was inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK) in a concentration‐dependent manner.
Overexpression of dominant negative mutants of Ras (H‐Ras‐15A) and Raf (Raf‐N4) significantly suppressed MEK1/2 and p42/p44 MAPK activation induced by OX‐LDL and PDGF‐BB, indicating that Ras and Raf may be required for activation of these kinases.
These results suggest that the mitogenic effect of OX‐LDL is mediated through a PTX‐sensitive G protein‐coupled receptor that involves the activation of the Ras/Raf/MEK/MAPK pathway similar to that of PDGF‐BB in rat cultured VSMCs.

British Journal of Pharmacology (2001) 132, 1531–1541; doi:10.1038/sj.bjp.0703976
The effect of SB‐269970, a 5‐HT7 receptor antagonist, on 5‐HT release from serotonergic terminals and cell bodies
Authors: Roberts Claire , Allen Lucy , Langmead Christopher J , Hagan Jim J , Middlemiss Derek N , Price Gary W 
Published: January 2005

The presence of 5‐HT7 receptor mRNA and protein in 5‐HT neurons suggests that this receptor may act as a 5‐HT autoreceptor. In this study, the effect of the 5‐HT7 receptor antagonist, SB‐269970 ((R)‐1‐[3‐hydroxy phenyl)sulfonyl]‐2‐[2‐(4‐methyl‐1‐piperidinyl)ethyl]pyrrolidine), was investigated on 5‐HT release in the guinea‐pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [3H]‐5‐HT release or fast cyclic voltammetry, respectively.
Cortical slices were loaded with [3H]‐5‐HT and release was evoked by electrical stimulation. 5‐CT inhibited the evoked release of [3H]‐5‐HT in a concentration‐dependent manner. SB‐269970 had no significant effect on [3H]‐5‐HT release while the 5‐HT1B receptor antagonist, SB‐224289 significantly potentiated [3H]‐5‐HT release. In addition, SB‐269970 was unable to attenuate the 5‐CT‐induced inhibition of release while SB‐224289 produced a rightward shift of the 5‐CT response, generating estimated pKB values of 7.8 and 7.6 at the guinea‐pig and rat terminal 5‐HT autoreceptors respectively.
Rat DRN slices were electrically stimulated and the evoked 5‐HT efflux detected by voltammetric analysis. 8‐OH‐DPAT inhibited evoked 5‐HT efflux and was fully reversed by WAY 100635. SB‐269970 had no effect on either 5‐HT efflux per se or 8‐OH‐DPAT‐induced inhibition of 5‐HT efflux. In addition, 5‐CT inhibited 5‐HT efflux in a concentration‐dependent manner. SB‐269970 was unable to attenuate the 5‐CT‐induced inhibition of 5‐HT efflux.
In conclusion, we were unable to provide evidence to suggest a 5‐HT autoreceptor role for 5‐HT7 receptors. However, investigations with more selective 5‐HT7 receptor agonists are needed to confirm the data reported here.

British Journal of Pharmacology (2001) 132, 1574–1580; doi:10.1038/sj.bjp.0703979
Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation
Authors: Vacaresse Nathalie , Vieira Otília , Robbesyn Fanny , Jürgens Günther , Salvayre Robert , Negre‐Salvayre Anne 
Published: January 2005

Oxidized low density lipoproteins (oxLDL) are thought to play a major role in atherosclerosis. OxLDL act in part through alteration of intracellular signalling pathways in cells of the vascular wall. We recently reported that the EGF receptor (EGFR) signalling pathway is activated by lipid peroxidation products (among them 4‐hydroxynonenal, 4‐HNE) contained in oxLDL.
The use of phenolic antioxidants, such as trolox, alpha‐tocopherol, caffeic acid and tyrphostins A‐25, A‐46 or A‐1478, showed that the oxLDL‐induced EGFR activation is constituted by two separate components, the first (early) one being antioxidant‐insensitive, the second (late) being antioxidant‐sensitive.
4‐HNE derivatization of EGFR and EGFR activation induced by exogenous 4‐HNE, suggest that the early (0.5 – 3 h) component of oxLDL‐induced EGFR activation is mediated (at least in part) by 4‐HNE (and possibly by other oxidized lipids). This early component is antioxidant‐insensitive.
The second component (4 – 5 h) of the oxLDL‐induced EGFR activation is antioxidant‐sensitive, since it is blocked by antioxidants such as trolox, caffeic acid or PDTC, which act by blocking the cellular oxidative stress (H2O2 generation) evoked by oxLDL. Conversely, exogenous H2O2 induced EGFR autophosphorylation (thus mimicking the second component) and was also inhibited by antioxidants. This effect is mediated in part through inhibition by oxidative stress of protein tyrosine phosphatases involved in EGFR dephosphorylation.

British Journal of Pharmacology (2001) 132, 1777–1788; doi:10.1038/sj.bjp.0703981
Long‐lasting antinociceptive effects of a novel dynorphin analogue, Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH2NH) Arg‐NH2, in mice
Authors: Hiramatsu Masayuki , Inoue Kaori , Ambo Akihiro , Sasaki Yusuke , Kameyama Tsutomu 
Published: January 2005

Tyr‐D‐Ala‐Phe‐Leu‐Arg ψ (CH2NH) Arg‐NH2 (SK‐9709) is a dynorphin derivative in which the peptide bond was replaced with a ψ (CH2NH) bond. In the present study, the antinociceptive effects of SK‐9709 were determined in an acetic acid‐induced writhing test and a hot‐plate test.
In the acetic acid‐induced writhing test, significant antinociceptive effects were observed after subcutaneous (s.c.), intracerebroventricular (i.c.v.) and intrathecal (i.t.) injection of SK‐9709, with maximal effects at 120, 30 and 15 min, respectively. The antinociceptive effects were dose‐dependent and ED50 values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 1.36 (0.61 – 3.02) μmol kg−1, 2.11 (1.18 – 3.79) and 0.79 (0.61 – 1.03) nmol per mouse, respectively.
The effects of SK‐9709 (s.c., i.c.v. and i.t.) were reversed by the opioid receptor antagonist naloxone (1.36 μmol kg−1, s.c.). The effects of SK‐9709 (s.c.) were also reversed by the selective μ‐opioid receptor antagonist β‐funaltrexamine (4.7 nmol per mouse, i.c.v.), and κ‐opioid receptor antagonist nor‐binaltorphimine (4.9 nmol per mouse, i.t.).
In the hot‐plate test, the antinociceptive effect of SK‐9709 (s.c., i.c.v. and i.t.) was also dose‐dependent with the maximal peak effect at 120, 15 and 15 min similarly to the acetic acid‐induced writhing test. The antinociceptive effects were dose‐dependent and ED50 values (range of 95% confidence limits) after s.c., i.c.v. and i.t. injection were 39.1 (5.4 – 283.0) μmol kg−1, 6.5 (4.0 – 10.7) and 7.4 (5.0 – 11.0) nmol per mouse, respectively.
These findings indicated that systemically administered SK‐9709 produced long‐lasting antinociceptive effects and these effects were mediated by both supra‐spinal μ‐ and spinal κ‐opioid receptors.

British Journal of Pharmacology (2001) 132, 1948–1956; doi:10.1038/sj.bjp.0703982
Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat
Authors: Garraway Sandra M , Hochman Shawn 
Published: January 2005

Spinal cord slices and whole‐cell patch clamp recordings were used to investigate the effects of serotonergic receptor ligands on dorsal root‐evoked synaptic responses in deep dorsal horn (DDH) neurons of the neonatal rat at postnatal days (P) 3 – 6 and P10 – 14.
Bath applied 5‐hydroxytryptamine (5‐HT) potently depressed synaptic responses in most neurons. Similarly, the 5‐HT1/7 receptor agonist, 5‐carboxamidotryptamine (5‐CT) depressed synaptic responses. This action was probably mediated by 5‐HT1A receptor activation, since it occurred in the presence of the 5‐HT7 receptor antagonist clozapine and was not observed in the presence of NAN‐190, a 5‐HT1A receptor antagonist. In the absence of any agonist, 5‐HT1A receptor antagonists often facilitated synaptic responses, suggesting that there is sufficient endogenous 5‐HT to tonically activate 5‐HT1A receptors.
8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT), the 5‐HT1A/7 receptor agonist, facilitated synaptic responses, an action probably mediated by 5‐HT7 receptors, since the facilitation could be reversed by subsequent application of the 5‐HT7 receptor antagonist clozapine.
Agonists for the 5‐HT1B, 5‐HT2 and 5‐HT3 receptors exerted only modest modulatory actions.
A pharmacological analysis of the depression evoked by 5‐HT suggested an action partly mediated by 5‐HT1A receptor activation, since antagonism of the 5‐HT1A receptor with NAN‐190 or WAY‐100635 partly reversed 5‐HT‐evoked depression. In comparison, 5‐HT7 receptor activation could account for much of the 5‐HT‐evoked facilitation.
We conclude that 5‐HT is capable of modulating sensory input onto DDH neurons via several receptor subtypes, producing both facilitatory and depressant actions. Also, the actions of most receptor ligands on the evoked responses were similar within the first 2 postnatal weeks.

British Journal of Pharmacology (2001) 132, 1789–1798; doi:10.1038/sj.bjp.0703983
An endogenous 5‐HT7 receptor mediates pigment granule dispersion in Xenopus laevis melanophores
Authors: Teh Muy‐Teck , Sugden David 
Published: January 2005

Melatonin (5‐methoxy N‐acetyltryptamine) and serotonin (5‐HT) exert rapid, but opposite effects on pigment granule distribution in Xenopus laevis melanophores. Low concentrations of melatonin (10−11 – 10−9 M) cause a dramatic perinuclear aggregation of the melanin‐containing granules, while 5‐HT (10−8 – 10−5 M) disperses pigment granules throughout the cell.
The present study found that pharmacological doses of melatonin (10−6 M) induced a time‐ and concentration‐dependent pigment granule dispersion, which was mediated by an endogenous melanophore 5‐HT receptor.
5‐HT produced a concentration‐dependent elevation of melanophore cyclic AMP, and 5‐HT‐induced dispersion was blocked by H89 (10−4 M), an inhibitor of protein kinase A (PKA), but not by a PKC inhibitor (Ro 31‐8220, 10−5 M), indicating a vital role for cyclic AMP in 5‐HT‐induced dispersion.
5‐HT‐mediated dispersion was not blocked by antagonists selective for Gs‐coupled 5‐HT4 (GR113808) or 5‐HT6 (Ro 04‐6790, Ro 63‐0563, olanzepine) receptors, nor by 5‐HT1 – 3 (pindolol, ketanserine, metoclopramide, MDL72222, tropisetron) receptor antagonists, but was inhibited by a selective 5‐HT7 receptor antagonist, DR4004, and other antagonists with a high affinity for 5‐HT7 receptors. The rank order of antagonist potency was: risperidone (mean pKB 7.82)>methiothepin (7.43)>DR4004 (6.92)>mesulergine (6.83)>methysergide (6.60)>[±]‐sulpiride (5.81)>spiperone (5.52). The agonist potency order [mean pEC50, 5‐CT (8.68)>5‐HT (7.13)>5‐MT (6.94)>8‐OH‐DPAT (4.79)>sumatriptan (<4)] was also consistent with an action on 5‐HT7 receptors.
RT – PCR confirmed that melanophores express 5‐HT7 receptor mRNA. The pigment dispersing effect of high melatonin concentrations in melanophores is most likely mediated by activation of 5‐HT7 receptors. Conceivably some of the effects attributed to pharmacological doses of melatonin in mammals may be mediated by activation of 5‐HT7 receptors.

British Journal of Pharmacology (2001) 132, 1799–1808; doi:10.1038/sj.bjp.0703988
Reduction of opioid dependence by the CB1 antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction
Authors: Mas‐Nieto Magdalena , Pommier Blandine , Tzavara Eleni T , Caneparo Anne , Nascimento Sophie Da , Fur Gérard Le , Roques Bernard P , Noble Florence 
Published: January 2005

Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB1 antagonist, SR141716A to reduce morphine‐induced addiction was investigated.
The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB1 antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine‐induced conditioned place preference.
SR141716A was co‐administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB1 antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB1 receptors is able to reduce morphine‐induced physical dependence.
Several biochemical mechanisms could explain the reduction of opioid dependence by CB1 antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction.

British Journal of Pharmacology (2001) 132, 1809–1816; doi:10.1038/sj.bjp.0703990
Role of the haeme oxygenase/carbon monoxide pathway in mechanical nociceptor hypersensitivity
Authors: Steiner A A , Branco L G S , Cunha F Q , Ferreira S H 
Published: January 2005

The cleavage of haeme by haeme oxygenase (HO) yields carbon monoxide (CO), a biologically active molecule which exerts most of its effects via activation of soluble guanylate cyclase (sGC). In the present study, we tested the hypothesis that endogenous CO could modulate inflammatory hyperalgesia. The intensity of hyperalgesia was investigated in a model of mechanical nociceptor hypersensitivity in rats.
The intra‐plantar (i.pl.) administration of the HO inhibitor, ZnDPBG (Zinc deuteroporphyrin 2,4‐bis glycol), potentiated in a dose‐dependent manner the mechanical nociceptor hypersensitivity evoked by i.pl. administration of carrageenan.
The mechanical hypersensitivity evoked by i.pl. injection of interleukin‐1β (IL‐1β), tumour necrosis factor‐α (TNF‐α), but not interleukin‐8 (IL‐8), prostaglandin E2 (PGE2) or dopamine, was also enhanced by ZnDPBG.
Moreover, the haeme (HO substrate) injection in the paws reduced the hypersensitivity evoked by IL‐1β, but not PGE2. Furthermore, i.pl. administration of the gas CO reduced the hypersensitivity elicited by PGE2.
The inhibitory effect of haeme and CO upon mechanical nociceptor hypersensitivity were counteracted by a soluble guanylate cyclase (sGC) inhibitor, ODQ (1H‐[1,2,4]‐oxadiazolo[4,3‐a]quinoxalin‐1‐one), suggesting that this effect of CO is mediated via cyclic GMP.
Finally, the inhibitory effect of CO upon mechanical nociceptor hypersensitivity was prevented by the NO synthase blocker, L‐NMMA (NG‐monomethyl L‐arginine), suggesting that the impairment of mechanical hypersensitivity elicited by CO depends on the integrity of the NO pathway.
In conclusion, the results presented in this paper imply that endogenously CO produced by HO plays an anti‐hyperalgesic role in inflamed paws, probably by increasing the intracellular levels of cyclic GMP in the primary afferent neurone.

British Journal of Pharmacology (2001) 132, 1673–1682; doi:10.1038/sj.bjp.0704014
Characterization of the effects of isoprostanes on platelet aggregation in human whole blood
Authors: Cranshaw Julius H , Evans Timothy W , Mitchell Jane A 
Published: January 2005

We tested the effects of 11 commercially‐available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer.
None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub‐threshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8‐iso PGE1>8‐iso PGE2>8‐iso PGF2α>8‐iso PGF3α>8‐iso‐13,14‐dihydro‐15‐keto PGF2α).
Blood incubated with LPS to induce a gross inflammatory response exhibited a time dependent (2 – 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619‐induced aggregation were enhanced in blood treated with LPS.
L‐NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L‐NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action.
Thus, in human whole blood the action of 8‐iso PGE1, 8‐iso PGE2, 8‐iso PGF2α, 8‐iso PGF3α, and 8‐iso‐13,14‐dihydro‐15‐keto PGF2α is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation.

British Journal of Pharmacology (2001) 132, 1699–1706; doi:10.1038/sj.bjp.0704019
Role of p38 MAP kinase in LPS‐induced airway inflammation in the rat
Authors: Haddad El‐Bdaoui , Birrell Mark , McCluskie Kerryn , Ling Andrea , Webber Stephen E , Foster Martyn L , Belvisi Maria G 
Published: January 2005

We investigated the effect of the p38 kinase inhibitor SB 203580 on airway inflammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 significantly inhibited (ED50=15.8 mg kg−1) plasma levels of TNF‐α in rats challenged with LPS (1.5 mg kg−1, i.p.).
Aerosolized LPS induced a peak in TNF‐α levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL) fluid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL‐1β levels and the initial plateau of neutrophilia observed in the BAL fluid.
SB 203580 (100 mg kg−1), had no effect on peak TNF‐α levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg−1) significantly reduced both TNF‐α levels and neutrophilic inflammation. However, the BAL fluid from rats pre‐treated with either compound significantly inhibited TNF‐α release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively).
Alternatively, SB 203580 (100 mg kg−1) produced dose‐related inhibition of BAL IL‐1β levels (67.5% inhibition, P<0.01) and BAL neutrophilia (45.9% inhibition, P<0.01) 4 h after LPS challenge.
P38 protein was present in lung tissue and the level of expression was not affected by LPS treatment.
P38 kinase appears to be involved in the release of IL‐1β and the sustained neutrophilic response in the BAL fluid. This data may suggest a role for p38 inhibitors in the treatment of airway inflammatory diseases in which neutrophilia is a feature of the lung pathology.

British Journal of Pharmacology (2001) 132, 1715–1724; doi:10.1038/sj.bjp.0704022
Effects of authentic and VLDL hydrolysis‐derived fatty acids on vascular smooth muscle cell growth
Authors: Gouni‐Berthold Ioanna , Berthold Heiner K , Seul Claudia , Ko Yon , Vetter Hans , Sachinidis Agapios 
Published: January 2005

There are contradictory findings regarding the effects of free fatty acids on vascular smooth muscle cell (VSMC) growth. In the present study we investigated the effects of fatty acids released from hydrolysis of human VLDL triglycerides by lipoprotein lipase and of the fatty acids most abundant in the hydrolysed VLDL, namely oleic, linoleic, palmitic and myristic acid, all non albumin‐bound, on VSMC growth.
The effect of fatty acids on VSMC growth was assessed by [3H]‐thymidine incorporation, colourimetrically, by cell counting, by determination of the cytoplasmic histone‐associated DNA fragments and the caspase 3 activity. The fatty acid concentrations were determined by gas chromatography‐mass spectrometry. Stimulation of ERK1/2 and p38 was determined by the chemiluminescence Western blotting method.
Incubation of VSMC with purified VLDL (100 μg ml−1) and lipoprotein lipase (35 u ml−1) led to almost complete cell death although the ERK1/2 and the p38 MAP kinases were stimulated. The EC50 of oleic, linoleic, myristic and palmitic acid were 4.6±1.3, 2.4±0.2, 116±10 and 287±30 μM, respectively. The estimated EC50 of myristic and palmitic acid when derived from hydrolysed VLDL were 10 and 8 times, respectively, lower than when used alone. Apoptosis was not involved in the fatty acid‐induced VSMC growth suppression/death.
We conclude that (a) non albumin‐bound fatty acids cause VSMC necrosis in a dose‐dependent manner with a parallel ERK1/2 and p38 stimulation, (b) unsaturated fatty acids are more toxic to VSMC than saturated, and (c) saturated fatty acids are more toxic to VSMC in the hydrolysed VLDL than when used individually.

British Journal of Pharmacology (2001) 132, 1725–1734; doi:10.1038/sj.bjp.0704026