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Biomedical subjects

G Bessard

Publications and source records attributed to G Bessard.

At least 19 recordsLinked to original sources
PubMed2005

6-tioguanine monitoring in steroid-dependent patients with inflammatory bowel diseases receiving azathioprine.

BACKGROUND: 6-Thioguanine (6-tioguanine) nucleotides are the active metabolites of azathioprine. AIM: The aim of the study was to evaluate the rate of clinical remission without steroids in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine, the medium- and long-term efficacy and the predictive factors of clinical response when monitoring 6-tioguanine. METHODS: Steroid-dependent Crohn's disease and ulcerative colitis patients receiving either azathioprine or not (treated later with a daily dose of 2.5 mg/kg) were prospectively included. 6-tioguanine was monitored at 1 and 2 months and every 3 months thereafter for 1 year. The azathioprine dose was adapted to reach a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells. Thiopurine methyltransferase genotype/phenotype was evaluated in some patients. RESULTS: A total of 106 patients were prospectively included (70 Crohn's disease, 36 ulcerative colitis). The clinical remission rate without steroids in patients receiving azathioprine, in intention-to-treat analysis, was 72% and 59% at 6 and 12 months, respectively. The remission rate was significantly higher in patients with 6-tioguanine >250 pmol/8 x 10(8) RBC (86% and 69% at 6 and 12 months, respectively; P < 0.01). No significant difference was observed between Crohn's disease and ulcerative colitis patients whether treated by azathioprine or not on inclusion. In the univariate analysis, the absence of Crohn's disease stenosis, a 6-tioguanine level >250 pmol/8 x 10(8) RBC, and an increase of erythrocyte mean corpuscular volume were the factors predictive of a favourable clinical response. In the multivariate analysis, only a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells was a predictive factor of favourable clinical remission. CONCLUSIONS: Clinical remission without steroids is significantly more likely when monitoring 6-tioguanine so as to reach a level of >250 pmol/8 x 10(8) red blood cells in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine (86% and 69% at 6 and 12 months, respectively).

Adolescent↗
PubMed2005

5-lipoxygenase expression and activity in aorta from streptozotocin-induced diabetic rats.

We previously reported an activation of the 5-lipoxygenase pathway in aorta from streptozotocin-induced diabetic rats. The aim of this study was to investigate whether this activation was associated with an increased expression of 5-lipoxygenase, an increased cysteinyl leukotriene (CysLT) production in response to arachidonic acid or calcium ionophore A23187 and/or a hypersensitivity of the aorta to CysLTs in streptozotocin-induced diabetic rats. In aorta from diabetic and control rats, reverse transcriptase-PCR and western blot analysis with a specific 5-lipoxygenase antibody provided evidence for the presence of 5-lipoxygenase in aorta. However, the expression of 5-lipoxygenase was not significantly different between diabetic and control rats. Challenge by A23187 (10 microM) and arachidonic acid (10 microM and 0.1 mM) with or without A23187 (10 micromol/l) induced a significant increase of CysLT release (measured by enzyme immunoassay) that was in the same range in aorta from control and diabetic rats. In contrast, aortas from diabetic rats showed a greater sensitivity to LTC4 and LTD4 contractile effects. These data suggested that the activation of the 5-lipoxygenase pathway previously reported in streptozotocin-induced diabetic rats could be explained by an augmented sensitivity to CysLTs of the diabetic aorta.

Animals↗
PubMed2004

Chronic intermittent hypoxia increases infarction in the isolated rat heart.

Coronary heart disease is frequently associated with obstructive sleep apnea syndrome and treating obstructive sleep apnea appears to significantly improve the outcome in coronary heart disease. Thus we have developed a rat model of chronic intermittent hypoxia (IH) to study the influence of this condition on myocardial ischemia-reperfusion tolerance and on functional vascular reactivity. Wistar male rats were divided in three experimental groups (n = 12 each) subjected to chronic IH (IH group), normoxia (N group), or control conditions (control group). IH consisted of repetitive cycles of 1 min (40 s with inspired O(2) fraction 5% followed by 20 s normoxia) and was applied for 8 h during daytime, for 35 days. Normoxic cycles were applied in the same conditions, inspired O(2) fraction remaining constant at 21%. On day 36, mean arterial blood pressure (MABP) was measured before isolated hearts were submitted to an ischemia-reperfusion protocol. The thoracic aorta and left carotid artery were also excised for functional reactivity studies. MABP was not significantly different between the three experimental groups. Infarct sizes (in percent of ventricles) were significantly higher in IH group (46.9 +/- 3.6%) compared with N (26.1 +/- 2.8%) and control (21.7 +/- 2.1%) groups. Vascular smooth muscle function was similar in aorta and carotid arteries from all groups. The endothelium-dependent relaxation in response to acetylcholine was also similar in aorta and carotid arteries from all groups. Chronic IH increased heart sensitivity to infarction, independently of a significant increase in MABP, and did not affect vascular reactivity of aorta and carotid arteries.

Animals↗
PubMed2004

Mass spectrometric determination of acromelic acid A from a new poisonous mushroom: Clitocybe amoenolens.

As Clitocybe acromelalga, the mushroom Clitocybe amoenolens is responsible for erythermalgia. Acromelic acids isolated from C. acromelalga have been suspected to be to some extend the active principles. The objective was to develop a specific and sensitive liquid chromatographic-mass spectrometric method that would allow acromelic acid A identification and quantification in mushrooms. The method involved a single-step methanol-water extraction followed by a selective cleanup of the extract with solid-phase extraction cartridges (strong-anion exchange). The chromatographic separation was achieved on a porous graphitic carbon column with acetonitrile-water-formic acid as mobile phase. Detection was done with a mass analyzer equipped with a TurboIonSpray source, operated in the negative ionization mode. Acromelic acid A concentration was determined in dried mushroom at around 325 ng/mg in C. amoenolens and 283 ng/mg in C. acromelalga.

Agaricales↗
PubMed2004

Oxidative stress and baroreflex sensitivity in healthy subjects and patients with mild-to-moderate hypertension.

Decreased baroreflex sensitivity (BRS) is a prognostic marker in essential hypertension. Animal experiments suggest that decreased BRS is related to increased oxidative stress. Our study was aimed at testing whether oxidative stress, estimated by isoprostane 15-F(2t)-IsoP urinary levels, is correlated to BRS variation in healthy subjects as well as in patients suffering from essential hypertension. Urinary 15-F(2t)-IsoP levels and BRS were evaluated in two groups of subjects: healthy volunteers (n=64) and patients with untreated mild-to-moderate hypertension (n=33). Data were analysed in 61 and 31 subjects, respectively, BRS analysis being impossible in three and two subjects, respectively. 15-F(2t)-IsoP levels were measured using gas chromatography/mass spectrometry. BRS was measured using the sequence method [PS+/RR+ and PS-/RR-] and crossspectral analysis (CSP) (MF gain) at rest, lying down. No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and BRS (sequence method and CSP) in either healthy controls or hypertensive patients. Our study shows that oxidative stress is not involved in interindividual variations of BRS in healthy subjects and patients suffering from mild-to-moderate hypertensionJournal of Human Hypertension (2004) 18, 517-521. doi:10.1038/sj.jhh.1001684 Published online 12 February 2004

Adult↗
PubMed2003

Drug interaction between infliximab and azathioprine in patients with Crohn's disease.

BACKGROUND: A drug interaction has been observed between infliximab and methotrexate in rheumatoid arthritis. AIM: To look for an interaction between infliximab and azathioprine in Crohn's disease patients using the active metabolites of azathioprine: 6-tioguanine nucleotides. METHODS: Patients receiving azathioprine who required infliximab for ileo-colonic or ano-perineal Crohn's disease were recruited prospectively. 6-tioguanine nucleotide levels were evaluated before infusion, within 1-3 weeks after the first infusion and 3 months after the first infusion. The clinical outcome was evaluated by the Harvey-Bradshaw index or the closure of ano-perineal fistulas. RESULTS: Thirty-two patients were included (17 received one infusion and 15 received three infusions). The mean 6-tioguanine nucleotide level was comparable before and 3 months after the first infusion, but a significant increase was observed within 1-3 weeks after the first infusion (P < 0.001). In parallel, a significant decrease in leucocyte count and increase in mean corpuscular volume were observed; these modifications were normalized 3 months after infusion. An increase in 6-tioguanine nucleotide level of greater than 400 pmol/8 x 108 erythrocytes was strongly related to good tolerance and a favourable response to infliximab, with a predictive value of 100%. CONCLUSIONS: This prospective study provides evidence for a drug interaction between azathioprine and infliximab.

Adolescent↗
PubMed2003

Automated solid-phase extraction and liquid chromatography-electrospray ionization-mass spectrometry for the determination of flunitrazepam and its metabolites in human urine and plasma samples.

A sensitive and specific method using reversed-phase liquid chromatography coupled with electrospray ionization-mass spectrometry (LC-ESI-MS) has been developed for the quantitative determination of flunitrazepam (F) and its metabolites 7-aminoflunitrazepam (7-AF), N-desmethylflunitrazepam (N-DMF) and 3-hydroxyflunitrazepam (3-OHF) in biological fluids. After the addition of deuterium labelled standards of F,7-AF and N-DMF, the drugs were isolated from urine or plasma by automated solid-phase extraction, then chromatographed in an isocratic elution mode with a salt-free eluent. The quantification was performed using selected ion monitoring of protonated molecular ions (M+H(+)). Experiments were carried out to improve the extraction recovery (81-100%) and the sensitivity (limit of detection 0.025 ng/ml for F and 7-AF, 0.040 ng/ml for N-DMF and 0.200 ng/ml for 3-OHF). The method was applied to the determination of F and metabolites in drug addicts including withdrawal urine samples and in one date-rape plasma and urine sample.

Adult↗
PubMed2001

Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides in guinea pig tracheal smooth muscle.

Relaxation and modulation of cyclic AMP production in response to atrial natriuretic peptides were investigated in epithelium-denuded guinea pig tracheal rings, treated with indomethacin (5 microM) and phosphoramidon (1 microM) and contracted with histamine (3 microM). Atrial natriuretic peptide (ANP) was a more potent relaxant than C-type natriuretic peptide whereas ANP-(4-23) was inactive suggesting the involvement of ANP(A) receptors in the relaxant effect of ANP. ODQ (1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one, 10 microM), a selective inhibitor of soluble guanylyl cyclase, markedly inhibited the relaxant response to sodium nitroprusside. The relaxant response to ANP was not altered by ODQ demonstrating the involvement of particulate guanylyl cyclase. ANP-induced relaxations, as well as sodium nitroprusside-induced relaxations, were similarly potentiated by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one, 3 microM), a type IV phosphodiesterase inhibitor, and by zaprinast (2-(2-propyloxyphenyl)-8-azapurin-6-one, 10 microM), a type V phosphodiesterase inhibitor. ANP-mediated response was unaffected by glibenclamide (10 microM), a selective blocker of ATP-sensitive K(+) channels, and by apamin (1 microM), a selective blocker of small-conductance Ca(2+)-activated K(+) channels. Iberiotoxin (100 nM) extensively prevented the relaxant effect of ANP suggesting the activation of large-conductance Ca(2+)-activated K(+) channels. In addition, ANP (10 nM) and ANP-(4-23) (100 nM) significantly reduced forskolin (1 microM)-stimulated cAMP accumulation suggesting, for the first time, the presence of functional ANP(C) receptors in guinea pig airway smooth muscle. However, relaxations to forskolin and to isoproterenol were not altered in the presence of ANP-(4-23) or ANP demonstrating that the inhibitory effect of ANP-(4-23) and ANP on adenylyl cyclase was not sufficient to alter the functional response induced by these two activators of adenylyl cyclase.

Adenylyl Cyclases↗
PubMed2001

Increased lipid peroxidation in patients with pulmonary hypertension.

Isoprostanes are chemically stable lipid peroxidation products of arachidonic acid, the quantification of which provides a novel approach to the assessment of oxidative stress in vivo. The main objective of this study was to quantify the urinary levels of isoprostaglandin F(2alpha) type III (iPF(2alpha)-III), an F(2)-isoprostane, in patients with pulmonary hypertension (PHT) in comparison with healthy controls. The secondary objective was to test whether baseline iPF(2alpha)-III levels correlate to the reversibility of pulmonary hypertension in response to inhaled NO challenge. Urinary iPF(2alpha)-III levels were measured by gas chromatography-mass spectrometry in 25 patients with PHT, 14 of whom were investigated for response to inhaled NO challenge. Urinary iPF(2alpha)-III levels in PHT patients (225 +/- 27 pmol/mmol creatinine) were 2.3 times as high as in controls (97 +/- 7 pmol/mmol creatinine, p < 0.001). The mean pulmonary arterial pressure variation and the pulmonary vascular resistance variation in response to inhaled NO were correlated to basal iPF(2alpha)-III levels. This study shows that oxidative stress is increased in patients with pulmonary hypertension. Furthermore, iPF(2alpha)-III levels inversely correlate to pulmonary vasoreactivity. These observations are consistent with the hypothesis that free radical generation is involved in PHT pathogenesis.

Adolescent↗
PubMed2001

Determination of isoprostaglandin F2alpha type III in human urine by gas chromatography-electronic impact mass spectrometry. Comparison with enzyme immunoassay.

F2-Isoprostanes are stable lipid peroxidation products of arachidonic acid, the quantification of which provides an index of oxidative stress in vivo. We describe a method for analysing isoprostaglandin F2alpha type III (15-F2t-IsoP) in biological fluids. The method involves solid-phase extraction on octadecyl endcapped and aminopropyl cartridges. After conversion to trimethylsilyl ester trimethylsilyl ether derivatives, isoprostaglandin F2alpha type III is analysed by mass spectrometry, operated in electronic impact selected ion monitoring mode. We have compared enzyme immunoassay (EIA; Cayman, Ann Arbor, MI, USA) to this method with 30 human urine aliquots following the same extraction procedure in order to determine the agreement between both methods. Isoprostaglandin F2alpha type III concentrations determined with gas chromatography-mass spectrometry (GC-MS) did not agree with those determined with EIA. Our results suggest that GC-MS and EIA do not measure the same compounds. As a consequence, comparison of clinical results using GC-MS and EIA should be avoided.

Cross Reactions↗
PubMed2001

Isoprostaglandin E2 type-III (8-iso-prostaglandin E2) evoked contractions in the human internal mammary artery.

E2-isoprostanes are recently discovered compounds that are produced in vivo from free radical-catalysed peroxidation of arachidonic acid. One such compound whose formation is favoured by this mechanism is isoprostaglandin E2 type III (iPE2-III, also named 8-iso-prostaglandin E2 or 15-E2t-isoprostaglandin). The aim of this study was to evaluate the vasomotor properties of iPE2-III in isolated human internal mammary artery. In organ bath, iPE2-III was approximately 10 times more potent than isoprostaglandin F2alpha-III and 27 times more potent than prostaglandin E2, whereas both isoprostaglandin F3alpha-III and 15-epi-isoprostaglandin F2alpha-II induced weak contractions. The responses to iPE2-III were inhibited in a concentration-dependent manner by the thromboxane A2 receptor antagonist GR 32191 (3.10(-9) to 3.10(-7) M). Indomethacin, a cyclooxygenase inhibitor and phosphoramidon, an endothelin converting enzyme inhibitor, did not affect iPE2-III response. These data shows that iPE2-III is a more potent vasoconstrictor of human internal mammary arteries than isoprostaglandin F2alpha-III. These effects are mediated by TP receptors, but involve neither cyclooxygenase products nor endothelins. iPE2-III production may induce more pronounced vasomotor effects than isoprostaglandin F2alpha-III in situations of oxidative stress, and in particular may modulate internal mammary artery tone following coronary bypass surgery.

Aged↗
PubMed2001

Enhanced in vivo lipid peroxidation in scleroderma spectrum disorders.

OBJECTIVE: A new family of prostaglandin F2 isomers called F2-isoprostanes, produced by free radical peroxidation of arachidonic acid, has recently been described in vivo. Its quantification has been suggested to be a reliable measure of oxidant injury in vivo. The purpose of this study was to investigate urinary F2-isoprostane formation as an index of lipid peroxidation in scleroderma spectrum disorders. METHODS: Urine samples were obtained from 52 patients with systemic sclerosis (SSc; n = 37) or undifferentiated connective tissue diseases (UCTD; n = 15) and from 20 healthy volunteers. Urinary isoprostaglandin F2alpha type III (iPF2alpha-III) and 11-dehydro thromboxane B2 (11-dehydroTXB2) concentrations were determined using enzyme immunoassays. RESULTS: The urinary concentration of iPF2alpha-III was approximately twice as high in patients (mean +/- SEM 229+/-16 pmoles/mmoles creatinine) as in controls (116+/-9 pmoles/mmoles creatinine) (P < 0.0001). However, the urinary concentration of iPF2alpha-III was not significantly different among patients with UCTD, limited SSc, and diffuse SSc (mean +/- SEM 221+/-27 versus 245+/-32 versus 220+/-25 pmoles/mmoles creatinine, respectively). No significant correlation was found between the urinary concentrations of iPF2alpha-III and 11-dehydroTXB2. CONCLUSION: This study provides evidence of enhanced lipid peroxidation in both SSc and UCTD, and suggests a rationale for antioxidant treatment of SSc. Formation of F2-isoprostanes has to be investigated as a means for the evaluation of such therapy.

Adult↗
PubMed2001

Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats.

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.

Angiotensin II↗
PubMed2001

Urinary F2-isoprostanes formation in kidney transplantation.

BACKGROUND: Oxygen free-radical mediated lipid peroxidation has been implicated in many diseases such as chronic renal failure, hemodialysis and chronic kidney transplant rejection. However, insight into the role of free radical generation in kidney transplantation has been constrained by the limitations of current indexes of oxidant stress in vivo. Isoprostaglandin F2alpha type-III (iPF2alpha-III, formerly known as 8-iso-prostaglandin F2alpha) is emerging as a reliable marker of oxidant stress in vivo. The purpose of our study was to investigate iPF2alpha-III formation as an index of lipid peroxidation in the 5 d following kidney transplantation. METHODS: Urinary iPF2alpha-III measurements were performed by enzyme immunoassay from day I to 5 in 11 patients undergoing kidney transplantation. Results were compared with 11 healthy volunteers matched in sex, age and cigarette smoking. RESULTS: Urinary excretion of iPF2alpha-III at day 1 did not significantly differ between control and transplant group (111 +/- 17 vs. 92 +/- 10 pM/ mM creatinine, respectively, NS). Urinary iPF2alpha-III levels did not differ between day 1 to 5, and were not correlated to cold ischaemia time. CONCLUSION: Our study shows no evidence of enhanced lipid peroxidation in the first 5 d following kidney transplantation.

Adult↗
PubMed2001

Formation of isoprostanes in children with type IIa hypercholesterolemia.

F2-isoprostanes are stable lipid peroxidation products of arachidonic acid and their quantification provides a novel approach to the assessment of oxidative stress in vivo. F2-isoprostanes are present in increased amounts in adult hypercholesterolemia, but no data exist concerning children. We investigated urinary isoprostaglandin F2, type III production as an index of lipid peroxidation in 15 children presenting with type IIa hypercholesterolemia (serum total cholesterol, 290 [SD +/- 70] mg/dl; low-density lipoprotein cholesterol, 210 [SD +/- 90] mg/dl) compared with 15 sex- and age-paired control children (serum total cholesterol, 160 [SD +/- 20] mg/dl). Urinary levels of isoprostaglandin F2alpha type III were measured by gas chromatography mass spectrometry. Urinary concentrations did not differ significantly in hypercholesterolemic children compared with control children (84.7 [SD +/- 37] vs. 96 [SD +/- 35] pmol/mmol creatinine, respectively). No significant correlation was found with total cholesterol, low-density-lipoprotein and high-density-lipoprotein cholesterol, and apolipoprotein B and A1 serum levels. F2-isoprostane urinary levels in children with type IIa hypercholesterolemia do not differ from those of age- and sex-matched control children and are not correlated to blood lipid parameters, suggesting that hypercholesterolemia is not associated with increased lipid peroxidation in childhood.

Adolescent↗
PubMed2001

Cysteinyl leukotrienes modulate angiotensin II constrictor effects on aortas from streptozotocin-induced diabetic rats.

Angiotensin II (Ang II) is a vasopressor peptide involved in the pathogenesis of cardiovascular diseases associated with diabetes mellitus. We have previously reported that the 5-lipoxygenase-derived products, particularly the cysteinyl leukotrienes (CysLTs), are involved in Ang II-induced contraction. In this study, we demonstrated that CysLTs contribute to the contraction elicited by Ang II in isolated aortas from streptozotocin-induced diabetic (SS) rats but not from insulin-treated diabetic rats, fructose-fed rats, or control rats. In an organ bath, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/L) reduced by 37.6+/-8.2% and 30.1+/-10.9% the Ang II-induced contractions in intact and endothelium-denuded aortic rings, respectively, from SS rats. In contrast, the CysLT(1) receptor antagonist (MK571, 1 micromol/L) or the dual CysLT(1)/CysLT(2) receptor antagonist (BAY-u9773, 0.1 micromol/L) did not affect Ang II-induced contraction. In addition, Ang II induced a 6.2+/-1.5-fold increase in CysLT release through the stimulation of the Ang II type 1 receptor. Furthermore, the urinary excretion of leukotriene E(4) was increased in SS rats (leukotriene E(4), 13.7+/-2.9 ng/24 h [SS rats, n=10] versus 1.5+/-0.5 ng/24 h [control rats, n=6]; P<0.0004). These data suggest the activation of the 5-lipoxygenase pathway in SS rats and the involvement of 5-lipoxygenase-derived products, particularly the CysLTs, in Ang II-induced contraction in aortas from SS rats through stimulation of CysLT receptors different from the well-characterized CysLT(1) or CysLT(2) receptor.

Angiotensin II↗
PubMed2000

Human internal mammary artery contraction by isoprostaglandin f(2alpha) type-III [8-iso-prostaglandin F(2alpha)].

Isoprostaglandin F(2alpha) type-III (formerly known as 8-iso-prostaglandin F(2alpha)) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F(2alpha) type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F(2alpha) type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. In organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F(2alpha) type-III stimulation. The responses to isoprostaglandin F(2alpha) type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2beta,3beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3x10(-9) to 3x10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3x10(-5) M), an EP(1)-DP receptor antagonist had no effect on isoprostaglandin F(2alpha) type-III-induced contractions. The maximal responses to isoprostaglandin F(2alpha) type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E(max): 147+/-20% vs. 213+/-19% in control group, P<0.05). Isoprostaglandin F(2alpha) type-III stimulated thromboxane B(2) release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5, 10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F(2alpha) type-III response. In conclusion, this study shows that (1) isoprostaglandin F(2alpha) type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F(2alpha), (2) the contractions induced by isoprostaglandin F(2alpha) type-III are mediated by TP receptor but not EP(1)-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F(2alpha) type-III. Isoprostaglandin F(2alpha) type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situations of oxidant stress such as coronary bypass surgery.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗