Gaëlle Hardy

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.

Response of rat thoracic aorta to F2-isoprostane metabolites

This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F2-isoprostane metabolites 15-keto-15-F2t-IsoP, 2,3-dinor-15-F2t-IsoP, and 2,3-dinor-5,6-dihydro -15-F2t-IsoP in comparison with 15-F2t-IsoP on the rat thoracic aorta. 15-keto-15-F2t-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD2 value of 5.80 ± 0.05, whereas 2,3-dinor-15-F2t-IsoP and 2,3-dinor-5,6-dihydro-15-F2t-IsoP had no effect. The parent compound 15-F2t-IsoP was more potent (pD2 value: 6.46 ± 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F2t-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F2t-IsoP, with a significant decrease in the Emax values for GR32191 10−7M. Pretreatment with 2,3-dinor-15-F2t-IsoP and 2,3-dinor-5,6-dihydro-15-F2t-IsoP induced no alteration of 15-F2t-IsoP concentration-response curves. In contrast, 15-keto-15-F2t-IsoP pretreatment competitively inhibited the response to 15-F2t-IsoP. When concentration ratios of EC50 values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA2 value of 6.13. 15-keto-15-F2t-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10−8M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F2t-IsoP and 2,3-dinor-5,6-dihydro-15-F2t-IsoP induced no vasodilation. In conclusion, among the F2-isoprostane metabolites, 2,3-dinor-15-F2t-IsoP and 2,3-dinor-5,6-dihydro-15-F2t-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F2t-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.

Involvement of cysteinyl leukotrienes in angiotensin II-induced contraction in isolated aortas from transgenic (mRen-2)27 rats.

Objectives We have previously reported that 5-lipoxygenase-derived products, and particularly the cysteinyl leukotrienes (CysLTs), were involved in angiotensin II (Ang II)-induced contractions in isolated aortas from spontaneously hypertensive rats. Design The aim of this study was to assess the role of CysLTs in the vascular response to Ang II in an Ang II-dependent model of hypertension, the (mRen-2)27 transgenic rats (TGs). Methods Intact aortic rings from TG and normotensive Sprague–Dawley rats (SDs) were suspended in organ chambers for isometric tension development in response to Ang II. In addition, the release of CysLTs in response to Ang II (0.3 μmol/l) was measured by enzyme immunoassay. Results In isolated aortas from TG rats, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 μmol/l) or the CysLT1 receptor antagonist (MK571, 1 μmol/l) significantly (P < 0.05) reduced Ang II-induced contractions by 52 and 42%, respectively. In addition, Ang II induced a 2.6-fold increase in CysLT release (pg/mg dry weight tissue: 58.3 ± 17.9 (Ang II, n = 7) versus 22.5 ± 5.9 (basal, n = 7) P < 0.05), which was inhibited by the AT1 receptor antagonist losartan (1 μmol/l). In contrast, in aortas from SD rats, pretreatment with AA861 or MK571 did not alter Ang II-induced contraction and CysLT production remained unchanged after exposure to Ang II. Conclusion These data suggest that CysLTs are involved in the contractile responses to Ang II in isolated aortas from TG but not from SD rats.

Inhibition of leukotriene synthesis with MK-886 prevents a rise in blood pressure and reduces noradrenaline-evoked contraction in l-NAME-treated rats

Long‐term treatment of rats with Nω‐nitro‐L‐arginine methyl ester (L‐NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with L‐NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta. Rats were randomly assigned to four groups and orally treated for 3 weeks with L‐NAME (1 mg ml−1), L‐NAME (1 mg ml−1) plus the leukotriene biosynthesis inhibitor MK‐886 (0.1 mg ml−1), MK‐886 (0.1 mg ml−1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid. The mean arterial blood pressure (MABP) increased significantly in L‐NAME‐treated rats (173.3±9.4 mmHg (n=25)) vs Methocel‐treated rats (110.7±4.8 mmHg (n=11), P<0.001). Chronic treatment with MK‐886 prevented this rise in MABP. Aortic rings with or without endothelium were suspended in organ baths for recording isometric changes in response to noradrenaline. Pretreatment with either MK‐886 (10 μM), the CysLT1 receptor antagonist MK571 (1 μM) or the dual CysLT1/CysLT2 receptor antagonist BAY‐u9773 (0.1 μM) reduced (P<0.05) noradrenaline‐induced contractions in intact aortic rings from L‐NAME‐treated rats only. Noradrenaline (0.3 μM) induced a two‐fold increase in cysteinyl leukotriene (CysLT) release (measured by enzyme immunoassay) in intact aortic rings from L‐NAME‐treated rats only. These data suggested (1) a role for the 5‐lipoxygenase pathway in the regulation of blood pressure in L‐NAME‐treated rats and (2) the involvement of endothelial CysLTs in noradrenaline‐induced contraction in aorta from L‐NAME‐treated rats.

Cyclosporine a and Cremophor EL induce contractions of human saphenous vein : Involvement of thromboxane A2 receptor-dependent pathway

Chronic treatment with Sandimmune (cyclosporine A [CsA] dissolved in Cremophor EL [CrEL]) is often associated with hypertension and nephrotoxicity. The aims of the present study were to assess the effect of Sandimmune and its two main components (CsA and CrEL) on human saphenous veins and to study the underlying mechanism of their contractile responses. In organ bath, concentration-response curves for Sandimmune (36 ng/ml-120 microg/ml of CsA). CsA (36 ng/ml-120 microg/ml), or CrEL (2.4 microg/ml-8 mg/ml) were elicited in the presence of a thromboxane A2 (TXA2) receptor antagonist (GR32191, 0.3 microM), a cyclooxygenase inhibitor (indomethacin, 1 microM), a 5-lipoxygenase inhibitor (AA861, 10 microM), or their respective vehicles. In addition, the production of TXA2 after CsA challenge was assessed by enzyme immunoassay. Sandimmune, CsA, and CrEL induced concentration-dependent contractions on human saphenous veins. In terms of potency, CsA was a more potent vasoconstrictor agent than CrEL (EC50 values: 11.9+/-3.7 microg/ml (CsA, n = 12) vs. 1.2+/-0.4 mg/ml (CrEL, n = 16), p < 0.05). In contrast, in terms of efficacy, CrEL induced greater contractions than CsA (Emax (% of KCl 90 mM-induced contraction): 98.1+/-16.1% (CrEL, n = 16) vs. 17.0+/-4.3% (CsA, n = 12) p < 0.05). Pretreatment with GR32191 significantly reduced by 85% and 56% the contractions elicited by CsA and CrEL, respectively, whereas indomethacin had no effect. Finally, CsA (12 and 120 microg/ml) failed to stimulate TXA2 production. These in vitro data suggest that Sandimmune-induced contractions on human vascular smooth muscle appear to be mediated by CsA in the therapeutic ranges of doses and by both CsA and CrEL, which, in supratherapeutic doses, acted through a TXA2 receptor-dependent pathway.

Protease inhibitors and diltiazem increase tacrolimus blood concentration in a patient with renal transplantation: a case report

Tacrolimus is a potent calcineurin inhibitor currently used for prophylaxis and treatment of allograft rejection. As tacrolimus metabolism occurs for the most part via the cytochrome P450-3A4 (CYP3A4) enzyme system, co-administration of drugs activating or inhibiting this metabolic pathway may affect tacrolimus pharmacokinetics. We report a case of dramatic increase in tacrolimus blood concentration that could be attributed, at least in part, to enzymatic inhibition by protease inhibitors and diltiazem.

Plasminogen gene mutation with normal C1 inhibitor hereditary angioedema: Three additional French families

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