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Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts EFFECT OF 7-KETOCHOLESTEROL AND 7β-HYDROXYCHOLESTEROL ON CELLULAR VIABILITY OF HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS. Agnoletto Laura Dip. di Farmacologia e Anestesiologia, Università di Padova, Padova E-mail : [email protected] Oxidized low density lipoproteins (oxLDLs) are involved in atherogenesis (1) and their cytotoxicity has been linked to the formation of oxysterols (oxidized products of cholesterol) (2). The major oxysterols found in oxLDLs are 7β-hydroxycholesterol (7βOHC) and 7ketocholesterol (7-KC) and it has been reported that high concentrations (>40µg/mL) of these oxysterols induce apoptosis on endothelial cells (EC) (3). However it has been shown that oxLDLs have a dual effect on EC viability inducing apoptosis or proliferation depending on their concentration (4). Recently it has been reported that low concentrations of oxLDLs induce upregulation of endothelial NO synthase (eNOS) leading to EC survival, while high concentrations of oxLDLs induce downregulation of eNOS leading to endothelial damage (5). The objective of this study was to investigate the effect of low concentrations of oxysterols on human umbilical vein endothelial cells (HUVEC) and the pathways involved. HUVEC were isolated from human umbilical cord and used from passage two to six. Cell viability was 3 determined by the measure of MTT reduction. Cell proliferation was measured by [ H] thymidine incorporation assay. Apoptosis was determined by: a) flow cytometric analysis of annexin V and propidium iodide binding; b) caspase-3 activity of cell lysates. Long term treatment (24 h, 48 h, 96 h) of HUVEC with low concentrations of 7-KC or 7βOHC (1-10 µg/mL) increased MTT reduction in a concentration dependent manner. For both oxysterols maximal effect was obtained at 10 µg/ml at each time of treatment (+100% and +200% for 7KC and 7βOHC, respectively). This effect was not 3 associated with an increase in cell proliferation as assessed by [ H] thymidine incorporation assay. Low concentrations of 7βOH caused a 25% decrease in caspase-3 activity (after 6 h). 7-KC was not able to reduce caspase-3 activity after 6 and 10 h treatment. Antiapoptotic effect of 7βOH was confirmed by flow cytometric analysis after 24 h and 48 h of incubation. Treatment of HUVEC for 24 h with cholesterol (1-10 µg/mL) produced no effect on cell viability indicating that oxidation in C7 is necessary for the antiapoptotic activity. Higher concentrations of the two oxysterols induced cell death. As reported for oxLDL, 7βOHC and 7-KC show a biphasic effect on HUVEC viability depending on their concentration. The pathways involved in these effects and in particular the role of eNOS are the object of current investigations in our laboratory. 1. Witztum J.L and Steinberg D. (1991) J. Clin. Invest. 88:1785-1792. 2. Schroepfer G.J. (2000) Physiol Rev. 80:361-554. 3. Lizard G. et al.(1999) Arterioscler. Thromb. Vasc. Biol. 19:1190 4. Galle J.et al. (2001) Kidney Int. Suppl 78:S120-S123 5. Ken-ichi Hirata et al. (1995) Circ. Res. 76:958-962 2 Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts NK-1 AND NK-3 TACHYKININ RECEPTORS IN PANCREATIC ACINAR CELLS AFTER ACUTE EXPERIMENTAL PANCREATITIS IN RATS Agostini Simona Dip. di Fisiologia Umana e Farmacologia “V. Erspamer”, Univ. “La Sapienza” Roma E-mail: [email protected] Activation of neurokinin-1 (NK-1) receptors but not of NK-3 stimulates amylase release from isolated pancreatic acini of the rat. Immunofluorescence studies show that NK-1 receptors are more strongly expressed than NK-3 receptors on pancreatic acinar cells under basal conditions. No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats. We therefore investigated the relationships between expression of these two TK receptors and experimental acute pancreatitis induced by stimulating pancreatic amylase with caerulein (CK) in rats. Hyperstimulation of the pancreas by CK caused an increase in plasma amylase and pancreatic water content, and resulted in morphological evidence of cytoplasmic vacuolization. Immunofluorescence analysis revealed a similar percentage of NK-1 receptor antibody immunoreactive acinar cells in rats with pancreatitis and in normal rat tissue but a larger percentage of NK-3 receptor immunoreactive cells in acute pancreatitis than in normal pancreas. Western blot of NK-1 and NK-3 receptor protein levels after CK-induced pancreatitis showed no change in NK-1 receptors but a stronger increase in NK-3 receptor expression in pancreatic acini in comparison with normal rats thus confirming the immunofluorescence data. These new findings support previous evidence that SP-mediated functions within the pancreas go beyond sensory signal transduction contributing to neurogenic inflammation, and suggest that SP plays a role in regulating pancreatic exocrine secretion via acinar NK-1 receptors. The significant increase in NK-3 receptors during pancreatic stimulation suggests that NK-3 receptors also intervene in the pathogenesis of mild acute pancreatitis in rats. 3 Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts FUNCTIONAL COUPLING OF ANGIOTENSIN II TYPE I RECEPTOR WITH INSULIN RESISTANCE AT GLUCOSE AND FATTY ACID UPTAKE IN IMMORTALISED CARDIOMYOCYTES (HL-1 CELLS) Alfarano Chiara Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze [email protected] Heart insulin-resistance causes incorrect energetic substrates supply, an increasingly recognized feature of cardiac disease. So far, the role of angiotensin II in raising insulinresistance has been studied limitedly to glucose uptake. We investigated whether, in isolated cardiomyocytes, angiotensin II raised insulin-resistance not only at glucose but also at fatty acid uptake. HL-1 cells, immortalised cardiomyocytes, were chosen as experimental model. In these cells facilitated glucose and palmitic acid 3 14 uptakes were measured radiochemically using [ H]-2-deoxy-D-glucose and [ C]-palmitic acid respectively. To mimic pathological microenvironments, cells were exposed to angiotensin II (100 nM) for 18 h in the absence or in the presence of irbesartan, PD123319, or PD98059, an inhibitor of ERK1/2 activation. Reactive oxygen species and angiotensin II receptor subtypes mRNA levels were visualised by dichlorofluorescein and by semi-quantitative RT-PCR respectively. HL-1 cells show 4 4 basal glucose and palmitic acid uptake (3.7 ± 0.7 pmol/10 cells/10 min and 53.9 ± 4.0 pmol/10 cells/5 min respectively) that are stimulated further by insulin. Angiotensin II increased cell oxidative stress and mRNA for type I receptor. Exposure to angiotensin II increased the palmitic acid uptake (76.6 ± 4 3.7 pmol/10 cells/5 min) but blunted the insulin stimulation of glucose and of palmitic acid uptake. Insulin effects at substrate uptakes were restored in the presence of irbesartan or PD98059. Our results show the potential role of angiotensin II in dysregulating heart energetic substrates supplementation and support the effectiveness of type I receptor blockers in the restoration of insulin regulatory role at fatty acid uptake. 4 Pharmacologyonline 3: 1-152 (2006) Young Researchers Abstracts 5-FLUOROURACIL EXPOSURE IN ADJUVANT CHEMOTHERAPY REGIMENS IS SIGNIFICANTLY RELATED TO DISEASE FREE SURVIVAL IN COLORECTAL CANCER PATIENTS Amatori Federica Maria Dip. di Medicina Interna, Divisione di Farmacologia e Chemioterapia, Università di Pisa, Pisa E-mail: [email protected] 5-Fluorouracil is still the mainstay in adjuvant protocols for colorectal cancers, alone or in combination with other antineoplastic agents. Several studies have investigated the disease free survival (DFS) improvement after fluoropyrimidine-based adjuvant chemotherapy, despite data concerning the possible role of 5-FU exposure on DFS are not yet available. Therefore the aim of the present study was to evaluate any correlation between 5-FU pharmacokinetics, including that of the first inactive metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU), and DFS in colorectal cancer patients candidate to receive 5-FU-based adjuvant chemotherapy. Through 3 years, 82 consecutive colorectal cancer patients, 53 men and 29 women (mean ± standard deviation age, 62.3 ± 9.2 and 58.8 ± 8.2 years, respectively), were enrolled. Planned treatment consisted of six cycles of L-leucovorin 100 mg/sqm and 5-FU 370 mg/sqm administered as i.v. boluses for 5 consecutive days every 4 weeks. Blood samples were withdrawn for up to 3 h after drug administration on day 1 of the first cycle, and 5-FU and 5-FDHU plasma levels were determined by using a validated UV-HPLC method. Individual plasma concentrations of drug and catabolite were fit according to a 2-compartments open model with the use of APO2PR computer software (Mediware, Groeningen) and the area under the time/concentration curve (AUC) value was calculated. Staging of tumors according to Astler and Coller’s classification and their histological grade (WHO grading system) were recorded, as well as relevant clinical and laboratory informations during the entire course of planned chemotherapy. In this study, 39 patients (28 males and 11 females) experienced disease recurrence, and in 89.7% of them the disease recurred within 3 years of study entry. Tumor staging affected significantly DFS among patients (p < 0.05), whereas a trend was observed for age (p = 0.056) and histological grade (p = 0.052). Pharmacokinetic analysis demonstrated that 5-FU AUC and 5-FU/5-FDHU AUC ratio were significantly lower (p < 0.05) in patients who experienced a recurrence (7.34 ± 3.61 hxmg/l and 0.73 ± 0.34, respectively) compared to other subjects (9.19 ± 4.13 hxmg/l and 0.97 ± 0.60, respectively). However, multivariate analysis showed that 5-FU exposure was not an independent factor (p = 0.07), when staging and grading were also considered, even if the risk of disease relapse was halved in patients exposed to higher concentrations of 5-FU (AUC > 7.9 hxmg/l).
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