%0 Journal Article %1 Cote2010 %A Côté, Jérôme %A Savard, Martin %A Bovenzi, Veronica %A Dubuc, Céléna %A Tremblay, Luc %A Tsanaclis, Ana Maria %A Fortin, David %A Lepage, Martin %A Gobeil, Fernand %D 2010 %J Neuropeptides %K agonists/metabolism;ReverseTranscriptasePolymeraseChainReaction drugeffects/metabolism;Bradykinin drugtherapy/metabolism;CapillaryPermeability physiology;Blood-BrainBarrier physiology;Glioma metabolism;Rats;Rats drugtherapy/metabolism;Immunohistochemistry;MagneticResonanceImaging;Male;NeoplasmTransplantation;NitricOxide Animals;BloodPressure BradykininB2 InbredF344;Receptor analogs/&/derivatives/pharmacology;BrainNeoplasms %N 2 %P 177--185 %R 10.1016/j.npep.2009.12.009 %T Selective tumor blood-brain barrier opening with the kinin B2 receptor agonist Phe(8)psi(CH(2)NH)Arg(9)-BK in a F98 glioma rat model: an MRI study. %U http://dx.doi.org/10.1016/j.npep.2009.12.009 %V 44 %X Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain barrier (BBB). One approach for transporting drugs across the BBB involves the activation of bradykinin-B2 receptors (BK-B2R). Our objective was to pharmacologically characterize the BBB permeability induced by the synthetic biostable BK-B2R analogue Phe(8)psi(CH(2)NH)Arg(9)-BK (R523) in F98 glioma-implanted Fischer rats. On day 10 post-inoculation, we detected the presence of B2R in the tumor cells and the peritumoral microvasculature (RT-PCR and immunohistochemistry). We assessed BBB permeability before and after the intracarotid (i.c.) infusion of R523 (0.1ml/min for 5min; 2.5, 10, and 50nmol/kg/min) using non-invasive dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the different sized-contrast agents Gd-DTPA (0.5kDa) and Gadomer (17kDa) (0.25mmol/kg via the caudal vein). T(1)-weighted images were analyzed for the presence or absence of contrast enhancement within and surrounding the tumor area and mathematically processed to yield a contrast agent distribution volume (CADV), which was used as an indicator of vascular permeability. Our results showed that the agonist R523 increased, in a dose-dependent manner, the CADV indexes of Gd-DTPA and Gadomer, with a maximum 2-fold increase in brain uptake of both CA. The increase in CADV induced by R523 (10nmol/kg/min) was prevented by the B2R antagonist HOE140 (20nmol/kg/min, i.c.) and the nitric oxide synthase inhibitor L-NA (5mg/kg, i.v.) but not by the B1R antagonist R892 (20nmol/kg/min, i.c.) or the cyclooxygenase inhibitor Meclofenamate (5mg/kg, i.v.). The BBB permeabilizing effect of R523 (10nmol/kg/min) lasted for <1h and was accompanied by a dose-related fall in arterial blood pressure. We concluded that R523 allows the extravasation of hydrophilic macromolecular agents (17kDa) into tumor tissues by inducing selective tumor BBB permeability via B2R- and NO-dependent mechanisms.

@article{Cote2010, abstract = {Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain barrier (BBB). One approach for transporting drugs across the BBB involves the activation of bradykinin-B2 receptors (BK-B2R). Our objective was to pharmacologically characterize the BBB permeability induced by the synthetic biostable BK-B2R analogue [Phe(8)psi(CH(2)NH)Arg(9)]-BK (R523) in F98 glioma-implanted Fischer rats. On day 10 post-inoculation, we detected the presence of B2R in the tumor cells and the peritumoral microvasculature (RT-PCR and immunohistochemistry). We assessed BBB permeability before and after the intracarotid (i.c.) infusion of R523 (0.1ml/min for 5min; 2.5, 10, and 50nmol/kg/min) using non-invasive dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with the different sized-contrast agents Gd-DTPA (0.5kDa) and Gadomer (17kDa) (0.25mmol/kg via the caudal vein). T(1)-weighted images were analyzed for the presence or absence of contrast enhancement within and surrounding the tumor area and mathematically processed to yield a contrast agent distribution volume (CADV), which was used as an indicator of vascular permeability. Our results showed that the agonist R523 increased, in a dose-dependent manner, the CADV indexes of Gd-DTPA and Gadomer, with a maximum 2-fold increase in brain uptake of both CA. The increase in CADV induced by R523 (10nmol/kg/min) was prevented by the B2R antagonist HOE140 (20nmol/kg/min, i.c.) and the nitric oxide synthase inhibitor L-NA (5mg/kg, i.v.) but not by the B1R antagonist R892 (20nmol/kg/min, i.c.) or the cyclooxygenase inhibitor Meclofenamate (5mg/kg, i.v.). The BBB permeabilizing effect of R523 (10nmol/kg/min) lasted for <1h and was accompanied by a dose-related fall in arterial blood pressure. We concluded that R523 allows the extravasation of hydrophilic macromolecular agents (17kDa) into tumor tissues by inducing selective tumor BBB permeability via B2R- and NO-dependent mechanisms.}, added-at = {2011-08-01T18:02:19.000+0200}, author = {Côté, Jérôme and Savard, Martin and Bovenzi, Veronica and Dubuc, Céléna and Tremblay, Luc and Tsanaclis, Ana Maria and Fortin, David and Lepage, Martin and Gobeil, Fernand}, biburl = {https://www.bibsonomy.org/bibtex/206cc4939a19fce7a81e361cafd13db26/crc_chus}, doi = {10.1016/j.npep.2009.12.009}, institution = {Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.}, interhash = {e5a0bf8b997bb90ea88fdc6fdd9fe1bc}, intrahash = {06cc4939a19fce7a81e361cafd13db26}, journal = {Neuropeptides}, keywords = {agonists/metabolism;ReverseTranscriptasePolymeraseChainReaction drugeffects/metabolism;Bradykinin drugtherapy/metabolism;CapillaryPermeability physiology;Blood-BrainBarrier physiology;Glioma metabolism;Rats;Rats drugtherapy/metabolism;Immunohistochemistry;MagneticResonanceImaging;Male;NeoplasmTransplantation;NitricOxide Animals;BloodPressure BradykininB2 InbredF344;Receptor analogs/&/derivatives/pharmacology;BrainNeoplasms}, language = {eng}, medline-pst = {ppublish}, month = Apr, number = 2, pages = {177--185}, pii = {S0143-4179(09)00148-6}, pmid = {20080302}, timestamp = {2011-08-01T18:02:19.000+0200}, title = {Selective tumor blood-brain barrier opening with the kinin B2 receptor agonist [Phe(8)psi(CH(2)NH)Arg(9)]-BK in a F98 glioma rat model: an MRI study.}, url = {http://dx.doi.org/10.1016/j.npep.2009.12.009}, username = {crc_chus}, volume = 44, year = 2010 }