Cyclic GMP-specific phosphodiesterase inhibition and intracarotid bradykinin infusion enhances permeability into brain tumors.
Intracarotid infusion of bradykinin selectively increases the delivery of compounds into brain tumors. This study sought to determine the role of cyclic GMP in increased permeability across the blood-tumor barrier (BTB) after infusion of bradykinin. In permeability studies, 186 Wistar rats with RG2 gliomas and C6 gliomas were used. Transport across the BTB was quantified by autoradiography and reported as a unidirectional transport, Ki, for [14C]dextran (Mr 70,000) and [14C]aminoisobutyric acid (Mr 103,000), with or without inhibition of cyclic GMP-specific phosphodiesterase or soluble guanylate cyclase. We also determined cyclic GMP levels in tumors and normal brain, with or without intracarotid bradykinin infusion, using RIA. Intracarotid infusion of bradykinin selectively increased permeability in RG2 tumors and C6 tumors for both tracers. Simultaneous infusion of bradykinin and a cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (20 mg/kg), resulted in significantly increased permeability across the BTB, compared to intracarotid bradykinin infusion alone. Zaprinast also significantly prolonged the permeability effects of bradykinin. Pretreatment using i.v. infusion of the soluble guanylate cyclase inhibitor, LY-83583 (125 microg/kg), significantly attenuated the bradykinin effect of opening the BTB. Cyclic GMP levels in RG2 and C6 tumors were significantly increased after intracarotid bradykinin infusion (2.8- and 2.2-fold, respectively). Cyclic GMP levels in normal brain were not increased by bradykinin infusion. These results show that increasing cyclic GMP in tumor microvessels can increase permeability in response to bradykinin.
Sugita
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Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
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D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001920:Bradykinin / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011688:Purinones / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar
D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D001920:Bradykinin