Dizocilpine

The objective of this study was to investigate the effects of repeated, short-term ischemia on bradykinin-- mediated permeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB). The mechanism by which bradykinin transiently opens the BTB, involves B2 receptors, Ca^sup 2+^ flux, nitric oxide (NO) and cyclic GMP (cGMP). Since global and focal cerebral ischemia are known to increase levels of brain nitric oxide synthase (bNOS) and endothelial nitric oxide synthase (eNOS) we tested the hypothesis that bradykinin may increase the BTB permeability to a greater extent under ischemic rather than nonischemic conditions. The vertebral arteries in female Wistar rats were coagulated immediately after intracerebral implantation of RG2 glioma. Short-term ischemia was produced in some rats by a modification of the four-- vessel occlusion procedure for incomplete forebrain ischemia, in which the common carotid arteries were clamped daily for 15 min on days 7, 8 and 9 after tumor implantation, after which reperfusion was allowed. On day 10 after tumor implantation, bradykinin (10 (mu)g kg^sup -1^ min^sup -1^) or phosphate-buffered saline (PBS) was infused for 15 min into the right carotid artery of anesthetized, sham-operated (nonischemic controls) and ischemic rats, followed by an intravenous bolus (100 (mu)Ci kg^sup -1^) each of [^sup 14^C]-iodo-antipyrine (lAP), [^sup 14^C]-- dextran or [^sup 14^C]-aminoisobutyric acid (AIB) to measure regional cerebral blood flow (rCBF), blood volume, or unidirectional transfer constant Ki, respectively, by quantitative autoradiography. A single 15-min ischemic episode significantly decreased rCBF in the tumor center (158.9 +/- 17.33 in control vs. 58.78 +/- 24.45 ml 100 g^sup -1^ min^sup -1^ in ischemic group; p

Keywords: Blood-brain barrier, blood-tumor barrier; incomplete forebrain ischemia; bradykinin; brain tumors; nitric oxide synthase; bradykinin B2 receptor

INTRODUCTION

CONCLUSION

We describe for the first time that repeated, short-term, ischemia augments the effect of bradykinin on BTB permeability in a glioma-bearing rat model. We suggest that elevated intratumoral levels of bNOS and eNOS following this ischemia may be responsible, in part, for the observed augmentation of BTB permeability response to intracarotid infusion of bradykinin.

ACKNOWLEDGMENTS

We thank Karen L. McKeown, PhD, for critical review of the manuscript. This work was supported by NIH Grants 1PO1NS25554 and 1RO1NS32103.

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Yunhui Liu, Kazuhiro Hashizume, Ken Samoto, Masao Sugita, Nagendra Ningaraj, Kamlesh Asotra and Keith L. Black

Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Correspondence and reprint requests to: Dr Keith L. Black, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800E, Los Angeles, California 90048, USA. [black@csmc.edu] Accepted for publication November 2000.

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