Enzymatic barrier protects brain capillaries from leukotriene C4.
Leukotriene C4 (LTC4) increases vascular permeability in systemic, brain tumor, and ischemic brain capillaries, but not in normal brain capillaries. This study examines whether the abundance of gamma-glutamyl transpeptidase (gamma-GTP) in normal brain capillaries might act as an enzymatic barrier to vasoactive leukotrienes in the brain. Blood-brain barrier (BBB) permeability was determined by quantitative autoradiography using 14C-aminoisobutyric acid. Ischemia was produced by occluding the middle cerebral artery. Seventy-two hours after occlusion, gamma-GTP activity in ischemic brain disappeared, and LTC4 (4-micrograms total dose), which was infused into the carotid artery ipsilateral to the occlusion, selectively increased permeability, Ki, approximately twofold within core ischemic tissue and adjacent tissue, compared to vehicle alone in seven brains (15.53 +/- 6.03 vs. 7.29 +/- 3.36, p < 0.05, and 8.76 +/- 4.02 vs. 4.32 +/- 2.65, p < 0.05, respectively). No effect on BBB was seen in nonischemic brain tissue. Twenty-four hours postocclusion, gamma-GTP activity was still present, and LTC4 infusion did not increase permeability within ischemic tissue. However, inhibition of gamma-GTP with acivicin allowed LTC4 to increase permeability even 24 hours after occlusion in ischemic core and adjacent tissue compared to vehicle alone in seven brains (17.21 +/- 16.32 vs. 8.23 +/- 6.58, p < 0.05, and 11.78 +/- 7.96 vs. 4.56 +/- 1.93, p < 0.01, respectively). Acivicin almost completely blocked both the histochemical activity of gamma-GTP in brain capillaries and the metabolism of LTC4 in isolated bovine capillaries. These findings suggest that gamma-GTP may help normal brain capillaries resist the vasoactive effects of LTC4. In contrast, gamma-GTP is lost in injured brain capillaries, which allows LTC4 (in combination with other factors) to increase vascular permeability in ischemic brain and brain tumors.
Black
K L
KL
Brain Research Institute, University of California, Los Angeles Medical Center.
Baba
T
T
Pardridge
W M
WM
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000201:enzymology; D002545:Brain Ischemia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002196:Capillaries / Q000187:drug effects / Q000201:enzymology; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D005260:Female; D007555:Isoxazoles / Q000494:pharmacology; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*
D000963:Antimetabolites; D007555:Isoxazoles; D018077:Receptors, Leukotriene; C083173:leukotriene C4 receptor; D017997:Leukotriene C4; D005723:gamma-Glutamyltransferase; C006303:acivicin