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1 Department of Peptide Biology, Baker Heart Research Institute, Melbourne, Vic., Australia
2 Department of Medicine, Monash University, Clayton, Vic., Australia
* To whom correspondence should be addressed. E-mail: michael.hickey{at}med.monash.edu.au.
Bradykinin is a vasoactive peptide that has been shown to increase the permeability of the cerebral microvasculature to blood-borne macromolecules. The two zinc metalloendopeptidases EC 3.4.24.15 (EP 24.15) and EC 3.4.24.16 (EP 24.16) degrade bradykinin in vitro, and are highly expressed in brain. However, the role that these enzymes play in bradykinin metabolism in vivo remains unclear. In the present study, we investigated the role of EP 24.15 and EP 24.16 in the regulation of the effects of bradykinin-induced alterations in microvascular permeability. Permeability of the cerebral microvasculature was assessed in anesthetized Sprague-Dawley rats by measuring the clearance of 70 kDa FITC dextran from the brain. Inhibition of EP 24.15 and EP 24.16 by the specific inhibitor JA-2 resulted in the potentiation of bradykinin-induced increases in cerebral microvessel permeability. The level of potentiation was comparable to that achieved by inhibition of angiotensin converting enzyme. These findings provide the first evidence of an in vivo role for EP 24.15/ EP 24.16 in brain function, specifically in regulating alterations in microvessel permeability induced by exogenous bradykinin.
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