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This Article Full Text Full Text (PDF) All Versions of this Article: 290/3/H1244    most recent 00934.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Biyashev, D. Articles by Hecquet, C. Search for Related Content PubMed PubMed Citation Articles by Biyashev, D. Articles by Hecquet, C.

Kallikrein activates bradykinin B₂ receptors in absence of kininogen

Departments of ¹Pharmacology and ²Anesthesiology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Submitted 1 September 2005 ; accepted in final form 31 October 2005

Kallikreins cleave plasma kininogens to release the bioactive peptides bradykinin (BK) or kallidin (Lys-BK). These peptides then activate widely disseminated B₂ receptors with consequences that may be either noxious or beneficial. We used cultured cells to show that kallikrein can bypass kinin release to activate BK B₂ receptors directly. To exclude intermediate kinin release or kininogen uptake from the cultured medium, we cultured and maintained cells in medium entirely free of animal proteins. We compared the responses of stably transfected Chinese hamster ovary (CHO) cells that express human B₂ receptors (CHO B₂) and cells that coexpress angiotensin I-converting enzyme (ACE) as well (CHO AB). We found that BK (1 nM or more) and tissue kallikrein (1–10 nM) both significantly increased release of arachidonic acid beyond unstimulated baseline level. An enzyme-linked immunoassay for kinin established that kallikrein did not release a kinin from CHO cells. We confirmed the absence of kininogen mRNA with RT-PCR to rule out kininogen synthesis by CHO cells. We next tested an ACE inhibitor for enhanced BK receptor activation in the absence of kinin release and synthesized an ACE-resistant BK analog as a control for these experiments. Enalaprilat (1 µM) potentiated kallikrein (100 nM) in CHO AB cells but was ineffective in CHO B₂ cells that do not bear ACE. We concluded that kallikrein activated B₂ receptors without releasing a kinin. Furthermore, inhibition of ACE enhanced the receptor activation by kallikrein, an action that may contribute to the manifold therapeutic effects of ACE inhibitors.

arachidonic acid; angiotensin I-converting enzyme inhibitor; kallidin; immunoassay

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