Biochemical basis of angioedema associated with recombinant tissue plasminogen activator treatment: an in vitro experimental approach.
BACKGROUND
Angioedema has been reported during recombinant tissue plasminogen activator (rtPA) treatment of acute ischemic stroke, often with concomitant use of angiotensin I-converting enzyme inhibitor treatment. Angioedema has been partly attributed to the nonapeptide bradykinin (BK), although its precise role has been poorly documented until now. The purposes of this report are 2-fold. First, we sought to define and characterize the in vitro kinin-forming capacity of rtPA when incubated with human plasma at a concentration within the therapeutic concentration range of rtPA attained in blood in vivo during fibrinolysis. Second, we sought to define the mechanism by which rtPA liberates BK from purified human single-chain high-molecular-weight kininogen, a key constituent of the contact system of plasma and the precursor of BK.


METHODS
When incubated with human plasma, in the presence of an angiotensin I-converting enzyme inhibitor, rtPA generates BK, which is further metabolized to des-Arg9-BK. The quantity of kinins generated by rtPA is similar to that observed during the activation of the contact system of plasma with a negatively charged surface, suggesting that it is physiologically relevant. The total amount of des-Arg9-BK liberated during the incubation period depends on the aminopeptidase P activity, its main degrading peptidase. Additionally, incubations using purified proteins of the fibrinolytic and the contact system pathways show that the rtPA kinin-forming capacity is mediated by plasmin.


CONCLUSIONS
We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK.
Molinaro
Giuseppe
G
Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada.
Gervais
Nicole
N
Adam
Albert
A
D000626:Aminopeptidases / Q000737:chemistry / Q000378:metabolism; D000799:Angioedema / Q000139:chemically induced; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry; D001711:Biotransformation / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004342:Drug Hypersensitivity / Q000378:metabolism; D015773:Enalaprilat / Q000494:pharmacology; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D006801:Humans; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010949:Plasma / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000009:adverse effects / Q000737:chemistry*; D012016:Reference Values; D010959:Tissue Plasminogen Activator / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D019679:Kininogen, High-Molecular-Weight; D011994:Recombinant Proteins; C024626:bradykinin, des-Arg(9)-; D000626:Aminopeptidases; C022750:X-Pro aminopeptidase; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D015773:Enalaprilat; D001920:Bradykinin