Metabolism of bradykinin and endogenous des-Arg9-bradykinin in human plasma: contribution to the pathophysiology of angiooedema associated with ACE inhibitors

2010

Date Source: 

Doctor Albert Adam, Professor Emeritus, in the Faculty of Pharmacy at the University of Montreal

Organizer: 

Miguel Chagnon, Department of Mathematics and Statistics, University of Montreal.


Overview
 

Angiotensin I-converting enzyme (ACE) inhibitors are an important class of drugs in use for nearly 30 years in the treatment of cardiovascular diseases, such as hypertension and congestive heart failure, for example. Approximately 500 million patients worldwide are currently being treated with ACE inhibitors. Despite being effective pharmaceutical agents, these drugs have side effects. The best known being a nonproductive cough that affects nearly 20% of all patients. There are also rare, but potentially deadly, adverse reactions that affect between 1% and 2% of patients. These adverse reactions vary in symptomology as a function of the clinical context. In the case of angiooedema (rapid swelling of the skin and mucosal tissues), anaphylactic reactions have been observed in dialysis patients and severe hypersensitivity reactions have been observed in patients receiving blood transfusions. These serious side effects have been attributed to bradykinin (a pro-inflammatory peptide and potent vasodilator) which has a short half-life that is rapidly inactivated in plasma by two exopeptidases, ACE and aminopeptidase P (APP). Bradykinin is also transformed by carboypeptidase N (CPN) and the active metabolite des-Arg
 

9-bradykinin (ARG) which in turn is inactivated by ACE and APP.
 

Objective
 

Even though potentially deadly side effects have been attributed to bradykinin, there is no experimental evidence. Consequently, the primary objective of this case study is to characterize the activation metabolism of bradykinin and
 

des-Arg9-bradykinin in plasma and their role in angiooedema.


Variables of Interest
 

The plasma concentration of the peptides bradykinin and des-Arg9-bradykinin was measured at different times that reflect equilibria between their formation and metabolism. The kinetic profiles of each these peptides (that is, the changes in concentrations over time for each individual patient) consist of three parts. The first being a period of increasing concentration. The second being a period of maximum concentration between synthesis and metabolism. The last period reflecting metabolism proceeding at a higher rate than synthesis. Any number of characteristics of these kinetic profiles can be studied. Among these for bradykinin and des-Arg9-bradykinin are

  • the total amount produced;
  • the maximum concentration;
  • the rate of increase until the maximum concentration;
  • the rate of decrease after the maximum concentration;
  • the time elapsed until the maximum concentration;
  • the time elapsed until half of the maximum concentration is reached;
  • the elapsed after the maximum concentration until half the concentration is reached.

 

Research Question: 

Compare the characteristics of the profiles for bradykinin and des-Arg9-bradykinin among the controls, cases with angiooedema, and cases without angiooedema.
 

Compare the other measures (gender and concentrations of angiotensin I-converting enzyme, aminopeptidase P, and carboxypeptidase N.) among the three groups of participants.
 

Study the relationships of the profiles for bradykinin and des-Arg9-bradykinin with gender and the concentrations of angiotensin I-converting enzyme, aminopeptidase P, and carboxypeptidase N.
 

 

Variables: 

The labels for the variables in the data set are as follows.
 

ECHANTIL is the identification number of the participant.
 

GROUPE denotes whether the subject is normal, a case with a history of angiooedema (AO+), or a case without a history of angiooedema (AO-).
 

SEXE equals 0 for males and 1 for females.
 

ACE is the concentration of angiotensin I-converting enzyme.
 

APP is the concentration of aminopeptidase P.
 

CPN is the concentration of carboxypeptidase N.
 

BK0 to BK60 is the concentration of bradykinin observed for each point in time.
 

ARG0 to ARG120 is the concentration of des-Arg9-bradykinin observed for each point in time.
 

The value NUL! indicates a missing datum.

 

Data Access: 

The data are a subset of the original data. Variables are available on 168 human participants in three groups: normal controls; cases treated by ACE inhibitors with a history of angiooedema (AO+), and; those cases treated by ACE inhibitors without a history of angiooedema (AO-). In sample of plasma from each patient, concentrations of endogenous bradykinin produced by kinin-forming activitation in plasma during a period of 60 minutes were measured in vitro using a physical chemical technique. Measurements were made at 0, 1, 2, 3, 4, 6, 12, 24, 36, and 60 minutes elapsed time. A similar approach was applied for measuring the amounts of des-Arg9-bradykinin at elapsed times of 0, 3, 6, 12, 18, 24, 36, 48, 60, and 120 minutes. As well, the concentrations of three metallopeptidases associated with bradykinin were measured: ACE, CPN, and APP. The gender of each patient was also noted.

 

Data Files: 

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