Dipeptidyl peptidase IV deficiency increases susceptibility to angiotensin-converting enzyme inhibitor-induced peritracheal edema.
BACKGROUND
Serum dipeptidyl peptidase IV (DPPIV) activity is decreased in some individuals with ACE inhibitor-associated angioedema. ACE and DPPIV degrade substance P, an edema-forming peptide. The contribution of impaired degradation of substance P by DPPIV to the pathogenesis of ACE inhibitor-associated angioedema is unknown.


OBJECTIVE
We sought to determine whether DPPIV deficiency results in increased edema formation during ACE inhibition. We also sought to develop an animal model using magnetic resonance imaging to quantify ACE inhibitor-induced edema.


METHODS
The effect of genetic DPPIV deficiency on peritracheal edema was assessed in F344 rats after treatment with saline, captopril (2.5 mg/kg), or captopril plus the neurokinin receptor antagonist spantide (100 mug/kg) by using serial T2-weighted magnetic resonance imaging.


RESULTS
Serum dipeptidyl peptidase activity was dramatically decreased in DPPIV-deficient rats (P < .001). The volume of peritracheal edema was significantly greater in captopril-treated DPPIV-deficient rats than in saline-treated DPPIV-deficient rats (P = .001), saline-treated rats of the normal substrain (P < .001), or captopril-treated rats of the normal substrain (P = .001). Cotreatment with spantide attenuated peritracheal edema in captopril-treated DPPIV-deficient rats (P = .005 vs captopril-treated DPPIV-deficient rats and P = .57 vs saline-treated DPPIV-deficient rats).


CONCLUSIONS
DPPIV deficiency predisposes to peritracheal edema formation when ACE is inhibited through a neurokinin receptor-dependent mechanism. Magnetic resonance imaging is useful for modeling ACE inhibitor-associated angioedema in rats.


CONCLUSIONS
Genetic or environmental factors that decrease DPPIV activity might increase the risk of ACE inhibitor-associated angioedema.
Byrd
James Brian
JB
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
Shreevatsa
Ajai
A
Putlur
Pradeep
P
Foretia
Denis
D
McAlexander
Laurie
L
Sinha
Tuhin
T
Does
Mark D
MD
Brown
Nancy J
NJ
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000172:deficiency*; D004198:Disease Susceptibility; D004487:Edema / Q000139:chemically induced* / Q000175:diagnosis; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344 / Q000235:genetics; D014133:Tracheal Diseases / Q000139:chemically induced / Q000175:diagnosis
D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4