Vol. 292, Issue 1, 295-298, January 2000

Inhibition of Aminopeptidase P Potentiates Wheal Response to Bradykinin in Angiotensin-Converting Enzyme Inhibitor-Treated Humans¹

Kyung-Soo Kim, Sandeep Kumar, William H. Simmons and Nancy J. Brown

Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (K.-S.K., S.K., N.J.B.); and Department of Molecular and Cellular Biochemistry, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois (W.H.S.)

Bradykinin is a nonapeptide that contributes to the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors. During ACE inhibition, an increased proportion of bradykinin is degraded through non-ACE pathways. Studies in animals suggest that aminopeptidase P (EC 3.4.11.9) may contribute to the metabolism of bradykinin. The purpose of the present study was to determine the contribution of aminopeptidase P to the degradation of bradykinin in humans in the presence and absence of ACE inhibition. To do this, we measured the wheal response to intradermal injection of bradykinin (0, 1, or 10 µg) in the presence or absence of intradermal administration of the specific aminopeptidase P inhibitor apstatin (5 or 10 µg) and oral administration of the ACE inhibitor quinapril (10 mg) in six healthy subjects. Both bradykinin (ANOVA; F = 101.18, P < .001) and apstatin alone (F = 7.01, P = .049) caused a wheal of dose-dependent size. There was no significant interaction between apstatin and bradykinin (F = 4.94, P = .175). Pretreatment with 10 mg of quinapril significantly shifted the dose-response curve for bradykinin to the left (effect of quinapril; F = 77.96, P < .001) and there was significant interaction between quinapril and bradykinin (F = 7.82, P = .041). The effect of quinapril was significantly potentiated by coinjection of 10 µg of apstatin (effect of apstatin; F = 21.60, P = .006), such that there was significant interactive effect of quinapril and apstatin (F = 20.83, P = .006) on the wheal response to bradykinin. Collectively, these data suggest that aminopeptidase P plays a minor role in the degradation of bradykinin in human skin in the absence of ACE inhibition but contributes significantly to the degradation of bradykinin in the presence of ACE inhibition.