Is Dipeptidylpeptidase IV the Missing Link in Angiotensin-Converting Enzyme Inhibitor–Induced Angioedema?

Abstract

Approximately 40 million people worldwide are currently treated with angiotensin-converting enzyme (ACE) inhibitors (ACEIs) for hypertension, congestive heart failure, coronary diseases, and diabetic nephropathy. The primary mechanism of action of ACEIs is blocking of the renin angiotensin system by inhibiting the conversion of angiotensin I to the vasoconstrictor angiotensin II. Few serious adverse events specific to ACE inhibition were initially reported, because they are actually rare. However, ≤0.68 of every 100 patients seem to experience angioedema with ACEI, sometimes months and even years after the start of medication.1 The pathophysiology of ACEI-induced angioedema is presently thought to result from the role of ACE in the degradation of other peptides including bradykinin (BK) and substance P (SP).2 These proinflammatory peptides are released by sensory nerves during inflammation.3 Both peptides elicit plasma exudation from postcapillary venules, leading to interstitial edema and affecting tissue function.3 The metabolism of BK and SP by proteases is redundant, with several enzymes available to terminate their biological action. Both ACE and neutral endopeptidase (NEP) play major roles in inactivating BK and SP.2 BK is also processed by aminopeptidase P, but a contribution of this peptidase in angioedema during ACEI is unlikely, despite a downregulation of its activity reported in some cases.4 BK is also a substrate of kininase I, capable of cleaving the last residue off its C-terminal end to generate des-Arg9-BK, a fragment without affinity for the B2 receptor but an agonist on the inducible B1 receptor expressed during inflammation.4 On the other hand, SP is sequentially truncated by dipeptidylpeptidase IV (DPPIV) into SP3-11 and then SP5-11, which is 1000-fold less potent than the native peptide.5 However, the physiological importance of DPPIV in the inactivation of SP and the role of a reduction of DPPIV activity …