Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema

Byrd, James Brian; Touzin, Karine; Sile, Saba; Gainer, James V.; Yu, Chang; Nadeau, John; Adam, Albert; Brown, Nancy J.

doi:10.1161/hypertensionaha.107.096552

Cited by 137 publications

(116 citation statements)

References 39 publications

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“…In addition to direct effects of bradykinin on pain, it also participates indirectly by stimulating the release of substance P from sensory nerves. 126 Furthermore, ACE also degrades substance P; 127,128 therefore, the levels of substance P are increased directly due to ACE inhibition or indirectly due to bradykinin. The nociceptive role of substance P and neurokinin 1 receptor is very well documented.…”

Section: Bradykininmentioning

confidence: 99%

Renin–angiotensin system in pain: Existing in a double life?

Bali

Singh

Jaggi

2014

J Renin Angiotensin Aldosterone Syst

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Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT 1 receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the paininducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT 1 blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT 2 receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.

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Section: Bradykininmentioning

confidence: 99%

Renin–angiotensin system in pain: Existing in a double life?

Bali

Singh

Jaggi

2014

J Renin Angiotensin Aldosterone Syst

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“…Certainly, the renal effects of DPP IV inhibitors in various patient populations merit a closer examination. In the meanwhile, it may be prudent to consider the concomitant use of an angiotensin receptor blocker or renin inhibitor (but perhaps not an angiotensin converting enzyme inhibitor which possibly could increase the risk of angioedema in patients treated with DPP IV inhibitors 19 ) in type 2 diabetics treated with DPP IV inhibitors until this issue is resolved.…”

Section: Perspectivesmentioning

confidence: 99%

Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension

Jackson

2008

Hypertension

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Abstract-DipeptidylIn this regard, there are 2 endogenous agonists of Y 1 Rs that would be presented to the kidney microcirculation, ie, peptide YY 1-36 (PYY ) and neuropeptide Y 1-36 (NPY 1-36 ). Both are pancreatic polypeptide-fold peptides. A fatty meal releases PYY 1-36 into the systemic circulation from endocrine L-cells in the small bowel, colon, and rectum producing physiologically active levels of PYY in plasma that are 500% to 1000% above basal circulating levels, 2-8 and this circulating PYY 1-36 would be delivered promptly to the renal microcirculation via the blood stream (humoral Y 1 R-agonist input to kidney microcirculation). Renal sympathetic nerves release NPY 1-36 in response to central nervous system-mediated activation of the renal sympathetic nerves (neural Y 1 Ragonist input to kidney microcirculation), resulting in high local levels of NPY 1-36 in sympathetically-innervated renal microvessels during renal sympathetic activation. 9 Because both PYY 1-36 and NPY 1-36 are potent Y 1 R agonists, 10,11 physiological processes that increase PYY 1-36 release from the gut, NPY 1-36 release from renal sympathetic nerves, or both simultaneously would activate Y 1 Rs in the renal microcirculation, which in genetically-susceptible kidneys would enhance Ang II-induced renal vasoconstriction.

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“…In their article, Byrd et al 6 found that BK half-life correlated inversely with ACE activity, whether the patients received ACEIs. This important finding confirms that BK concentrations are strongly under the control of ACE expression.…”

Section: Ace Inhibition and Angioedemamentioning

confidence: 99%

“…4 On the other hand, SP is sequentially truncated by dipeptidylpeptidase IV (DP-PIV) 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 in ACEI-induced angioedema had not been evaluated before the article by Byrd et al, 6 published in this issue of Hypertension.…”

mentioning

confidence: 99%

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

Grouzmann

Buclin

2008

Hypertension

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A pproximately 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, Յ0.68 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 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-Arg 9 -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 (DP-PIV) 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 in ACEI-induced angioedema had not been evaluated before the article by Byrd et al,6 published in this issue of Hypertension. ACE Inhibition and AngioedemaThe incidence of ACEI-induced angioedema ranges from 0.1% in patients treated with short-acting drugs such as captopril to 0.68% in patients treated with more potent inhibitors such as enalapril, as reported in the Omapatrilat Cardiovascular Treatment Versus Enalapril Study. 7 Recently, dual vasopeptidase inhibition seemed very promising by blocking NEP, thereby increasing circulating concentrations of natriuretic peptides, and ACE, thus hampering angiotensin II generation. Omapatrilat was the first dual inhibitor in this new class of drugs that was highly active in hypertension. 7 Unfortunately, vasopeptidase inhibitors caused up to a 2.1% rate of angioedema after a short period of treatment. Interestingly, smoking was associated with an even higher 3.9% occurrence of angioedema in omapatrilat-treated patients. 7 In contrast, diabetic patients seem less prone to develop angioedema during ACE or ACE/NEP blockade. 5 In this context, the new drug application for omapatrilat has been withdrawn pending safety reassessment. The increased rate of angioedema induced by dual ACE/NEP inhibitors strengthens the hypothesis that BK and/or SP are invol...

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Dipeptidyl Peptidase IV in Angiotensin-Converting Enzyme Inhibitor–Associated Angioedema

Cited by 137 publications

References 39 publications

Renin–angiotensin system in pain: Existing in a double life?

Renin–angiotensin system in pain: Existing in a double life?

Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension

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

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