Neprilysin Inhibitors and Bradykinin

Abstract

Bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischemia reperfusion injury. However, bradykinin also contributes to pathological states such as angioedema and inflammation. Bradykinin is metabolized by many different peptidases that play a major role in the control of bradykinin levels. Peptidase inhibitor therapies such as angiotensin converting enzyme (ACE) and neprilysin inhibitors increase bradykinin levels, and the challenge for such therapies is to achieve the beneficial cardiovascular and renal effects without the adverse consequences such as angioedema that may result from increased bradykinin levels. Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure. Initial attempts to combine neprilysin inhibition with inhibition of the renin angiotensin system led to the development of omapatrilat, a drug that combines ACE and neprilysin inhibition. However, omapatrilat produced an unacceptably high incidence of angioedema in patients with hypertension (2.17%) in comparison with the ACE inhibitor enalapril (0.68%), although angioedema incidence was less in patients with heart failure with reduced ejection fraction (HFrEF) treated with omapatrilat (0.8%), and not different from that for enalapril therapy (0.5%). More recently, LCZ696, a drug that combines angiotensin receptor blockade and neprilysin inhibition, was approved for the treatment of HFrEF. The approval of LCZ696 therapy for HFrEF represents the first approval of long-term neprilysin inhibitor administration. While angioedema incidence was acceptably low in HFrEF patients receiving LCZ696 therapy (0.45%), it remains to be seen whether LCZ696 therapy for other conditions such as hypertension is also accompanied by an acceptable incidence of angioedema.

How ACE inhibitors transformed the renin–angiotensin system

“…The dry cough that is a side‐effect of ACE inhibition was attributed to the effects of raised levels of bradykinin, as was the rare case of angioedema. The latter effect had a higher incidence when ACE inhibition was combined with inhibition of neutral endopeptidase (neprilysin; NEP), another enzyme inactivating bradykinin, and this was a major reason for the rejection by the FDA of omapatrilat (Campbell, 2018). The low levels of angioedema in the successful clinical trials of LCZ696 (sacubitril/valsartan), in which the NEP inhibitor is combined with an ARB, would support this assumption (Hubers & Brown, 2016).…”

The Rationale of Neprilysin Inhibition in Prevention of Myocardial Ischemia-Reperfusion Injury during ST-Elevation Myocardial Infarction

“…Bk has a very short half-life because many different enzymes cleave it and may participate in its metabolism, and peptidase activity (ACE, NEP, NEP2, aminopeptidase, carboxypeptidase, endothelin converting enzyme) plays a major role in the tissue-specific regulation of Bk levels [131]. Therefore, it is difficult to modulate Bk concentration by blocking a single degradation pathway.…”

“…Therefore, it is difficult to modulate Bk concentration by blocking a single degradation pathway. However, an enzyme's contribution to Bk degradation and the effect of inhibition of that enzyme on Bk degradation depends not only on the concentration of the enzyme, but also on the Bk concentration and the K m (Michaelis constant) of each peptidase [131]. Thus, depending on an enzyme's abundance and k cat (turnover number), an enzyme with a low K m , such as ACE, may have a predominant role in Bk metabolism when Bk levels are low, whereas an enzyme with a higher Km (e.g., carboxypeptidase and NEP) may play a more dominant role when Bk levels are high [89], such as in STEMI [91,132].…”

“…Furthermore, the effect of an enzyme inhibition on Bk levels depends not only on the specific enzyme's contribution to Bk metabolism relative to other enzymes, but also on the baseline degradation rate for Bk in each district [131]. It has been demonstrated that NEP contribution to Bk degradation is higher than ACE in the heart [133,134].…”

Bradykinin—from snake poison to therapeutic options

“…Besides its role in metabolism, bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischaemia reperfusion injury. 15 The lung is able to excrete vasoactive substances, bradykinin was among them (reviewed in 16 ). Kinins are highly unstable peptides and can be degraded very fast by several kininases including angiotensin-converting enzyme (ACE).…”