Neprilysin Inhibitors and Bradykinin

Figures

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  Figure 1. Sites of cleavage of bradykinin by different enzymes. ACE, angiotensin converting enzyme; ECE-1, endothelin converting enzyme-1; ECE-2, endothelin converting enzyme-2; NEP2, neprilysin homolog membrane metalloendopeptidase-like 1. (2–5, 7, 25–28, 30, 32–38).

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  Figure 2. Formation of bradykinin and kallidin peptides. In humans, plasma kallikrein cleaves high molecular weight kininogen to produce bradykinin, whereas tissue kallikrein cleaves both high and low molecular weight kininogens to produce kallidin (Lys0-bradykinin). Bradykinin can also be generated by aminopeptidase-mediated cleavage of kallidin. A proportion of high molecular weight kininogen is hydroxylated on the third proline (Hyp3) of the bradykinin sequence, leading to the formation of both hydroxylated and non-hydroxylated bradykinin and kallidin peptides. In the rat, both plasma and tissue kallikrein produce bradykinin, which is not hydroxylated (44–47).

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  Figure 3. Illustration of how the effect of inhibition of an enzyme on bradykinin levels depends not only on the specific enzyme's contribution to bradykinin metabolism, relative to other enzymes, but also the baseline degradation rate for bradykinin. Pulmonary inactivation of bradykinin is approximately 99% (51). Thus, 1% inhibition of pulmonary inactivation will double the amount of bradykinin surviving pulmonary degradation, and may therefore double the level of bradykinin in arterial blood.

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  Figure 4. Relative contributions of low Km (Michaelis constant) enzyme and high Km enzyme to bradykinin degradation by a mixture of low and high Km enzymes. An enzyme's contribution to bradykinin degradation, and the effect of inhibition of that enzyme on bradykinin degradation, depends not only on the concentration of the enzyme but also on the bradykinin concentration and the Km of the enzyme for bradykinin degradation. Thus, depending on an enzyme's abundance and kcat (turnover number), an enzyme with a low Km, such as ACE, may have a predominant role in bradykinin metabolism when bradykinin levels are low, whereas an enzyme with a higher Km, such as carboxypeptidase M or N, may play a more dominant role when bradykinin levels are high. Based on data reported by Kuoppala et al. (35).

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  Figure 5. Illustration of two different mechanisms by which neprilysin inhibitors may potentiate bradykinin receptor-mediated actions. Firstly, neprilysin inhibitors may increase bradykinin receptor occupancy by inhibiting bradykinin degradation and increasing bradykinin levels in the vicinity of the receptor. Secondly, neprilysin inhibitors may promote cross-talk between the neprilysin-inhibitor complex and the bradykinin receptor. Bradykinin receptor antagonists, anti-bradykinin antibodies, and kallikrein inhibitors have different effects on these two mechanisms of neprilysin inhibitor-induced potentiation of bradykinin receptor-mediated actions. A bradykinin receptor antagonist that occupies the bradykinin receptor can prevent both mechanisms of neprilysin inhibitor-induced potentiation of bradykinin receptor-mediated actions. However, bradykinin antibodies that prevent bradykinin binding to its receptor by sequestering bradykinin, and kallikrein inhibitors that prevent bradykinin binding to its receptor by preventing its formation, do not impact on cross-talk between the neprilysin-inhibitor complex and the bradykinin receptor.

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  Figure 6. Potential mechanisms by which LCZ696 may potentiate bradykinin receptor-mediated actions. Valsartan may increase bradykinin levels, and LBQ657 may also increase bradykinin levels by inhibiting bradykinin degradation by neprilysin, and possibly angiotensin converting enzyme (ACE) and neprilysin homolog membrane metalloendopeptidase-like 1 (NEP2). In addition, LBQ657 may potentiate bradykinin receptor-mediated actions by cross-talk between the LBQ657-inhibitor complex and the bradykinin receptor.