Effects of neutral endopeptidase 24.11 inhibition on myocardial infarct size and ischemic preconditioning in rabbits

Nakano, Atsushi; Miura, Tetsuji; Miki, Takayuki; Nozawa, Yukinaga; Ichikawa, Yoshihiko; Ura, Nobuyuki; Shimamoto, Kazuaki

doi:10.1007/s00210-002-0600-8

Cited by 4 publications

(4 citation statements)

References 35 publications

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“…Icatibant prevented neprilysin inhibitor-induced reduction in ischemia-reperfusion injury in the rat heart ( 101 ), and neprilysin inhibitor-induced potentiation of pre-conditioning-induced reduction in infarct size in the rabbit heart ( 102 ). In addition, icatibant prevented neprilysin inhibitor-induced reversal of isoproterenol-induced myocardial hypoperfusion in the rat ( 103 ), and neprilysin inhibitor-induced nitric oxide production by isolated canine coronary microvessels ( 104 ).…”

Section: Role Of Kinins In Mediating the Effects Of Neprilysin Inhibimentioning

confidence: 99%

Neprilysin Inhibitors and Bradykinin

Campbell

2018

Front. Med.

122

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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.

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Section: Role Of Kinins In Mediating the Effects Of Neprilysin Inhibimentioning

confidence: 99%

Neprilysin Inhibitors and Bradykinin

Campbell

2018

Front. Med.

122

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“…Liu et al 1995). Neutral endopeptidase inhibition by thiorphan does not affect basic cardiac ischemic tolerance, as determined by infarct size reduction, but potentiates preconditioning-induced cardioprotection via a bradykinin (B2) receptor-mediated mechanism (Nakano et al 2002).…”

Section: Substances Used In the Treatment Of Risk Factors For Ischemic Heart Diseasementioning

confidence: 99%

Occult Cardiotoxicity—Toxic Effects on Cardiac Ischemic Tolerance

2009

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The outcome of cardiac ischemic events depends not only on the extent and duration of the ischemic stimulus but also on the myocardial intrinsic tolerance to ischemic injury. Cardiac ischemic tolerance reflects myocardial functional reserves that are not always used when the tissue is appropriately oxygenated. Ischemic tolerance is modulated by ubiquitous signal transduction pathways, transcription factors and cellular enzymes, converging on the mitochondria as the main end effector. Therefore, drugs and toxins affecting these pathways may impair cardiac ischemic tolerance without affecting myocardial integrity or function in oxygenated conditions. Such effect would not be detected by current toxicological studies but would considerably influence the outcome of ischemic events. The authors refer to such effect as "occult cardiotoxicity." In this review, the authors summarize current knowledge about main mechanisms that determine cardiac ischemic tolerance, methods to assess it, and the effects of drugs and toxins on it. The authors offer a view that low cardiac ischemic tolerance is a premorbid status and, therefore, that occult cardiotoxicity is a significant potential source of cardiac morbidity. The authors propose that toxicologic assessment of compounds would include the assessment of their effect on cardiac ischemic tolerance.

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“…As proof of its molecular effects, NEP/AT1Rs inhibition gave good results in different animal experimental models of MI [211][212][213]. In fact, it has been demonstrated that SAC/VAL prevents cardiac rupture in a murine model of MI [214] and plays a pro-survival effect in reperfused rabbit hearts after prolonged ischemia [215].…”

Section: Clinical Perspectives For Nep Inhibition In Miri Preventionmentioning

confidence: 97%

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

Bellis¹,

Mauro

Barbato³

et al. 2020

Cells

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During the last three decades, timely myocardial reperfusion using either thrombolytic therapy or primary percutaneous intervention (pPCI) has allowed amazing improvements in outcomes with a more than halving in 1-year ST-elevation myocardial infarction (STEMI) mortality. However, mortality and left ventricle (LV) remodeling remain substantial in these patients. As such, novel therapeutic interventions are required to reduce myocardial infarction size, preserve LV systolic function, and improve survival in reperfused-STEMI patients. Myocardial ischemia-reperfusion injury (MIRI) prevention represents the main goal to reach in order to reduce STEMI mortality. There is currently no effective therapy for MIRI prevention in STEMI patients. A significant reason for the weak and inconsistent results obtained in this field may be the presence of multiple, partially redundant, mechanisms of cell death during ischemia-reperfusion, whose relative importance may depend on the conditions. Therefore, it is always more recognized that it is important to consider a “multi-targeted cardioprotective therapy”, defined as an additive or synergistic cardioprotective agents or interventions directed to distinct targets with different timing of application (before, during, or after pPCI). Given that some neprilysin (NEP) substrates (natriuretic peptides, angiotensin II, bradykinin, apelins, substance P, and adrenomedullin) exert a cardioprotective effect against ischemia-reperfusion injury, it is conceivable that antagonism of proteolytic activity by this enzyme may be considered in a multi-targeted strategy for MIRI prevention. In this review, by starting from main pathophysiological mechanisms promoting MIRI, we discuss cardioprotective effects of NEP substrates and the potential benefit of NEP pharmacological inhibition in MIRI prevention.

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Effects of neutral endopeptidase 24.11 inhibition on myocardial infarct size and ischemic preconditioning in rabbits

Cited by 4 publications

References 35 publications

Neprilysin Inhibitors and Bradykinin

Neprilysin Inhibitors and Bradykinin

Occult Cardiotoxicity—Toxic Effects on Cardiac Ischemic Tolerance

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

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