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Kinin-degrading pathways in the human heart
J O Kokkonen1, K A Lindstedt, A Kuoppala
1Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
Insights
The kinin system protects the heart from damage and failure. Inhibiting enzymes that degrade bradykinin (BK), like angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), may enhance these protective effects.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
Background:
- Kinins demonstrate cardioprotective effects against ischemia-reperfusion injury and mitigate left ventricular hypertrophy and heart failure progression in experimental models.
- The integrity of the kinin system is crucial for preventing heart failure in humans.
- Bradykinin (BK) levels and activity are regulated by enzymatic degradation, primarily by angiotensin-converting enzyme (ACE) in the vascular bed and neutral endopeptidase (NEP) in the cardiac interstitium.
Purpose of the Study:
- To investigate the role of the kinin system in human heart failure prevention.
- To explore strategies for potentiating beneficial kinin effects by inhibiting BK-degrading enzymes.
Main Methods:
- Review of existing literature on kinin system function and degradation pathways in the human heart.
- Analysis of the enzymatic degradation of bradykinin (BK) by angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) in different cardiac compartments.
Main Results:
- Experimental animal studies indicate kinins protect the myocardium from ischemia-reperfusion injury and reduce cardiac hypertrophy.
- Bradykinin (BK) is degraded by ACE in the vascular bed and NEP in the cardiac interstitium.
- Inhibition of BK-degrading enzymes is a strategy to potentiate BK's beneficial effects.
Conclusions:
- An intact kinin system is likely critical for preventing heart failure in humans.
- Combined inhibition of ACE and NEP may offer a more effective approach to elevate BK concentrations and potentiate its cardioprotective actions compared to ACE inhibition alone.
Abstract:
In experimental animals, kinins protect the myocardium from ischemia-reperfusion injuries and reduce left ventricular hypertrophy and progression of heart failure. This suggests that in humans, also, the presence of an intact kinin system is critical for the prevention of heart failure. In addition to the kinin-generating system, the concentration of kinins, and consequently the extent of their actions, is regulated by their degradation. In the vascular bed of the human heart, bradykinin (BK) is degraded by angiotensin-converting enzyme (ACE). In contrast, in the interstitium of the human heart, BK is degraded by neutral endopeptidase (NEP). For potentiating the beneficial effects of BK, one strategy is elevation of the BK concentration by inhibition of BK-degrading enzymes. An even more effective form of pharmacological control of BK elevation than inhibition of ACE alone might be the combined inhibition of ACE and NEP.