ACE inhibitor mechanism of action
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Angiotensin-Converting Enzyme (ACE) Inhibitor Mechanism of Action
ACE Function and Inhibition: Blood Pressure Regulation
Angiotensin-converting enzyme (ACE) is a transmembrane-bound dipeptidyl peptidase that plays a central role in blood pressure regulation by converting angiotensin I to angiotensin II, a potent vasoconstrictor. ACE inhibitors block this conversion, leading to reduced levels of angiotensin II and, consequently, lower blood pressure and decreased cardiovascular risk 13.
Bradykinin Modulation and Vasodilation
ACE also degrades bradykinin, a peptide that promotes vasodilation. By inhibiting ACE, these drugs increase bradykinin levels, which enhances vasodilation, natriuresis, and reduces oxidative stress and inflammation. The increased bradykinin signaling is now recognized as a major contributor to the cardioprotective and antihypertensive effects of ACE inhibitors, sometimes even more so than the reduction in angiotensin II, especially at higher drug dosages 28.
Additional Substrate Effects: Ac-SDKP and Cardiac Protection
Beyond angiotensin I and bradykinin, ACE also hydrolyzes other peptides such as N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Inhibition of Ac-SDKP breakdown by ACE inhibitors has been shown to reduce cardiac fibrosis, cell proliferation, and inflammation, providing further cardiac protection independent of blood pressure reduction .
Mechanisms of ACE Inhibitory Peptides
Many food-derived and synthetic peptides act as ACE inhibitors. These peptides can bind to ACE in different ways, including non-competitive and mixed-type inhibition, often inducing conformational changes in the enzyme that reduce its activity. Such peptides have been identified from sources like casein, sufu, sea cucumber, and hazelnut, and have demonstrated significant antihypertensive effects in animal models 567910. Molecular docking studies confirm that these peptides interact with the ACE active site or other regions, stabilizing the enzyme-inhibitor complex and enhancing inhibitory effects 567910.
Metabolic Effects: Glucose Control
ACE inhibitors also have beneficial metabolic effects, particularly in insulin-resistant states. By increasing bradykinin and reducing angiotensin II, they enhance glucose uptake in skeletal muscle through nitric oxide-mediated pathways and improved insulin signaling, which can help manage glucose levels in type 2 diabetes .
Conclusion
ACE inhibitors lower blood pressure and protect the heart by blocking the conversion of angiotensin I to angiotensin II, increasing bradykinin levels, and preventing the breakdown of other protective peptides like Ac-SDKP. Their mechanisms involve both direct enzyme inhibition and modulation of multiple signaling pathways, contributing to their broad therapeutic benefits in cardiovascular and metabolic diseases 12356789+1 MORE.
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