Mechanism of Action of Angiotensin-Converting Enzyme (ACE) Inhibitors
ACE inhibitors like lisinopril work primarily by blocking the conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction, aldosterone secretion, and sympathetic activity, which leads to decreased blood pressure and improved cardiovascular outcomes. 1
Primary Mechanism of Action
- ACE inhibitors bind to and inhibit angiotensin-converting enzyme (ACE), a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the potent vasoconstrictor angiotensin II 1
- By preventing this conversion, ACE inhibitors reduce circulating and tissue levels of angiotensin II, which is the principal pressor agent of the renin-angiotensin-aldosterone system (RAAS) 2, 1
- Reduced angiotensin II leads to decreased vasopressor activity and decreased aldosterone secretion from the adrenal cortex 1
Secondary Mechanisms and Effects
- ACE is identical to kininase, an enzyme that degrades bradykinin; ACE inhibition therefore increases bradykinin levels, which may contribute to vasodilation effects 1
- ACE inhibitors reduce oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxidase, providing vasoprotective effects beyond blood pressure lowering 2
- These medications cause preferential dilation of efferent arterioles in the kidney, reducing intraglomerular pressure, which contributes to their renoprotective effects 2, 3
- ACE inhibitors limit cardiac and vascular remodeling, reduce oxidative stress, improve endothelial function, and decrease fibrosis and inflammation 4
Pharmacodynamic Effects
- Blood pressure reduction occurs through multiple mechanisms: decreased peripheral vascular resistance, inhibition of angiotensin II-mediated vasoconstriction, and reduced aldosterone-mediated sodium and water retention 1
- The antihypertensive effect begins approximately 1 hour after oral administration, with peak reduction achieved by 6 hours 1
- ACE inhibitors are effective in both high-renin and low-renin hypertension, although the response may be smaller in low-renin populations (often Black patients) 1
- These medications do not typically cause reflex tachycardia when lowering blood pressure 1
Tissue-Specific Effects
- ACE inhibitors affect ACE activity in multiple tissues including the heart, kidneys, and blood vessels 5
- The duration of tissue ACE inhibition may be longer than plasma ACE inhibition, contributing to sustained clinical effects 5
- X-ray crystallography studies have revealed that the active site of ACE is located deep within a central cavity of the enzyme, which explains the high specificity of ACE inhibitors 6
Clinical Considerations
- ACE inhibitors may cause a small increase in serum potassium due to decreased aldosterone secretion 1
- When combined with thiazide diuretics, the blood pressure-lowering effects are approximately additive, and the diuretic-induced potassium loss is attenuated 1
- Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive efficacy of ACE inhibitors by interfering with prostaglandin-mediated vasodilation 1, 2
- In patients with renal artery stenosis or volume depletion, ACE inhibitors may cause acute renal failure by preventing angiotensin II-mediated efferent arteriolar constriction, which normally helps maintain glomerular filtration pressure 2
ACE inhibitors have become cornerstone treatments for hypertension, heart failure, diabetic nephropathy, and post-myocardial infarction care due to their well-established mechanisms and beneficial effects on cardiovascular and renal outcomes 2, 4.