Mechanism Of Action For Lisinopril

Angiotensin-Converting Enzyme (ACE) Inhibition

Lisinopril is a potent angiotensin-converting enzyme (ACE) inhibitor that works by blocking the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. This inhibition leads to vasodilation, reduced blood pressure, and decreased aldosterone secretion, which increases sodium and water excretion. By reducing the levels of angiotensin II, lisinopril also decreases the release of aldosterone from the adrenal cortex, further contributing to its antihypertensive effects.

Cardioprotective Effects

Oxidative Stress and Cardiomyocyte Protection

Lisinopril has been shown to enhance the recovery of cardiomyocytes during reoxygenation and reduce oxidative damage. It achieves this by improving the viability of cardiomyocytes exposed to oxidative agents such as ammonium persulfate and tertbutylhydroperoxide, although it does not exhibit direct antioxidant properties. Additionally, lisinopril increases the expression of proteins that protect against oxidative stress, such as catalase, SOD2, and thioredoxin, in human cardiomyocytes.

Prevention of Left Ventricular Remodeling

Lisinopril also plays a role in preventing left ventricular remodeling in heart failure by inhibiting matrix metalloproteinase (MMP) activity, particularly MMP-2. This inhibition helps prevent left ventricular dilatation and myocardial hypertrophy, contributing to better cardiac function and structure.

Tissue-Specific Effects

ACE2 Expression

Lisinopril increases the tissue levels of ACE2, the receptor for SARS-CoV-2, in various organs including the small intestine, lung, kidney, and brain. This increase in ACE2 levels is significant and persists even after the cessation of lisinopril treatment. However, the combination of lisinopril with losartan, an angiotensin receptor blocker, does not increase ACE2 levels, indicating a complex interaction between these drugs.

Pharmacokinetics and Absorption

Lisinopril is an orally active, nonsulfhydryl ACE inhibitor that is not metabolized or bound to proteins. It is excreted unchanged in the urine, and its bioavailability is approximately 25%, unaffected by food or age. The absorption of lisinopril is relatively low and occurs via a nonpassive, carrier-mediated transport system in the intestines. This low absorption rate contributes to its prolonged ACE inhibition and nonlinear pharmacokinetics.

Binding Interactions

Lisinopril binds to bovine serum albumin (BSA) primarily through van der Waals forces and hydrogen bonding, forming a stable lisinopril-BSA complex. This binding induces slight conformational changes in BSA but retains its α-helical structure. The flexibility of lisinopril enhances the stability of this complex, which is crucial for its pharmacokinetic profile.

Conclusion

Lisinopril's mechanism of action involves the inhibition of ACE, leading to reduced angiotensin II levels and subsequent vasodilation and decreased aldosterone secretion. It offers cardioprotective effects by reducing oxidative stress and preventing left ventricular remodeling. Additionally, lisinopril increases tissue ACE2 levels and has a complex absorption mechanism. Its binding interactions with serum proteins further contribute to its pharmacokinetic properties. These multifaceted actions make lisinopril a valuable drug in the treatment of hypertension and heart failure.

Mechanism of action for lisinopril

Summary

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