Mechanism Of Action Of 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, which helps in reducing blood pressure and alleviating the workload on the heart. By decreasing angiotensin II levels, lisinopril also reduces aldosterone secretion, leading to increased sodium and water excretion, further contributing to its antihypertensive effects.

Cardioprotective Effects

Oxidative Stress and Myocardial Reoxygenation

Lisinopril has been shown to enhance the recovery of cardiomyocytes during reoxygenation and mitigate oxidative damage. In studies involving chick embryonic ventricular cardiomyocytes, lisinopril significantly improved the restoration of contractile frequency during myocardial reoxygenation and reduced the impact of oxidative agents like ammonium persulfate and tertbutylhydroperoxide. This suggests that lisinopril's cardioprotective effects may involve mechanisms related to the endogenous renin-angiotensin system and direct cellular actions.

Antioxidant Properties

Lisinopril also exhibits antioxidant properties, which contribute to its cardioprotective effects. It has been shown to upregulate proteins that protect against oxidative stress, such as catalase, SOD2, and thioredoxin, in human cardiomyocytes. Additionally, it reduces the expression of proteins involved in cardiac fibrosis, such as osteopontin and Galectin-3, and activates Sirtuin 1 and Sirtuin 6 pathways, which are crucial for cellular protection against oxidative damage and fibrosis.

Pulmonary and Systemic Hemodynamics

Hypoxic Pulmonary Vasoconstriction

Lisinopril has been found to attenuate acute hypoxic pulmonary vasoconstriction (HPV) in humans. In a randomized, double-blind, placebo-controlled study, lisinopril significantly blunted the increase in mean pulmonary artery pressure and total pulmonary vascular resistance induced by hypoxemia without affecting systemic hemodynamic parameters. This indicates that angiotensin II may play a modulatory role during HPV, and ACE inhibition could be beneficial in managing hypoxemic pulmonary hypertension.

Lung Fibrosis

Lisinopril has demonstrated efficacy in reducing lung fibrosis induced by paraquat, a commonly used herbicide. In animal studies, lisinopril significantly decreased hydroxyproline content in lung tissue and protected against paraquat-induced lung fibrosis, likely through the inhibition of angiotensin II, which stimulates fibroblast proliferation and collagen synthesis.

Pharmacokinetics and Bioavailability

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 coadministration with other drugs. The drug achieves peak serum concentrations 6-8 hours after oral dosing and reaches a steady state in 2-3 days. Its absorption mechanism involves a nonpassive, carrier-mediated transport system, which explains its prolonged ACE inhibition and low oral bioavailability.

Interaction with ACE2 and COVID-19 Implications

Lisinopril has been shown to increase tissue levels of ACE2, the cellular receptor for SARS-CoV-2, in various tissues, including the small intestine, lung, kidney, and brain. This increase in ACE2 levels could have implications for the transmission and pathogenesis of COVID-19. Interestingly, the combination of lisinopril with losartan prevented the lisinopril-induced increase in ACE2 levels, suggesting a complex interaction between ACE inhibitors and angiotensin receptor blockers.

Conclusion

Lisinopril's mechanism of action primarily involves the inhibition of ACE, leading to reduced levels of angiotensin II and subsequent vasodilation. Its cardioprotective effects are enhanced by its ability to mitigate oxidative stress and fibrosis. Additionally, lisinopril's impact on pulmonary hemodynamics and lung fibrosis, along with its pharmacokinetic properties and interaction with ACE2, highlight its multifaceted therapeutic potential.

Mechanism of action of lisinopril

Summary

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