Mode of action of lisinopril

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Mode of Action of Lisinopril

Introduction to Lisinopril and ACE Inhibition

Lisinopril is a widely used angiotensin-converting enzyme (ACE) inhibitor, primarily prescribed for managing hypertension and heart failure. Unlike some other ACE inhibitors, lisinopril is not a prodrug and is effective in its administered form. It works by inhibiting the enzyme ACE, which plays a crucial role in the renin-angiotensin-aldosterone system (RAAS), thereby reducing the production of angiotensin II, a potent vasoconstrictor.

Binding Interaction with Proteins

Lisinopril's interaction with proteins, such as bovine serum albumin (BSA), has been studied to understand its pharmacokinetics and mode of action. Research shows that lisinopril binds to BSA, forming a complex that slightly alters the protein's conformation while retaining its α-helical structure. The binding is spontaneous and primarily driven by van der Waals forces and hydrogen bonding. This interaction is significant as it influences the drug's distribution and efficacy in the body.

Cardioprotective Effects

Lisinopril has demonstrated cardioprotective effects, particularly in conditions of oxidative stress and myocardial reoxygenation. Studies on cardiomyocytes have shown that lisinopril enhances the recovery of contractile function during reoxygenation and mitigates the effects of oxidative agents like ammonium persulfate and tert-butyl hydroperoxide. This protective effect is likely mediated through the endogenous renin-angiotensin system and direct cellular actions.

Impact on ACE2 and COVID-19 Implications

Recent studies have explored the impact of lisinopril on ACE2, the receptor for SARS-CoV-2. Lisinopril increases ACE2 levels in various tissues, which could have implications for COVID-19 transmission and pathogenesis. Interestingly, the combination of lisinopril with losartan, an angiotensin receptor blocker, prevents this increase in ACE2 levels, suggesting a complex interaction between these drugs in regulating ACE2 expression.

Antihypertensive Efficacy

Lisinopril is effective in reducing both systolic and diastolic blood pressure. Clinical studies have shown that lisinopril, either alone or in combination with hydrochlorothiazide (HCTZ), significantly lowers blood pressure in patients with mild to moderate hypertension. The combination therapy is more effective than either drug alone, providing a greater reduction in blood pressure with a good safety profile .

Hematopoietic Protection

Lisinopril also exhibits protective effects on the hematopoietic system. It prevents the entry of hematopoietic stem cells into the cell cycle after irradiation by increasing the levels of the hemoregulatory peptide AcSDKP. This action is linked to the inhibition of ACE, which normally catabolizes AcSDKP, thereby protecting the hematopoietic stem cells from damage.

Antiproteinuric Effects

In patients with nephrotic syndrome, lisinopril reduces proteinuria, an effect that is enhanced when combined with the NSAID indomethacin. This combination therapy results in a significant reduction in urinary protein excretion, likely due to different mechanisms of action that both drugs employ to lower intraglomerular capillary pressure. However, this combination requires careful monitoring of renal function and serum potassium levels due to the risk of severe hyperkalemia.

Conclusion

Lisinopril's mode of action extends beyond simple ACE inhibition. It involves complex interactions with proteins, protective effects on cardiomyocytes and hematopoietic stem cells, modulation of ACE2 levels, and significant antihypertensive and antiproteinuric effects. These multifaceted actions make lisinopril a valuable therapeutic agent in managing hypertension, heart failure, and renal conditions, with additional implications for COVID-19 treatment strategies.