Losartan mechanism
Pro Research Analysisby 
Searched over 200M research papers for "losartan mechanism"
Mechanism of Action of Losartan
Introduction to Losartan and Its Primary Function
Losartan is a widely used angiotensin II type 1 (AT1) receptor antagonist, primarily prescribed for the treatment of hypertension. By blocking the AT1 receptor, losartan inhibits the effects of angiotensin II, a potent vasoconstrictor, thereby reducing blood pressure and offering protective effects against various cardiovascular and renal conditions5.
Inhibition of TGF-β/Smad Signaling Pathway
One of the key mechanisms by which losartan exerts its therapeutic effects is through the inhibition of the TGF-β/Smad signaling pathway. This pathway is crucial in the process of endothelial-to-mesenchymal transition (EndMT), which contributes to myocardial fibrosis. Studies have shown that losartan effectively suppresses the activation of TGF-β/Smad signaling, thereby reducing EndMT and myocardial fibrosis in hypertensive conditions1.
Preservation of Glomerular Basement Membrane Function
Losartan also plays a significant role in preserving the function of the glomerular basement membrane (GBM) in nephropathy. It reduces proteinuria by maintaining the anionic charge sites on the GBM, which are essential for its size and charge selectivity. This preservation helps in reducing urinary protein levels and protecting renal function without significantly affecting hemodynamics2.
Modulation of Vascular Responses and ROCK1 Activity
In diabetic conditions, losartan has been shown to counteract the hyper-reactivity to angiotensin II and reduce the over-activation of RhoA-kinase (ROCK1) in vascular tissues. This modulation helps in preventing excessive vasoconstriction and vascular complications associated with diabetes3.
Cardioprotection Through Bradykinin-Dependent and Independent Mechanisms
Losartan provides myocardial protection by preconditioning the heart, which involves both bradykinin-dependent and independent mechanisms. It enhances post-ischemic ventricular recovery, reduces infarct size, and decreases cardiomyocyte apoptosis. The cardioprotective effects are partly mediated through the bradykinin B2 receptor, which is involved in blocking angiotensin II formation4.
Interaction with Angiotensin-Converting Enzyme (ACE)
Quantum biochemistry studies have revealed that losartan can interact with the angiotensin-converting enzyme (ACE), inhibiting its activity. This interaction provides an additional mechanism by which losartan can exert its antihypertensive effects, beyond its primary action on the AT1 receptor5.
Improvement of Endothelial Function in Diabetes
In patients with non-insulin-dependent diabetes mellitus (NIDDM), losartan improves endothelial function by enhancing endothelium-dependent vasodilation. This improvement is achieved through the blockade of the angiotensin II type 1 receptor, which helps in maintaining vascular health and preventing diabetic vascular complications6.
Reduction of Inflammatory Cytokines in Neuropathic Pain
Losartan has been found to alleviate mechanical hyperalgesia in chemotherapy-induced neuropathic pain by inhibiting inflammatory cytokines in the dorsal root ganglia. This anti-inflammatory effect contributes to its analgesic properties and offers a potential therapeutic option for managing neuropathic pain7.
Role of Nitric Oxide and AT2 Receptors in Vascular Responses
The antihypertensive effects of losartan also involve the modulation of nitric oxide (NO) and angiotensin II type 2 (AT2) receptors. Losartan reduces the constrictor response to phenylephrine in aortic rings from hypertensive rats, an effect that is dependent on the presence of NO and the activity of AT2 receptors8.
Protection Against Cerebral Ischemia/Reperfusion Injury
Losartan protects against cerebral ischemia/reperfusion injury by reducing apoptosis through the β-arrestin1-mediated phosphorylation of Akt. This pathway enhances cell survival and provides neuroprotection, highlighting the potential benefits of losartan in treating cerebrovascular diseases9.
Prevention of Sepsis-Induced Acute Lung Injury
In sepsis-induced acute lung injury (ALI), losartan exerts protective effects by inhibiting the activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs). This inhibition reduces the release of pro-inflammatory cytokines, thereby preventing lung damage and improving survival rates in sepsis10.
Conclusion
Losartan's multifaceted mechanisms of action, including inhibition of the TGF-β/Smad signaling pathway, preservation of GBM function, modulation of vascular responses, and anti-inflammatory effects, make it a versatile therapeutic agent. Its ability to provide cardioprotection, improve endothelial function, and protect against various forms of tissue injury underscores its importance in clinical practice.
Sources and full results
Most relevant research papers on this topic
Losartan Attenuates Myocardial Endothelial-To-Mesenchymal Transition in Spontaneous Hypertensive Rats via Inhibiting TGF-β/Smad Signaling
Losartan effectively suppresses cardiac fibrosis in hypertensive rats by inhibiting endothelial-to-mesenchymal transition through the classical TGF-/Smad pathway.
RCT
Animal Study
Rigorous JournalLosartan preserves glomerular basement membrane anionic charge sites in a rat model of nephropathy.
Losartan reduces urinary protein and preserves glomerular basement membrane anionic sites in a rat model of nephropathy, but has no effect on hemodynamics.
RCTAnimal StudyLosartan counteracts the hyper-reactivity to angiotensin II and ROCK 1 over-activation in aortas isolated from streptozotocin-injected diabetic rats
Losartan treatment partially corrects angiotensin II hyper-contracture in diabetic rats' aortas, limiting the increase in blood pressure and reducing the risk of complications from diabetes.
RCTAnimal StudyMyocardial Protection by Preconditioning of Heart With Losartan, an Angiotensin II Type 1-Receptor Blocker: Implication of Bradykinin-Dependent and Bradykinin-Independent Mechanisms
Losartan reduces myocardial ischemia/reperfusion injury by blocking both AT1 and bradykinin B2 receptors, providing cardioprotection through both bradykinin-dependent and independent mechanisms.
RCTAnimal Study
Highly CitedLosartan as an ACE inhibitor: a description of the mechanism of action through quantum biochemistry
Losartan effectively treats hypertension by blocking the activity of the angiotensin I-converting enzyme, revealing a new mechanism of action for its treatment.
Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes.
Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non-insulin-dependent diabetes mellitus patients, making it a potential alternative to ACE inhibitors for maintaining endothelial function.
RCTHighly CitedLosartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia
Losartan effectively reduces chemotherapy-induced peripheral neuropathy by decreasing inflammatory cytokines in the dorsal root ganglion, offering a potential new treatment option for CIPN patients.
Non-RCTAnimal StudyRigorous JournalLosartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors.
Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats, with nitric oxide and AT2 receptors playing a role in this effect.
In Vitro StudyLosartan protects against cerebral ischemia/reperfusion‐induced apoptosis through &bgr;‐arrestin1‐mediated phosphorylation of Akt
Losartan protects against cerebral ischemia/reperfusion injury by reducing apoptosis through phosphorylation of Akt and -arrestin1-mediated activation of Akt.
Non-RCTAnimal StudyRigorous JournalLOSARTAN PREVENTS SEPSIS-INDUCED ACUTE LUNG INJURY AND DECREASES ACTIVATION OF NUCLEAR FACTOR&kgr;B AND MITOGEN-ACTIVATED PROTEIN KINASES
Losartan protects against acute lung injury and acute respiratory distress syndrome in sepsis patients, with its protective effect partly dependent on NF-&kgr;B and MAPK mechanisms.
Highly Cited