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Current Medicinal Chemistry 2009Besides the importance of the renin-angiotensin system (RAS) in the circulation and other organs, the local RAS in the kidney has attracted a great attention in research... (Review)
Review
Besides the importance of the renin-angiotensin system (RAS) in the circulation and other organs, the local RAS in the kidney has attracted a great attention in research in last decades. The renal RAS plays an important role in the body fluid homeostasis and long-term cardiovascular regulation. All major components and key enzymes for the establishment of a local RAS as well as two important angiotensin II (Ang II) receptor subtypes, AT1 and AT2 receptors, have been confirmed in the kidney. In additional to renal contribution to the systemic RAS, the intrarenal RAS plays a critical role in the regulation of renal function as well as in the development of kidney disease. Notably, kidney AT1 receptors locating at different cells and compartments inside the kidney are important for normal renal physiological functions and abnormal pathophysiological processes. This mini-review focuses on: 1) the local renal RAS and its receptors, particularly the AT1 receptor and its mechanisms in physiological and pathophysiological processes; and 2) the chemistry of the selective AT1 receptor blocker, losartan, and the potential mechanisms for its actions in the renal RAS-mediated disease.
Topics: Angiotensin II Type 1 Receptor Blockers; Humans; Kidney; Losartan; Molecular Structure; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 19747145
DOI: 10.2174/092986709789105000 -
American Journal of Physiology. Renal... Aug 2018Renin-angiotensin-system blockers are thought to increase the risk of acute kidney injury after surgery and hemorrhage. We found that losartan does not cause renal...
Renin-angiotensin-system blockers are thought to increase the risk of acute kidney injury after surgery and hemorrhage. We found that losartan does not cause renal cortical hypoxia after hemorrhage in rats because of decreased renal vascular resistance, but we did not evaluate resuscitation. We aimed to study losartan's effect on renal cortical and medullary oxygenation, as well as norepinephrine's vasopressor effect in a model of resuscitated hemorrhage. After 7 days of losartan (60 mg·kg·day) or control treatment, male Wistar rats were hemorrhaged 20% of their blood volume and resuscitated with Ringer's acetate. Mean arterial pressure, renal blood flow, and kidney tissue oxygenation were measured at baseline and after resuscitation. Finally, the effect of norepinephrine on mean arterial pressure and renal blood flow was investigated. As expected, losartan lowered mean arterial pressure but not renal blood flow. Losartan did not affect renal oxygen consumption and oxygen tension. Mean arterial pressure and renal blood flow were lower after resuscitated hemorrhage. A smaller increase of renal vascular resistance in the losartan group translated to a smaller decrease in cortical oxygen tension, but no significant difference was seen in medullary oxygen tension, either between groups or after hemorrhage. The effect of norepinephrine on mean arterial pressure and renal blood flow was similar in control- and losartan-treated rats. Losartan does not decrease renal oxygenation after resuscitated hemorrhage because of a smaller increase in renal vascular resistance. Further, losartan does not decrease the efficiency of norepinephrine as a vasopressor, indicating that blood pressure may be managed effectively during losartan treatment.
Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Arterial Pressure; Disease Models, Animal; Hemodynamics; Hemorrhage; Kidney; Losartan; Male; Norepinephrine; Oxygen Consumption; Rats, Wistar; Renal Circulation; Resuscitation; Vascular Resistance; Vasoconstrictor Agents
PubMed: 29667909
DOI: 10.1152/ajprenal.00095.2018 -
Frontiers in Immunology 2022Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly...
Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium-glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by which the SGLT2 inhibitor canagliflozin attenuates podocyte injury by reversing the imbalance in Helper T cell 1 (Th1)/Helper T cell 2 (Th2) in peripheral blood of rats with membranous nephropathy (MN). MN rats were gavaged with canagliflozin (10 mg/kg/d) and losartan (10 mg/kg/d), respectively, for eight weeks. Compared with the MN group, the urinary ratio of total protein and the creatinine levels of the canagliflozin group decreased significantly. Canagliflozin improved the glomerulus pathological damage, increased the expression levels of podocyte marker proteins. The protective effect of canagliflozin on kidneys was more obvious than that of losartan. Treatment with canagliflozin increased the proportion of Th1 cells by 2.3 times, decreased the proportion of Th2 cells by 68.5%, and significantly restrained the synthesis of immunoglobulin G1 in B-cells and glomerulus subepithelial immune complex deposition. Co-culture of B-cells derived from MN rats with podocytes triggered the activation of phosphorylation of mTOR and ULK1 of podocytes, inhibited podocyte autophagy and resulted in podocyte injury. B-cells derived from canagliflozin treatment rats reversed these effects above. In conclusion, canagliflozin exerts a protective effect on kidneys by reversing the imbalance in Th1/Th2 cells in MN rats and restoring the autophagy of podocytes inhibited by the abnormal immunoglobulin G secretion from B-cells.
Topics: Rats; Animals; Podocytes; Glomerulonephritis, Membranous; Canagliflozin; Losartan; Autophagy; Renal Insufficiency, Chronic
PubMed: 36531996
DOI: 10.3389/fimmu.2022.993869 -
Frontiers in Immunology 2022Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1)...
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells' infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment.
Topics: Animals; Cell Line, Tumor; Humans; Immunotherapy; Losartan; Mice; Mice, Inbred BALB C; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 35812418
DOI: 10.3389/fimmu.2022.938439 -
Journal of the... Dec 2015We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the... (Clinical Trial)
Clinical Trial
OBJECTIVE
We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day).
METHODS
Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis.
RESULTS
The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects.
CONCLUSION
Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.
Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure; Creatinine; Diastole; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycated Hemoglobin; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Losartan; Male; Potassium; Systole; Treatment Outcome; Uric Acid
PubMed: 25143336
DOI: 10.1177/1470320314529358 -
Experimental Physiology Jul 2018What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by... (Randomized Controlled Trial)
Randomized Controlled Trial
NEW FINDINGS
What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation. Losartan and allopurinol are effective therapies for achieving blood pressure control in sleep apnoea.
ABSTRACT
Chemoreflex sensitization produced by chronic intermittent hypoxia in rats is attenuated by angiotensin II type 1 receptor (AT R) blockade. Both AT R blockade and xanthine oxidase inhibition ameliorate chronic intermittent hypoxia-induced endothelial dysfunction. We hypothesized that treatment with losartan and allopurinol would reduce chemoreflex sensitivity and improve hypoxic vasodilatation in patients with obstructive sleep apnoea. Eighty-six hypertensive patients with apnoea-hypopnoea index ≥25 events h and no other cardiovascular, pulmonary, renal or metabolic disease were randomly assigned to receive allopurinol, losartan or placebo for 6 weeks. Treatment with other medications and/or continuous positive airway pressure remained unchanged. Tests of chemoreflex sensitivity and hypoxic vasodilatation were performed during wakefulness before and after treatment. Ventilation (pneumotachography), muscle sympathetic nerve activity (microneurography), heart rate (electrocardiography), arterial oxygen saturation (pulse oximetry), blood pressure (sphygmomanometry), forearm blood flow (venous occlusion plethysmography) and cerebral flow velocity (transcranial Doppler ultrasound) were measured during eupnoeic breathing and graded reductions in inspired O tension. Losartan and allopurinol lowered arterial pressure measured during eupnoeic breathing and exposure to acute hypoxia. Neither drug altered the slopes of ventilatory, sympathetic or cardiovascular responses to acute hypoxia. We conclude that losartan and allopurinol are viable pharmacotherapeutic adjuncts for achieving blood pressure control in hypertensive obstructive sleep apnoea patients, even those who are adequately treated with continuous positive airway pressure.
Topics: Adult; Aged; Allopurinol; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Cerebrovascular Circulation; Female; Heart Rate; Humans; Hypertension; Hypoxia; Losartan; Male; Muscle, Skeletal; Sleep Apnea, Obstructive; Treatment Outcome; Young Adult
PubMed: 29750475
DOI: 10.1113/EP087006 -
The New England Journal of Medicine Jul 2009Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin system.
METHODS
We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models.
RESULTS
A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.
CONCLUSIONS
Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)
Topics: Adult; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Double-Blind Method; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney Glomerulus; Logistic Models; Losartan; Male; Mesangial Cells; Renin-Angiotensin System; Retina
PubMed: 19571282
DOI: 10.1056/NEJMoa0808400 -
Scientific Reports Nov 2023Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix...
The treatment with trandolapril and losartan attenuates pressure and volume overload alternations of cardiac connexin-43 and extracellular matrix in Ren-2 transgenic rats.
Heart failure (HF) is life-threatening disease due to electro-mechanical dysfunction associated with hemodynamic overload, while alterations of extracellular matrix (ECM) along with perturbed connexin-43 (Cx43) might be key factors involved. We aimed to explore a dual impact of pressure, and volume overload due to aorto-caval fistula (ACF) on Cx43 and ECM as well as effect of renin-angiotensin blockade. Hypertensive Ren-2 transgenic rats (TGR) and normotensive Hannover Sprague-Dawley rats (HSD) that underwent ACF were treated for 15-weeks with trandolapril or losartan. Blood serum and heart tissue samples of the right (RV) and left ventricles (LV) were used for analyses. ACF-HF increased RV, LV and lung mass in HSD and to lesser extent in TGR, while treatment attenuated it and normalized serum ANP, BNP-45 and TBARS. Cx43 protein and its ser368 variant along with PKCε were lower in TGR vs HSD and suppressed in both rat strains due to ACF but prevented more by trandolapril. Pro-hypertrophic PKCδ, collagen I and hydroxyproline were elevated in TGR and increased due to ACF in both rat strains. While SMAD2/3 and MMP2 levels were lower in TGR vs HSD and reduced due to ACF in both strains. Findings point out the strain-related differences in response to volume overload. Disorders of Cx43 and ECM signalling may contribute not only to HF but also to the formation of arrhythmogenic substrate. There is benefit of treatment with trandolapril and losartan indicating their pleiotropic anti-arrhythmic potential. It may provide novel input to therapy.
Topics: Rats; Animals; Rats, Transgenic; Losartan; Renin; Connexin 43; Rats, Sprague-Dawley; Heart Failure; Hypertension; Blood Pressure; Fistula; Extracellular Matrix
PubMed: 38017033
DOI: 10.1038/s41598-023-48259-2 -
Journal of Physiology and Pharmacology... Jun 2023Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity....
Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity. Recently, the associations between the angiotensin converting enzyme 2 (ACE2) pathway and thrombosis have been reported. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) are widely used cardiovascular pharmacologic agents that upregulate ACE2 levels. An observation of the alterations in pro-coagulation factors after exposure to ACEIs and ARBs may provide valuable insight into the thrombosis mechanism and how it may relate to ACE2. This study use adipose tissue harvested from an obese male donor was isolated and exposed to perindopril, losartan, and ACE2 recombinant as binding assay, following exposure with 10 nm of SARS-CoV-2 S1 spike protein. After 48 hours, tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) as pro-coagulation factors as well as ACE2 levels and binding evaluated. The results shows TF level was significantly reduced in Perindopril group compared to control (4.834; p=0.005), while a non-significant reduction was observed in Losartan group (5.624; p=0.111). However, Losartan group showed a better reduction of PAI-1 levels (2.633; p≤0.001) than Perindopril group (3.484; p=0.001). These findings were consistent with the observations in ACE2 recombinant group, suggesting that both drugs lowered the bindings of ACE2 and SARS-CoV-2 spike proteins. This study indicated that both perindopril and losartan may attenuate pro-coagulation factors in human adipocytes exposed to SARS-CoV-2 spike proteins, and therefore showcased a potential role of ACE2 in the mechanism of COVID-19-related thrombosis. Further investigation in non-COVID-19 populations should commence and may be of value to expanding this potential in general cardiovascular diseases.
Topics: Humans; Male; Perindopril; Spike Glycoprotein, Coronavirus; Losartan; Plasminogen Activator Inhibitor 1; Angiotensin-Converting Enzyme 2; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; COVID-19; SARS-CoV-2; Blood Coagulation Factors; Adipocytes; Thromboplastin; Cardiovascular Agents; Obesity
PubMed: 37661180
DOI: 10.26402/jpp.2023.3.03 -
BMC Cardiovascular Disorders Aug 2022Non-communicable diseases are a growing burden in many African countries; cardiovascular disease is the main disease. Antihypertensive medicines (AHM) are a common...
BACKGROUND
Non-communicable diseases are a growing burden in many African countries; cardiovascular disease is the main disease. Antihypertensive medicines (AHM) are a common treatment option but we know little about community use in most low- and medium-income countries (LMIC). We aimed to describe the use of antihypertensive medicines (AHM) in Ghana and Nigeria using a novel data source.
METHODS
We used data from mPharma-a health and pharmaceutical company which distributes pharmaceuticals to hospital and retail pharmacies. We extracted data using the anatomical therapeutic chemical (ATC) classification codes and calculated use in defined daily doses and explored patterns by class, medicines, dose, and originator or generic product.
RESULTS
AHM use differed between Ghana and Nigeria. The most used classes in Ghana were angiotensin receptor blockers (ARB) followed by calcium channel blockers (CCB) and angiotensin-converting-enzyme inhibitors (ACEi). The five most used products were 16 mg candesartan, 30 mg nifedipine, 10 mg lisinopril, 5 mg amlodipine and 50 mg losartan. In Nigeria ARB, CCB and diuretics were widely used; the top five products were 50 mg losartan, 10 mg lisinopril, 30 mg nifedipine, 40 mg furosemide, and 5 mg amlodipine. More originator products were used in Ghana than Nigeria.
CONCLUSION
The differences between Ghana and Nigeria may result from a combination of medical, contextual and policy evidence and reflect factors related to clinical guidance (e.g. standard treatment guidelines), accessibility to prescribers and the role of community pharmacies, and structure of the health system and universal health coverage including funding for medicines. We show the feasibility of using novel data sources to gain insights on medicines use in the community.
Topics: Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Ghana; Humans; Hypertension; Lisinopril; Losartan; Nifedipine; Nigeria
PubMed: 35948937
DOI: 10.1186/s12872-022-02799-z