The aim of the present study was to assess systemic circulatory and tissue activities of both the classical arm and of the alternative arm of the renin-angiotensin system (RAS) in a new transgenic rat line (TG7371) that expresses angiotensin-(1-7) (ANG 1-7)-producing fusion protein; the results were compared with the activities measured in control transgene-negative Hannover Sprague-Dawley (HanSD) rats. Plasma and tissue concentrations of angiotensin II (ANG II) and ANG 1-7, and kidney mRNA expressions of receptors responsible for biological actions of ANG II and ANG 1-7 [i.e. ANG II type 1 and type 2 (AT1 and AT2) and Mas receptors] were assessed in TG7371 transgene-positive and in HanSD rats. We found that male TG7371 transgene-positive rats exhibited significantly elevated plasma, kidney, heart and lung ANG 1-7 concentrations as compared with control male HanSD rats; by contrast, there was no significant difference in ANG II concentrations and no significant differences in mRNA expression of AT1, AT2 and Mas receptors. In addition, we found that in male TG7371 transgene-positive rats blood pressure was lower than in male HanSD rats. These data indicate that the balance between the classical arm and the alternative arm of the RAS was in male TGR7371 transgene-positive rats markedly shifted in favor of the latter. In conclusion, TG7371 transgene-positive rats represent a new powerful tool to study the long-term role of the alternative arm of the RAS in the pathophysiology and potentially in the treatment of cardio-renal diseases.

• MeSH
• Angiotensin I * metabolism   MeSH
• Angiotensin II * MeSH
• Cardiovascular Diseases metabolism   genetics   MeSH
• Blood Pressure physiology   MeSH
• Rats MeSH
• Kidney metabolism   MeSH
• Kidney Diseases metabolism   genetics   MeSH
• Peptide Fragments * metabolism   MeSH
• Rats, Sprague-Dawley * MeSH
• Rats, Transgenic * MeSH
• Proto-Oncogene Mas MeSH
• Receptor, Angiotensin, Type 1 genetics   metabolism   MeSH
• Receptors, G-Protein-Coupled genetics   metabolism   MeSH
• Recombinant Fusion Proteins metabolism   MeSH
• Renin-Angiotensin System * physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.

• MeSH
• Amino Acids, Diamino MeSH
• Angiotensin-Converting Enzyme 2 metabolism   MeSH
• COVID-19 * prevention & control   MeSH
• Cytokines metabolism   MeSH
• Epithelial Cells * drug effects   virology   MeSH
• Fullerenes * pharmacology   chemistry   MeSH
• Spike Glycoprotein, Coronavirus * metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Nanoparticles * chemistry   MeSH
• Nasal Mucosa drug effects   cytology   MeSH
• Reactive Oxygen Species metabolism   MeSH
• SARS-CoV-2 * drug effects   MeSH
• Cytokine Release Syndrome * prevention & control   MeSH
• Cell Survival * drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

• MeSH
• Biochemistry MeSH
• Metabolic Diseases MeSH
• Pathology MeSH

• Conspectus
• Patologie. Klinická medicína
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• biochemie
• patologie
• NML Publication type
• učebnice vysokých škol

Vysoký krevní tlak je jedním z nejčastějších zdravotních problémů vyššího věku a jedním z hlavních kardiovaskulárních rizikových faktorů. Osoby starší 65 let trpí především izolovanou systolickou hypertenzí se zvýšeným pulzním tlakem, který je důsledkem ztráty tepenné elasticity. S věkem roste pravděpodobnost výskytu dalších kardiovaskulárních a ledvinných onemocnění a diabetu. Pro léčbu proto užíváme přednostně léky, které mají kromě snížení krevního tlaku prokázaný kardioprotektivní efekt a nemají negativní vliv na přidružená onemocnění. Blokátory renin-angiotenzinového systému, blokátory vápníkových kanálů a thiazidová analoga tvoří základ léčby a můžeme je výhodně kombinovat. Antihypertenzní léčba vede k poklesu rizika kardiovaskulárních příhod a srdečního selhání také u nejstarších osob ve věku nad 80 let.

Hypertension is one of the most common problems at higher age and belongs to the most important cardiovascular risk factors. Subjects aged 65 years and more have typically isolated systolic hypertension with increased pulse pressure as a consequence of decreased elasticity of central arteries. With increasing age, the prevalence of cardiovascular and renal diseases and diabetes is higher. Therefore, we use drugs that have cardiprotective effect and do not affect negatively concomitant diseases. Blockers of renin-angiotensin system, calcium channels blockers and thiazide-type diuretics are basic drugs; their combination results in effective control of hypertension. The risk of cardiovascular events and of heart failure is decreased after antihypertensive treatment also in subjects aged 80 years and more.

• MeSH
• Antihypertensive Agents therapeutic use   MeSH
• Hypertension * diagnosis   drug therapy   MeSH
• Isolated Systolic Hypertension * diagnosis   drug therapy   MeSH
• Drug Therapy, Combination MeSH
• Humans MeSH
• Blood Pressure Determination methods   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Review MeSH

This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.

• MeSH
• Acetylcysteine analogs & derivatives   MeSH
• Aldosterone MeSH
• Aminobutyrates * MeSH
• Biphenyl Compounds pharmacology   MeSH
• Fibrosis MeSH
• Drug Combinations MeSH
• Hypertension * drug therapy   MeSH
• Hypertrophy, Left Ventricular MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Prehypertension * MeSH
• Renin-Angiotensin System MeSH
• Renin MeSH
• Heart Failure * MeSH
• Stroke Volume MeSH
• Tetrazoles pharmacology   therapeutic use   MeSH
• Valsartan pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.

• MeSH
• Angiotensin Receptor Antagonists adverse effects   MeSH
• Kidney Failure, Chronic * MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Glomerulonephritis, IGA * drug therapy   MeSH
• Irbesartan adverse effects   MeSH
• Humans MeSH
• Proteinuria drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.

• MeSH
• Budesonide adverse effects   MeSH
• Adult MeSH
• Glomerulonephritis, IGA * drug therapy   MeSH
• Humans MeSH
• Adolescent MeSH
• Proteinuria drug therapy   etiology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• Asia MeSH
• Europe MeSH

BACKGROUND: Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are known to be effective in managing cardiovascular diseases, but more evidence supports the use of an ACEI. This study investigated the difference in cardiovascular disease incidence between relatively low-compliance ACEIs and high-compliance ARBs in the clinical setting. METHODS: Patients who were first prescribed ACEIs or ARBs at two tertiary university hospitals in Korea were observed in this retrospective cohort study for the incidence of heart failure, angina, acute myocardial infarction, cerebrovascular disease, ischemic heart disease, and major adverse cardiovascular events for 5 years after the first prescription. Additionally, 5-year Kaplan-Meier survival curves were used based on the presence or absence of statins. RESULTS: Overall, 2,945 and 9,189 patients were prescribed ACEIs and ARBs, respectively. When compared to ACEIs, the incidence of heart failure decreased by 52% in those taking ARBs (HR [95% CI] = 0.48 [0.39-0.60], P < 0.001), and the incidence of cerebrovascular disease increased by 62% (HR [95% CI] = 1.62 [1.26-2.07], P < 0.001). The incidence of ischemic heart disease (P = 0.223) and major adverse cardiovascular events (P = 0.374) did not differ significantly between the two groups. CONCLUSIONS: ARBs were not inferior to ACEIs in relation to reducing the incidence of cardiocerebrovascular disease in the clinical setting; however, there were slight differences for each disease. The greatest strength of real-world evidence is that it allows the follow-up of specific drug use, including drug compliance. Large-scale studies on the effects of relatively low-compliance ACEIs and high-compliance ARBs on cardiocerebrovascular disease are warranted in the future.

• MeSH
• Angiotensin Receptor Antagonists adverse effects   MeSH
• Cerebrovascular Disorders * epidemiology   chemically induced   MeSH
• Incidence MeSH
• Myocardial Infarction * chemically induced   MeSH
• Angiotensin-Converting Enzyme Inhibitors adverse effects   MeSH
• Myocardial Ischemia * epidemiology   chemically induced   MeSH
• Humans MeSH
• Retrospective Studies MeSH
• Heart Failure * drug therapy   epidemiology   chemically induced   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-43 (Cx43) signaling pathways in hemodynamically overloaded rat heart as well as the possible implication of angiotensin (1-7) (Ang (1-7)) to prevent/attenuate adverse myocardial remodeling. Male 8-week-old, normotensive Hannover Spraque-Dawley rats (HSD), hypertensive (mRen-2)27 transgenic rats (TGR) and Ang (1-7) transgenic rats (TGR(A1-7)3292) underwent aortocaval fistula (ACF) to produce volume overload. Five weeks later, biometric and heart tissue analyses were performed. Cardiac hypertrophy in response to volume overload was significantly less pronounced in TGR(A1-7)3292 compared to HSD rats. Moreover, a marker of fibrosis hydroxyproline was increased in both ventricles of volume-overloaded TGR while it was reduced in the Ang (1-7) right heart ventricle. The protein level and activity of MMP-2 were reduced in both ventricles of volume-overloaded TGR/TGR(A1-7)3292 compared to HSD. SMAD2/3 protein levels were decreased in the right ventricle of TGR(A1-7)3292 compared to HSD/TGR in response to volume overload. In parallel, Cx43 and pCx43 implicated in electrical coupling were increased in TGR(A1-7)3292 versus HSD/TGR. It can be concluded that Ang (1-7) exhibits cardio-protective and anti-fibrotic potential in conditions of cardiac volume overload.

• MeSH
• Angiotensin II MeSH
• Fibrosis MeSH
• Hypertension * metabolism   MeSH
• Connexin 43 MeSH
• Rats MeSH
• Rats, Transgenic MeSH
• Heart MeSH
• Heart Failure * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

• MeSH
• Aspirin adverse effects   therapeutic use   MeSH
• Atorvastatin adverse effects   therapeutic use   MeSH
• Myocardial Infarction complications   prevention & control   therapy   MeSH
• Angiotensin-Converting Enzyme Inhibitors * adverse effects   therapeutic use   MeSH
• Platelet Aggregation Inhibitors * adverse effects   therapeutic use   MeSH
• Ischemic Stroke prevention & control   MeSH
• Cardiovascular Diseases * etiology   mortality   prevention & control   MeSH
• Humans MeSH
• Ramipril adverse effects   therapeutic use   MeSH
• Secondary Prevention methods   MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * adverse effects   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Randomized Controlled Trial MeSH