There is ample evidence on the benefit of angiotensin receptor-neprilysin inhibitors (ARNIs) in heart failure, yet data regarding the potential protective action of ARNIs in hypertensive heart disease are sparse. The aim of this study was to show whether an ARNI exerts a protective effect in a model of Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertension with a hypertensive heart and to compare this potential benefit with an angiotensin-converting enzyme inhibitor, captopril. Five groups of adult male Wistar rats were studied (14 per group) for four weeks: untreated controls; ARNI (68 mg/kg/day); L-NAME (40 mg/kg/day); L-NAME treated with ARNI; and L-NAME treated with captopril (100 mg/kg/day). L-NAME administration induced hypertension, accompanied by increased left ventricular (LV) weight and fibrotic rebuilding of the LV in terms of increased concentration and content of hydroxyproline in insoluble collagen and in total collagen and with a histological finding of fibrosis. These alterations were associated with a compromised systolic and diastolic LV function. Treatment with either an ARNI or captopril reduced systolic blood pressure (SBP), alleviated LV hypertrophy and fibrosis, and prevented the development of both systolic and diastolic LV dysfunction. Moreover, the serum levels of prolactin and prolactin receptor were reduced significantly by ARNI and slightly by captopril. In conclusion, in L-NAME-induced hypertension, the dual inhibition of neprilysin and AT1 receptors by ARNI reduced SBP and prevented the development of LV hypertrophy, fibrosis, and systolic and diastolic dysfunction. These data suggest that ARNI could provide protection against LV structural remodeling and functional disorders in hypertensive heart disease.
- Publikační typ
- časopisecké články 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
- acetylcystein analogy a deriváty MeSH
- aldosteron MeSH
- aminobutyráty * MeSH
- bifenylové sloučeniny farmakologie MeSH
- fibróza MeSH
- fixní kombinace léků MeSH
- hypertenze * farmakoterapie MeSH
- hypertrofie levé komory srdeční MeSH
- krysa rodu rattus MeSH
- potkani Wistar MeSH
- prehypertenze * MeSH
- renin-angiotensin systém MeSH
- renin MeSH
- srdeční selhání * MeSH
- tepový objem MeSH
- tetrazoly farmakologie terapeutické užití MeSH
- valsartan farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Lactacystin is a specific proteasome inhibitor that blocks the hydrolysis of intracellular proteins by ubiquitin/proteasome system inhibition. The administration of lactacystin to rats induced hypertension and remodeling of the left ventricle and aorta. This study tested whether lactacystin induces structural and fibrotic rebuilding of the kidneys and whether melatonin and captopril can prevent these potential changes. Six weeks of lactacystin administration to rats increased their average systolic blood pressure (SBP). In the kidneys, lactacystin reduced glomerular density, increased the glomerular tuft area, and enhanced hydroxyproline concentrations. It also elevated the intraglomerular proportion including the amounts of collagen (Col) I and Col III. Lactacystin also raised the tubulointerstitial amounts of Col I and the sum of Col I and Col III with no effect on vascular/perivascular collagen. Six weeks of captopril treatment reduced SBP, while melatonin had no effect. Both melatonin and captopril increased glomerular density, reduced the glomerular tuft area, and lowered the hydroxyproline concentration in the kidneys. Both drugs reduced the proportion and total amounts of intraglomerular and tubulointerstitial Col I and Col III. We conclude that chronic lactacystin treatment stimulated structural and fibrotic remodeling of the kidneys, and melatonin and captopril partly prevented these alterations. Considering the effect of lactacystin on both the heart and kidneys, chronic treatment with this drug may be a prospective model of cardiorenal damage suitable for testing pharmacological drugs as protective agents.
- Publikační typ
- časopisecké články MeSH
This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.
- Publikační typ
- časopisecké články MeSH
Prebiehajúca pandémia novým koronavírusom zasiahla takmer 200 krajín po celom svete. Väčšina dostupných štúdií preukázala, že diabetes mellitus je jednou z najzávažnejších komorbidít pri infekcii COVID-19 (COronaVIrus Disease 2019). Je spojená so závažnejším priebehom ochorenia, akútnym respiračným distres syndrómom a významne vyššou mortalitou v tejto skupine pacientov. V súčasnosti sme preto postavení pred nové úlohy, ktoré súvisia so zmenenou zdravotnou situáciou.
Ongoing pandemy caused by novel coronavirus affected almost 200 countries all over the world. Most of the available studies have shown that with COVID -19 (COronaVIrus Disease 2019) diabetes mellitus as a distinctive comorbidity is associated with more severe disease, acute respiratory distress syndrome and increased mortality in this group of infected patients. At present we are facing new challenges regarding the changed health situation.
- MeSH
- COVID-19 * komplikace mortalita MeSH
- diabetes mellitus * MeSH
- kardiovaskulární nemoci * MeSH
- komorbidita MeSH
- Publikační typ
- přehledy MeSH
This study investigated whether ivabradine, a selective If current inhibitor reducing heart rate (HR), is able to improve survival and prevent left ventricular (LV) remodeling in isoproterenol-induced heart damage. Wistar rats were treated for 6 weeks: controls (n = 10), ivabradine (10 mg/kg/day orally; n = 10), isoproterenol (5 mg/kg/day intraperitoneally; n = 40), and isoproterenol plus ivabradine (n = 40). Isoproterenol increased mortality, induced hypertrophy of both ventricles and LV fibrotic rebuilding, and reduced systolic blood pressure (SBP). Ivabradine significantly increased survival rate (by 120%) and prolonged average survival time (by 20%). Furthermore, ivabradine reduced LV weight and hydroxyproline content in soluble and insoluble collagen fraction, reduced HR and attenuated SBP decline. We conclude that ivabradine improved survival in isoproterenol-damaged hearts.
- MeSH
- funkce levé komory srdeční účinky léků MeSH
- infarkt myokardu patofyziologie MeSH
- isoprenalin MeSH
- ivabradin aplikace a dávkování farmakologie MeSH
- kardiotonika aplikace a dávkování farmakologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- remodelace komor účinky léků MeSH
- srdeční selhání farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Metformín je perorálne podávaný bigvanid, látka znižujúca glykémiu, ktorá sa už desaťročia používa v liečbe u pacientov s diabetes mellitus 2. typu i pri prediabetu. Na rozdiel od iných bigvanidov nevedie ku laktátovej acidóze, preto sa používa v liečbe ako liek prvej línie. Má široké použitie ako v monoterapii, tak aj v kombinovanej liečbe s viacerými antidiabetikami. Ako každé liečivo má však aj svoje vedľajšie nežiaduce účinky, ktoré sú prítomné u približne 30–40 % pacientov pri liekových formách so štandardným uvoľňovaním z perorálnej formy. Ich výskyt je možné znížiť aj voľbou farmaceutických foriem lieku s pomalým uvoľňovaním. Môže to byť užitočné pri manažmente pacienta s diabetes mellitus 2. typu ošetrovaným v primárnej praxi.
Metformin is an oral bigvanide hypoglycemic agent, used during decades for the treatment of patients with type 2 diabetes mellitus and prediabetes. In contrary to other bigvanides it does not lead to lactate acidosis, therefore used in first line treatment. It has broad range in mono-therapy, as well as in combined treatment with other antidiabetics. As in other used treatment modalities it has side effects present in 30–40 % of patients using standard immediate released formulas. Their incidence can be lowered with use of slow elease formulas. This can be helpfull in the primary care management of patient with type 2 diabetes mellitus.
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- léky s prodlouženým účinkem MeSH
- lidé MeSH
- metformin * aplikace a dávkování farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Hodnoty artériového tlaku krvi (TK) podliehajú počas 24 hodín variabilným zmenám v súlade s fyziologickými dennými rytmami. Narušenie prirodzeného cirkadiánneho rytmu TK sa spája so zhoršenou kardiovaskulárnou (KVS) prognózou. Zvýšenie nočného TK alebo aspoň nedostatočný pokles TK v noci, tzv. non‑dipping, sa môže spájať s morfologickou a funkčnou alteráciou periférnych orgánov a dokonca s vyšším výskytom závažných KVS udalostí. Chronoterapia hypertenzie znamená aplikáciu antihypertenzívnej liečby s cieľom zachovania dennej variability TK v zmysle zníženého nočného TK (a dostatočného nočného TK dippingu), čo by mohlo priniesť aditívny benefit k bežnému rannému podávaniu antihypertenzív. Prihliadnuc na cirkadiánne rytmy vo farmakokinetike a farmakodynamike antihypertenzív, redukciu nočného TK je možné dosiahnuť podávaním aspoň časti aplikovaných antihypertenzív vo večerných hodinách. Predkladaný komentár analyzuje benefity, úskalia a perspektívy chronoterapie hypertenzie.
Arterial blood pressure (BP) undergoes variable changes over 24 hours conforming to physiological daily rhythms. Disruption of the natural BP circadian rhythm is associated with worsened cardiovascular disease (CVD) prognosis. Increased nocturnal BP or at least insufficient BP decline at night, i.e. non-dipping, may be associated with morphological and functional alterations of peripheral organs and even with a higher incidence of major CVD events. Hypertension chronotherapy means the application of antihypertensive treatment in order to maintain the daily BP variability in terms of reduced nocturnal BP (thus also maintaining sufficient nocturnal BP dipping), which could bring an additive benefit to the usual morning administration of antihypertensive medications. Taking into account the circadian rhythms in the pharmacokinetics and pharmacodynamics of antihypertensives, the reduction of nocturnal BP can be achieved by administering at least part of the applied antihypertensive medications at bedtime. This commentary analyzes the benefits, pitfalls and perspectives of hypertension chronotherapy.
Current knowledge on the renin-angiotensin system (RAS) indicates its central role in the pathogenesis of cardiovascular remodelling via both hemodynamic alterations and direct growth and the proliferation effects of angiotensin II or aldosterone resulting in the hypertrophy of cardiomyocytes, the proliferation of fibroblasts, and inflammatory immune cell activation. The noncoding regulatory microRNAs has recently emerged as a completely novel approach to the study of the RAS. A growing number of microRNAs serve as mediators and/or regulators of RAS-induced cardiac remodelling by directly targeting RAS enzymes, receptors, signalling molecules, or inhibitors of signalling pathways. Specifically, microRNAs that directly modulate pro-hypertrophic, pro-fibrotic and pro-inflammatory signalling initiated by angiotensin II receptor type 1 (AT1R) stimulation are of particular relevance in mediating the cardiovascular effects of the RAS. The aim of this review is to summarize the current knowledge in the field that is still in the early stage of preclinical investigation with occasionally conflicting reports. Understanding the big picture of microRNAs not only aids in the improved understanding of cardiac response to injury but also leads to better therapeutic strategies utilizing microRNAs as biomarkers, therapeutic agents and pharmacological targets.
- MeSH
- fibróza MeSH
- kardiomegalie genetika metabolismus patologie MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- myokard metabolismus patologie MeSH
- nemoci srdce genetika metabolismus patologie MeSH
- renin-angiotensin systém * MeSH
- signální transdukce * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The renin-angiotensin-aldosterone system (RAAS) ranks among the most challenging puzzles in cardiovascular medicine [...].
- MeSH
- COVID-19 patofyziologie terapie MeSH
- lidé MeSH
- renin-angiotensin systém * MeSH
- SARS-CoV-2 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- úvodníky MeSH
