Muscarinic acetylcholine receptors are metabotropic G-protein coupled receptors. Muscarinic receptors in the cardiovascular system play a central role in its regulation. Particularly M2 receptors slow down the heart rate by reducing the impulse conductivity through the atrioventricular node. In general, activation of muscarinic receptors has sedative effects on the cardiovascular system, including vasodilation, negative chronotropic and inotropic effects on the heart, and cardioprotective effects, including antifibrillatory effects. First, we review the signaling of individual subtypes of muscarinic receptors and their involvement in the physiology and pathology of the cardiovascular system. Then we review age and disease-related changes in signaling via muscarinic receptors in the cardiovascular system. Finally, we review molecular mechanisms involved in cardioprotection mediated by muscarinic receptors leading to negative chronotropic and inotropic and antifibrillatory effects on heart and vasodilation, like activation of acetylcholine-gated inward-rectifier K+-currents and endothelium-dependent and -independent vasodilation. We relate this knowledge with well-established cardioprotective treatments by vagal stimulation and muscarinic agonists. It is well known that estrogen exerts cardioprotective effects against atherosclerosis and ischemia-reperfusion injury. Recently, some sex hormones and neurosteroids have been shown to allosterically modulate muscarinic receptors. Thus, we outline possible treatment by steroid-based positive allosteric modulators of acetylcholine as a novel pharmacotherapeutic tactic. Keywords: Muscarinic receptors, Muscarinic agonists, Allosteric modulation, Cardiovascular system, Cardioprotection, Steroids.

• MeSH
• agonisté muskarinových receptorů farmakologie   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• lidé MeSH
• receptory muskarinové * metabolismus   MeSH
• vazodilatace fyziologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.

• MeSH
• benzhydrylové sloučeniny * farmakologie   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• glifloziny * farmakologie   MeSH
• glukosidy * farmakologie   MeSH
• hypertenze farmakoterapie   MeSH
• játra * účinky léků   metabolismus   patologie   MeSH
• kardiotonika farmakologie   MeSH
• krevní glukóza metabolismus   účinky léků   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• ochranné látky farmakologie   MeSH
• potkani inbrední SHR * MeSH
• ztučnělá játra prevence a kontrola   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• akutní srdeční selhání,
• MeSH
• diagnostické zobrazování MeSH
• diuretika terapeutické užití   MeSH
• dusičnany terapeutické užití   MeSH
• kardiogenní šok diagnóza   MeSH
• kardiotonika terapeutické užití   MeSH
• klinické laboratorní techniky MeSH
• lidé MeSH
• mimotělní membránová oxygenace MeSH
• opioidní analgetika terapeutické užití   MeSH
• oxygenoterapie MeSH
• plicní edém etiologie   MeSH
• podpůrné srdeční systémy MeSH
• srdeční selhání * diagnóza   etiologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

OBJECTIVES: In stress echocardiography (SE), dipyridamole (DIP) and dynamic stress (ExSE) are reported as being safer than dobutamine stress echocardiography (DSE). We investigated whether these commonly used stressors cause myocardial injury, measured by high sensitivity troponin T (hsTnT). METHODS: One hundred and thirty five patients (DSE n = 46, ExsE n = 46, DIP n = 43) with negative result of SE were studied. The exclusion criteria were known ischaemic heart disease (IHD), baseline wall motion abnormalities, left ventricle systolic dysfunction/regional wall motion abnormalities, septum/posterior wall ≥13 mm, diabetes/pre-diabetes, baseline hsTnT level ≥14 ng/L, baseline blood pressure ≥160/100 mmHg, peak pulmonary pressure ≥45mmHg, eGFR <1ml/s/1.73m2 , more than mild to moderate valvular disease and dobutamine side effects. HsTnT was measured before and 180 minutes after the test. RESULTS: All patients had low pre-test probabilities of having obstructive IHD. HsTnT increased in DSE, less so in ExSE, and was unchanged in the DIP group (∆hsTnT 9.4 [1.5-58.6], 1.1 [-0.9-15.7], -0.1 [-1.4-2.1] ng/L, respectively, p<0.001). In DSE, the ∆hsTnT was associated with peak dobutamine dose (r = 0.30, p = 0.045), test length (r = 0.43, p = 0.003) and atropine use (p<0.001). In ExSE, the hsTnT increase was more likely in females (p = 0.012) and the elderly (>65 years) (r = 0.32, p = 0.03); no association was found between atropine use (p = 0.786) or test length and ∆hsTnT (r = 0.10, p = 0.530). CONCLUSIONS: DSE is associated with myocardial injury in patients with negative SE, no injury was observed in DIP and only mild case in ExSE. Whether myocardial injury is causative of the higher reported adverse event rates in DSE remains to be determined.

• MeSH
• deriváty atropinu MeSH
• dipyridamol MeSH
• dobutamin MeSH
• echokardiografie MeSH
• ischemická choroba srdeční * komplikace   MeSH
• kardiotonika MeSH
• lidé MeSH
• nemoci koronárních tepen * komplikace   MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• zátěžová echokardiografie MeSH
• zátěžový test MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

• MeSH
• kardiotonika škodlivé účinky   farmakologie   terapeutické užití   MeSH
• kardiovaskulární nemoci mortalita   MeSH
• kontrakce myokardu účinky léků   MeSH
• lidé středního věku MeSH
• lidé MeSH
• močovina škodlivé účinky   analogy a deriváty   farmakologie   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• srdeční myosiny účinky léků   metabolismus   MeSH
• systolické srdeční selhání farmakoterapie   metabolismus   patofyziologie   MeSH
• tepový objem MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie 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

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

• MeSH
• bazální metabolismus účinky léků   MeSH
• biologické markery krev   MeSH
• desaturasy mastných kyselin metabolismus   MeSH
• hyperlipoproteinemie typ IV farmakoterapie   metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• kardiotonika farmakologie   MeSH
• krysa rodu rattus MeSH
• kyselina arachidonová metabolismus   MeSH
• mediátory zánětu krev   MeSH
• metabolismus lipidů účinky léků   MeSH
• metformin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   MeSH
• potkani Wistar MeSH
• prediabetes farmakoterapie   metabolismus   MeSH
• rizikové faktory MeSH
• srdce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

• MeSH
• antiflogistika farmakologie   terapeutické užití   MeSH
• antioxidancia terapeutické užití   MeSH
• apoptóza * účinky léků   MeSH
• hemodynamika účinky léků   MeSH
• hypertenze maligní farmakoterapie   enzymologie   patologie   patofyziologie   MeSH
• kardiotonika farmakologie   terapeutické užití   MeSH
• látky reagující s kyselinou thiobarbiturovou metabolismus   MeSH
• myokard patologie   MeSH
• NG-nitroargininmethylester chemie   farmakologie   MeSH
• oxidace-redukce MeSH
• potkani inbrední SHR MeSH
• protein X asociovaný s bcl-2 metabolismus   MeSH
• resveratrol chemie   farmakologie   terapeutické užití   MeSH
• srdeční komory účinky léků   patologie   patofyziologie   MeSH
• tělesná hmotnost účinky léků   MeSH
• velikost orgánu účinky léků   MeSH
• zánět komplikace   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.

• MeSH
• daunomycin toxicita   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• inhibitory topoisomerasy II chemická syntéza   metabolismus   terapeutické užití   MeSH
• kardiomyocyty účinky léků   MeSH
• kardiotonika chemická syntéza   metabolismus   terapeutické užití   MeSH
• kardiotoxicita farmakoterapie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• novorozená zvířata MeSH
• piperaziny chemická syntéza   metabolismus   terapeutické užití   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• Saccharomyces cerevisiae - proteiny metabolismus   MeSH
• Saccharomyces cerevisiae chemie   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The bisdioxopiperazine topoisomerase IIβ inhibitor ICRF-193 has been previously identified as a more potent analog of dexrazoxane (ICRF-187), a drug used in clinical practice against anthracycline cardiotoxicity. However, the poor aqueous solubility of ICRF-193 has precluded its further in vivo development as a cardioprotective agent. To overcome this issue, water-soluble prodrugs of ICRF-193 were prepared, their abilities to release ICRF-193 were investigated using a novel UHPLC-MS/MS assay, and their cytoprotective effects against anthracycline cardiotoxicity were tested in vitro in neonatal ventricular cardiomyocytes (NVCMs). Based on the obtained results, the bis(2-aminoacetoxymethyl)-type prodrug GK-667 was selected for advanced investigations due to its straightforward synthesis, sufficient solubility, low cytotoxicity and favorable ICRF-193 release. Upon administration of GK-667 to NVCMs, the released ICRF-193 penetrated well into the cells, reached sufficient intracellular concentrations and provided effective cytoprotection against anthracycline toxicity. The pharmacokinetics of the prodrug, ICRF-193 and its rings-opened metabolite was estimated in vivo after administration of GK-667 to rabbits. The plasma concentrations of ICRF-193 reached were found to be adequate to achieve cardioprotective effects in vivo. Hence, GK-667 was demonstrated to be a pharmaceutically acceptable prodrug of ICRF-193 and a promising drug candidate for further evaluation as a potential cardioprotectant against chronic anthracycline toxicity.

• MeSH
• antracykliny škodlivé účinky   MeSH
• dexrazoxan chemie   farmakologie   MeSH
• diketopiperaziny chemie   farmakologie   MeSH
• DNA-topoisomerasy typu II metabolismus   MeSH
• inhibitory topoisomerasy II chemie   farmakologie   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• kardiotonika chemie   farmakologie   MeSH
• kardiotoxicita farmakoterapie   metabolismus   MeSH
• králíci MeSH
• piperazin chemie   farmakologie   MeSH
• prekurzory léčiv chemie   farmakologie   MeSH
• razoxan chemie   farmakologie   MeSH
• voda chemie   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH