We aimed to determine the impact of Ca(2+)-related disorders induced in intact animal hearts on ultrastructure of the cardiomyocytes prior to occurrence of severe arrhythmias. Three types of acute experiments were performed that are known to be accompanied by disturbances in Ca(2+) handling. Langedorff-perfused rat or guinea pig hearts subjected to K(+)-deficient perfusion to induce ventricular fibrillation (VF), burst atrial pacing to induce atrial fibrillation (AF) and open chest pig heart exposed to intramyocardial noradrenaline infusion to induce ventricular tachycardia (VT). Tissue samples for electron microscopic examination were taken during basal condition, prior and during occurrence of malignant arrhythmias. Cardiomyocyte alterations preceding occurrence of arrhythmias consisted of non-uniform sarcomere shortening, disruption of myofilaments and injury of mitochondria that most likely reflected cytosolic Ca(2+) disturbances and Ca(2+) overload. These disorders were linked with non-uniform pattern of neighboring cardiomyocytes and dissociation of adhesive junctions suggesting defects in cardiac cell-to-cell coupling. Our findings identified heterogeneously distributed high [Ca(2+)](i)-induced subcellular injury of the cardiomyocytes and their junctions as a common feature prior occurrence of VT, VF or AF. In conclusion, there is a link between Ca(2+)-related disorders in contractility and coupling of the cardiomyocytes pointing out a novel paradigm implicated in development of severe arrhythmias.
- MeSH
- draslík MeSH
- homeostáza MeSH
- kardiomyocyty metabolismus ultrastruktura MeSH
- krysa rodu Rattus MeSH
- morčata MeSH
- noradrenalin MeSH
- poruchy metabolismu vápníku komplikace patologie MeSH
- prasata MeSH
- srdeční arytmie etiologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- morčata MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- draslík MeSH
- noradrenalin MeSH
We aimed to explore the effects of melatonin and n-3 polyunsaturated fatty acids (PUFA) supplementation on plasma and aortic nitric oxide (NO) levels in isoproterenol (Iso) affected spontaneously hypertensive (SHR) and Wistar rats. Untreated control rats were compared with Iso injected (118 mg/kg, s.c.) rats, and Iso injected plus supplemented with melatonin (10 mg/kg, p.o.) or PUFA (1.68 g/kg, p.o.) for two months. Plasma and aortic basal, L-NAME inhibited, adrenaline and acetylcholine stimulated NO were determined using Griess method. Plasma NO levels were lower in SHR versus Wistar rats. Iso decreased NO in Wistar while not in SHR. PUFA but not melatonin intake of Iso treated SHR increased plasma NO along with a decrease in systolic blood pressure. Basal aortic NO level was higher in SHR than Wistar rats and not altered by Iso. Intake of melatonin increased but PUFA decreased basal NO levels in Wistar+Iso and did not affect in SHR+Iso rats. Acetylcholine and adrenaline induced aortic NO release was significantly increased in Wistar+Iso but not SHR+Iso group. Melatonin intake increased Ach induced aortic NO in Wistar+Iso and SHR+Iso groups, whereas there was no effect of PUFA intake. Findings suggest that PUFA modulates plasma and melatonin aortic NO levels of isoproterenol affected rats in a strain-dependent manner.
- MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- aorta účinky léků metabolismus MeSH
- hypertenze krev farmakoterapie MeSH
- isoprenalin MeSH
- melatonin farmakologie terapeutické užití MeSH
- omega-3 mastné kyseliny farmakologie terapeutické užití MeSH
- oxid dusnatý krev MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- potravní doplňky MeSH
- preklinické hodnocení léčiv MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia MeSH
- isoprenalin MeSH
- melatonin MeSH
- omega-3 mastné kyseliny MeSH
- oxid dusnatý MeSH
Mechanisms underlying atrial fibrillation (AF), the most common cardiac arrhythmia, particularly in aged population, are not fully elucidated. We have previously shown an increased propensity of old guinea pigs (GPs) heart to inducible AF when comparing to young animals. This study aimed to verify our hypothesis that susceptibility of aged heart to AF may be attributed to abnormalities in myocardial connexin-43 (Cx43) and extracellular matrix that affect cardiac electrical properties. Experiments were conducted on male and female 4-week-old and 24-week-old GPs. Atrial tissue was processed for analysis of Cx43 topology using immunohistochemistry, expression of Cx43 protein using immunobloting, and expression of mRNA of Cx43 and extracellular matrix metalloproteinase-2 (MMP-2) using real time PCR. Immunohistochemistry revealed uniform Cx43 distribution predominantly on lateral sides of the cardiomyocytes of young male and female GP atria. In contrast, non-uniform distribution, mislocalization and reduced immunolabeling of Cx43 were detected in atria of old GPs. In parallel, the atrial tissue levels of Cx43 mRNA were significantly decreased, while mRNA expression of MMP-2 was significantly increased in old versus young GPs. The changes were more pronounced in old GPs males comparing to females. Findings indicate that age-related down-regulation of atrial Cx43 and up-regulation of MMP-2 as well as disordered Cx43 distribution can facilitate development of AF in old guinea pig hearts.
- MeSH
- down regulace MeSH
- fibrilace síní etiologie metabolismus MeSH
- konexin 43 metabolismus MeSH
- matrixová metaloproteinasa 2 metabolismus MeSH
- morčata MeSH
- myokard metabolismus ultrastruktura MeSH
- stárnutí metabolismus MeSH
- upregulace MeSH
- zvířata MeSH
- Check Tag
- morčata MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- konexin 43 MeSH
- matrixová metaloproteinasa 2 MeSH
Thyroid hormones are powerful modulators of heart function and susceptibility to arrhythmias via both genomic and non-genomic actions. We aimed to explore expression of electrical coupling protein connexin-43 (Cx43) in the heart of rats with altered thyroid status and impact of omega-3 polyunsaturated fatty acids (omega-3) supplementation. Adult male Lewis rats were divided into following six groups: euthyroid controls, hyperthyroid (treated with T(3)) and hypothyroid (treated with methimazol) with or without six-weeks lasting supplementation with omega-3 (20 mg/100 g/day). Left and right ventricles, septum and atria were used for immunoblotting of Cx43 and protein kinase C (PKC). Total expression of Cx43 and its phosphorylated forms were significantly increased in all heart regions of hypothyroid rats compared to euthyroid controls. In contrast, the total levels of Cx43 and its functional phosphorylated forms were decreased in atria and left ventricle of hyperthyroid rats. In parallel, the expression of PKC epsilon that phosphorylates Cx43, at serine 368, was increased in hypothyroid but decreased in hyperthyroid rat hearts. Omega-3 intake did not significantly affect either Cx43 or PKC epsilon alterations. In conclusion, there is an inverse relationship between expression of cardiac Cx43 and the levels of circulating thyroid hormones. It appears that increased propensity of hyperthyroid while decreased of hypothyroid individuals to malignant arrhythmias may be in part attributed to the changes in myocardial Cx43.
- MeSH
- fosforylace MeSH
- hormony štítné žlázy krev MeSH
- hypertyreóza metabolismus MeSH
- hypotyreóza metabolismus MeSH
- konexin 43 metabolismus MeSH
- matrixová metaloproteinasa 2 metabolismus MeSH
- myokard enzymologie MeSH
- náhodné rozdělení MeSH
- omega-3 mastné kyseliny farmakologie MeSH
- potkani inbrední LEW MeSH
- potravní doplňky MeSH
- proteinkinasa C metabolismus MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- Gja1 protein, rat MeSH Prohlížeč
- hormony štítné žlázy MeSH
- konexin 43 MeSH
- matrixová metaloproteinasa 2 MeSH
- Mmp2 protein, rat MeSH Prohlížeč
- omega-3 mastné kyseliny MeSH
- proteinkinasa C MeSH
Gap junction connexin channels are important determinants of myocardial conduction and synchronization that is crucial for coordinated heart function. One of the main risk factors for cardiovascular events that results in heart attack, congestive heart failure, stroke as well as sudden arrhythmic death is hypertension. Mislocalization and/or dysfunction of specific connexin-43 channels due to hypertension-induced myocardial remodeling have been implicated in the occurrence of life-threatening arrhythmias and heart failure in both, humans as well as experimental animals. Recent studies suggest that down-regulation of myocardial connexin-43, its abnormal distribution and/or phosphorylation might be implicated in this process. On the other hand, treatment of hypertensive animals with cardioprotective drugs (e.g. statins) or supplementation with non-pharmacological compounds, such as melatonin, omega-3 fatty acids and red palm oil protects from lethal arrhythmias. The antiarrhythmic effects are attributed to the attenuation of myocardial connexin-43 abnormalities associated with preservation of myocardial architecture and improvement of cardiac conduction. Findings uncover novel mechanisms of cardioprotective (antihypertensive and antiarrhythmic) effects of compounds that are used in clinical settings. Well-designed trials are needed to explore the antiarrhythmic potential of these compounds in patients suffering from hypertension.
- MeSH
- antiarytmika farmakologie terapeutické užití MeSH
- antioxidancia farmakologie terapeutické užití MeSH
- hypertenze farmakoterapie metabolismus patologie MeSH
- konexin 43 metabolismus MeSH
- lidé MeSH
- melatonin farmakologie terapeutické užití MeSH
- mezerový spoj ultrastruktura MeSH
- myokard ultrastruktura MeSH
- oleje rostlin farmakologie terapeutické užití MeSH
- omega-3 mastné kyseliny farmakologie terapeutické užití MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antiarytmika MeSH
- antioxidancia MeSH
- GJA1 protein, human MeSH Prohlížeč
- konexin 43 MeSH
- melatonin MeSH
- oleje rostlin MeSH
- omega-3 mastné kyseliny MeSH
Previous data suggest that type 1 diabetes mellitus leads to the deterioration of myocardial intercellular communication mediated by connexin-43 (Cx43) channels. We therefore aimed to explore Cx43, PKC signaling and ultrastructure in non-treated and omega-3 fatty acid (omega-3) treated spontaneously diabetic Goto-Kakizaki (GK) rats considered as type 2 diabetes model. Four-week-old GK and non-diabetic Wistar-Clea rats were fed omega-3 (200 mg/kg/day) for 2 months and compared with untreated rats. Real-time PCR and immunoblotting were performed to determine Cx43, PKC-epsilon and PKC-delta expression. In situ Cx43 was examined by immunohistochemistry and subcellular alterations by electron microscopy. Omega-3 intake reduced blood glucose, triglycerides, and cholesterol in diabetic rats and this was associated with improved integrity of cardiomyocytes and capillaries in the heart. Myocardial Cx43 mRNA and protein levels were higher in diabetic versus non-diabetic rats and were further enhanced by omega-3. The ratio of phosphorylated (functional) to non-phosphorylated Cx43 was lower in diabetic compared to non-diabetic rats but was increased by omega-3, in part due to up-regulation of PKC-epsilon. In addition, pro-apoptotic PKC-delta expression was decreased. In conclusion, spontaneously diabetic rats at an early stage of disease benefit from omega-3 intake due to its hypoglycemic effect, upregulation of myocardial Cx43, and preservation of cardiovascular ultrastructure. These findings indicates that supplementation of omega-3 may be beneficial also in the management of diabetes in humans.
- MeSH
- experimentální diabetes mellitus metabolismus patologie prevence a kontrola MeSH
- fixní kombinace léků MeSH
- konexin 43 metabolismus MeSH
- krysa rodu Rattus MeSH
- kyselina eikosapentaenová farmakologie terapeutické užití MeSH
- kyseliny dokosahexaenové farmakologie terapeutické užití MeSH
- myokard metabolismus ultrastruktura MeSH
- potravní doplňky MeSH
- preklinické hodnocení léčiv MeSH
- proteinkinasa C-delta metabolismus MeSH
- proteinkinasa C-epsilon metabolismus MeSH
- srdce účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- fixní kombinace léků MeSH
- Gja1 protein, rat MeSH Prohlížeč
- konexin 43 MeSH
- kyselina eikosapentaenová MeSH
- kyseliny dokosahexaenové MeSH
- Omacor MeSH Prohlížeč
- proteinkinasa C-delta MeSH
- proteinkinasa C-epsilon MeSH
