It was suggested that impaired β-adrenergic relaxation in spontaneously hypertensive rats (SHR) might contribute to their high blood pressure (BP). Our study was focused on isoprenaline-induced dilatation of conduit femoral or resistance mesenteric arteries and on isoprenaline-induced BP reduction in SHR and Wistar-Kyoto rats (WKY). We confirmed decreased β-adrenergic relaxation of SHR femoral arteries due to the absence of its endothelium-independent component, whereas endothelium-dependent component of β-adrenergic smooth muscle relaxation was similar in both strains. Conversely, isoprenaline-induced relaxation of resistance mesenteric arteries was similar in both strains and this was true for endothelium-dependent and endothelium-independent components. We observed moderately reduced sensitivity of SHR mesenteric arteries to salmeterol (β2-adrenergic agonist) and this strain difference disappeared after endothelium removal. However, there was no difference in mesenteric arteries relaxation by dobutamine (β1-adrenergic agonist) which was independent of endothelium. The increasing isoprenaline doses elicited similar BP decrease in both rat strains, although BP sensitivity to isoprenaline was slightly decreased in SHR. The blockade of cyclooxygenase (indomethacin) and NO synthase (L-NAME) further reduced BP sensitivity to isoprenaline in SHR. On the other hand, salmeterol elicited similar BP decrease in both strains and the blockade of cyclooxygenase and NO synthase increased BP sensitivity to salmeterol in SHR as compared to WKY. In conclusion, attenuated β-adrenergic vasodilatation of conduit arteries of SHR but similar β-adrenergic relaxation of resistance mesenteric arteries from WKY and SHR and their similar BP response to β-adrenergic agonists do not support major role of altered β-adrenergic vasodilatation for high BP in genetic hypertension.
- MeSH
- Adrenergic Agents * MeSH
- Adrenergic beta-Agonists pharmacology MeSH
- Mesenteric Arteries MeSH
- Endothelium, Vascular MeSH
- Vascular Resistance MeSH
- Prostaglandin-Endoperoxide Synthases MeSH
- Hypertension * MeSH
- Isoproterenol pharmacology MeSH
- Rats MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Salmeterol Xinafoate MeSH
- Nitric Oxide Synthase MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article 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
- Ventricular Function, Left drug effects MeSH
- Myocardial Infarction physiopathology MeSH
- Isoproterenol MeSH
- Ivabradine administration & dosage pharmacology MeSH
- Cardiotonic Agents administration & dosage pharmacology MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Rats, Wistar MeSH
- Ventricular Remodeling drug effects MeSH
- Heart Failure drug therapy MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
To study the effect of sinomenine (Sin) on isoproterenol (Iso, β-agonist)-induced cardiac hypertrophy (CH), we set up four mouse groups: control, Iso model, Iso+metoprolol (Met, β blocker) 60 mg/kg and Iso+Sin 120 mg/kg. CH was induced by Iso (s.c. for 28 days) in mice, and Sin or Met were orally administered by gavage for 28 days in total. Left ventricular diastolic anterior wall thickness (LVAWd), left ventricular diastolic posterior wall thickness (LVPWd), left ventricular ejection fraction (LVEF), and short axis shortening (FS) were measured by echocardiography. Malondialdehyde (MDA) and total superoxide dismutase (T-SOD) were measured by commercial kits. Lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) were measured by ELISA kits. Histological changes were observed using hematoxylin-eosin (HE) and Masson staining. Protein level of nuclear transcription factor-kappa B (NF-κB) was detected by immunohistochemistry. Compared with the control group, LVAWd, Left ventricular weight index (LVWI) and myocardial fibrosis of the Iso model group significantly increased, as well as NF-κB, LDH, MDA, TNF-α, and IL-1β levels. However, the activity of T-SOD decreased. Compared with the Iso model group, LVWI of Iso model+Sin or Iso model+Met group was improved, LVAWd, LVPWd and myocardial fibrosis decreased, and NF-κB, LDH, MDA, TNF-α and IL-1β levels decreased. T-SOD activity also increased. This study reveals that Sin inhibits the activation of NF-κB, lowers the levels of TNF-α and IL-1β, has anti-oxidative stress effect and inhibits myocardial inflammation in mouse heart, thereby demonstrating its efficacy in preventing Iso induced CH.
Nicotinic receptors (NRs) play an important role in the cholinergic regulation of heart functions, and converging evidence suggests a diverse repertoire of NR subunits in the heart. A recent hypothesis about the plasticity of β NR subunits suggests that β2-subunits and β4-subunits may substitute for each other. In our study, we assessed the hypothetical β-subunit interchangeability in the heart at the level of mRNA. Using two mutant mice strains lacking β2 or β4 NR subunits, we examined the relative expression of NR subunits and other key cholinergic molecules. We investigated the physiology of isolated hearts perfused by Langendorff's method at basal conditions and after cholinergic and/or adrenergic stimulation. Lack of β2 NR subunit was accompanied with decreased relative expression of β4-subunits and α3-subunits. No other cholinergic changes were observed at the level of mRNA, except for increased M3 and decreased M4 muscarinic receptors. Isolated hearts lacking β2 NR subunit showed different dynamics in heart rate response to indirect cholinergic stimulation. In hearts lacking β4 NR subunit, increased levels of β2-subunits were observed together with decreased mRNA for acetylcholine-synthetizing enzyme and M1 and M4 muscarinic receptors. Changes in the expression levels in β4-/- hearts were associated with increased basal heart rate and impaired response to a high dose of acetylcholine upon adrenergic stimulation. In support of the proposed plasticity of cardiac NRs, our results confirmed subunit-dependent compensatory changes to missing cardiac NRs subunits with consequences on isolated heart physiology.NEW & NOTEWORTHY In the present study, we observed an increase in mRNA levels of the β2 NR subunit in β4-/- hearts but not vice versa, thus supporting the hypothesis of β NR subunit plasticity that depends on the specific type of missing β-subunit. This was accompanied with specific cholinergic adaptations. Nevertheless, isolated hearts of β4-/- mice showed increased basal heart rate and a higher sensitivity to a high dose of acetylcholine upon adrenergic stimulation.
- MeSH
- Acetylcholine pharmacology MeSH
- Muscarinic Antagonists pharmacology MeSH
- Atropine pharmacology MeSH
- Cholinesterase Inhibitors pharmacology MeSH
- Hexamethonium pharmacology MeSH
- Isoproterenol pharmacology MeSH
- Myocardium metabolism MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Neostigmine pharmacology MeSH
- Receptors, Nicotinic metabolism MeSH
- Heart drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Obstructive sleep apnoea (OSA) is associated with type 2 diabetes mellitus (T2DM). However, mechanisms mediating association between these two conditions remain unclear. This study investigated, whether the OSA-associated changes in adipose tissue lipolysis might contribute to impaired glucose homeostasis in patient with T2DM. Thirty-five matched subjects were recruited into three groups: T2DM + severe OSA (T2DM + OSA, n = 11), T2DM with mild/no OSA (T2DM, n = 10) and healthy controls (n = 14). Subcutaneous abdominal adipose tissue microdialysis assessed spontaneous, epinephrine- and isoprenaline-stimulated lipolysis. Glucose metabolism was assessed by intravenous glucose tolerance test. Spontaneous lipolysis was higher in the T2DM + OSA compared with the T2DM (60.34 ± 23.40 vs. 42.53 ± 10.16 μmol/L, p = 0.013), as well as epinephrine-stimulated lipolysis (236.84 ± 103.90 vs. 167.39 ± 52.17 μmol/L, p < 0.001). Isoprenaline-stimulated lipolysis was unaffected by the presence of OSA (p = 0.750). The α2 anti-lipolytic effect was decreased in T2DM + OSA by 59% and 315% compared with T2DM and controls (p = 0.045 and p = 0.007, respectively). The severity of OSA (AHI) was positively associated with spontaneous (p = 0.037) and epinephrine-stimulated (p = 0.026) lipolysis. The α2-adrenergic anti-lipolytic effect (p = 0.043) decreased with increasing AHI. Spontaneous lipolysis was positively associated with Insulin resistance (r = 0.50, p = 0.002). Epinephrine-stimulated lipolysis was negatively associated with the Disposition index (r = - 0.34, p = 0.048). AHI was positively associated with Insulin resistance (p = 0.017) and negatively with the Disposition index (p = 0.038). Severe OSA in patients with T2DM increased adipose tissue lipolysis, probably due to inhibition of the α2-adrenergic anti-lipolytic effect. We suggest that dysregulated lipolysis might contribute to OSA-associated impairments in insulin secretion and sensitivity.
- MeSH
- Epinephrine administration & dosage MeSH
- Diabetes Mellitus, Type 2 complications epidemiology metabolism pathology MeSH
- Glucose metabolism MeSH
- Homeostasis physiology MeSH
- Insulin metabolism MeSH
- Insulin Resistance physiology MeSH
- Isoproterenol administration & dosage MeSH
- Middle Aged MeSH
- Humans MeSH
- Lipolysis drug effects genetics MeSH
- Sleep Apnea, Obstructive complications epidemiology metabolism pathology MeSH
- Aged MeSH
- Adipose Tissue drug effects metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
This study aimed to investigate the anti-fibrotic effects of ghrelin in isoproterenol (ISO)-induced myocardial fibrosis and the underlying mechanism. Sprague-Dawley rats were randomized to control, ISO, and ISO + ghrelin groups. ISO (2 mg/kg per day, subcutaneous) or vehicle was administered once daily for 7 days, then ghrelin (100 microg/kg per day, subcutaneous) was administered once daily for the next 3 weeks. Ghrelin treatment greatly improved the cardiac function of ISO-treated rats. Ghrelin also decreased plasma brain natriuretic peptide level and ratios of heart weight to body weight and left ventricular weight to body weight. Ghrelin significantly reduced myocardial collagen area and hydroxyproline content, accompanied by decreased mRNA levels of collagen type I and III. Furthermore, ghrelin increased plasma level of growth differentiation factor 15 (GDF15) and GDF15 mRNA and protein levels in heart tissues, which were significantly decreased with ISO alone. The phosphorylation of Akt at Ser473 and GSK-3beta at Ser9 was decreased with ISO, and ghrelin significantly reversed the downregulation of p-Akt and p-GSK-3beta. Mediated by GDF15, ghrelin could attenuate ISO-induced myocardial fibrosis via Akt-GSK-3beta signaling.
- MeSH
- Adrenergic beta-Agonists pharmacology MeSH
- Fibrosis chemically induced drug therapy pathology MeSH
- Ghrelin administration & dosage MeSH
- Isoproterenol pharmacology MeSH
- Cardiomyopathies chemically induced drug therapy metabolism pathology MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Myocardium metabolism pathology MeSH
- Rats, Sprague-Dawley MeSH
- Proto-Oncogene Proteins c-akt metabolism MeSH
- Growth Differentiation Factor 15 metabolism MeSH
- Heart drug effects physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cardiomyocytes (CM) placed on microelectrode array (MEA) were simultaneously probed with cantilever from atomic force microscope (AFM) system. This electric / nanomechanical combination in real time recorded beating force of the CMs cluster and the triggering electric events. Such "organ-on-a-chip" represents a tool for drug development and disease modeling. The human pluripotent stem cells included the WT embryonic line CCTL14 and the induced dystrophin deficient line reprogrammed from fibroblasts of a patient affected by Duchenne Muscular Dystrophy (DMD, complete loss of dystrophin expression). Both were differentiated to CMs and employed with the AFM/MEA platform for diseased CMs' drug response testing and DMD characterization. The dependence of cardiac parameters on extracellular Ca2+ was studied. The differential evaluation explained the observed effects despite variability of biological samples. The β-adrenergic stimulation (isoproterenol) and antagonist trials (verapamil) addressed ionotropic and chronotropic cell line-dependent features. For the first time, a distinctive beating-force relation for DMD CMs was measured on the 3D cardiac in vitro model.
- MeSH
- Biosensing Techniques * MeSH
- Cell Differentiation genetics MeSH
- Muscular Dystrophy, Duchenne physiopathology MeSH
- Dystrophin genetics MeSH
- Fibroblasts drug effects ultrastructure MeSH
- Induced Pluripotent Stem Cells metabolism ultrastructure MeSH
- Isoproterenol pharmacology MeSH
- Myocytes, Cardiac cytology MeSH
- Myocardial Contraction genetics physiology MeSH
- Humans MeSH
- Microelectrodes MeSH
- Microscopy, Atomic Force MeSH
- Verapamil pharmacology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
There is a great urgency of detecting and monitoring myocardial fibrosis in clinical practice with the aim to improve and personalize therapy against cardiac remodelling. Hence, the aim of this study was to describe alterations in and show potential correlations between the structural characteristics and the molecular and biochemical markers of cardiac remodelling on a model of isoproterenol-induced heart failure. Two groups of 3-month-old male Wistar rats (n = 8 per group) were sacrificed after four weeks of treatment: control (placebo), ISO (5 mg/kg/day intraperitoneally). Chronic ISO treatment led to heart failure (HF) characterized by significant reduction of systolic blood pressure (SBP) accompanied by an increase in left ventricular weight (LVW) along with increased collagen content in the LV. The collagen content correlated negatively with SBP (R = -0.776, P < 0.001) and positively with LVW (R = 0.796, P < 0.001), with Col1a1 (0.83; P < 0.001) and Acta2 (0.73; P < 0.01). Moreover, the mRNA expression of fibrotic remodelling indicator, i.e. TGF-β1 tended to increase, while the level of fibrinolysis markers (MCP-1, TIMP-2, MMP) were unchanged. The plasma markers of collagen, procollagen I C-terminal propeptide (PICP) was 37.34 ± 7.10 pg/mL in control and was reduced by 42% (P < 0.05) in the ISO group and procollagen III N-terminal propeptide (PIIINP) was 1216.7 ± 191.0 pg/mL in control and was decreased by 66% (P < 0.05) in the ISO group. Surprisingly, there was no positive correlation between plasma markers of collagen, i.e. PICP and PIIINP and collagen content or molecular markers of collagen. However, both PICP and PIIINP correlated with BW (R = 0.712, resp. 0.803, P < 0.001), which was significantly reduced (by 25%, P < 0.05) in the ISO group. In conclusion, we assume that the collagen content of the left ventricle does not need unavoidably correlate with plasma markers of collagen, which might be affected by confounding factors in heart failure, such as loss of body weight, presumably associated with a catabolic condition.
- MeSH
- Isoproterenol MeSH
- Collagen metabolism MeSH
- Blood Pressure MeSH
- Peptide Fragments blood MeSH
- Rats, Wistar MeSH
- Procollagen blood MeSH
- Ventricular Remodeling * MeSH
- Heart Ventricles metabolism MeSH
- Heart Failure chemically induced metabolism physiopathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Syndrom Brugadových (BrS) je relativně vzácný hereditární arytmický syndrom, který je charakterizován typickým elektrokardiografickým obrazem ve svodech z pravého prekordia a rizikem maligních komorových arytmií. Popisujeme případ arytmické bouře u pacienta s BrS. Cílem kazuistiky je připomenout nutnost volby nezvyklé farmakoterapie izoprenalinem. Jedná se sice o situaci vzácnou, avšak život ohrožující, kdy tato znalost může být pro záchranu pacienta rozhodující.
The Brugada syndrome (BrS) is a relatively rare hereditary arrhythmic syndrome. It is characterized by typical electrocardiographic pattern in the right precordial leads and increased risk of malignant ventricular arrhythmias. We are describing a case of an arrhythmic storm in a patient with BrS. The aim of this report is to stress the necessary choice of uncommon pharmacotherapy with isoproterenol. In this rare, nevertheless life threatening situation, such knowledge could be substantial for patient rescue.
- Keywords
- esmocard, arytmická bouře,
- MeSH
- Anti-Arrhythmia Agents therapeutic use MeSH
- Adrenergic beta-Antagonists therapeutic use MeSH
- Brugada Syndrome * drug therapy physiopathology MeSH
- Defibrillators, Implantable MeSH
- Adult MeSH
- Ventricular Dysfunction, Left drug therapy therapy MeSH
- Echocardiography MeSH
- Ventricular Fibrillation MeSH
- Isoproterenol pharmacology therapeutic use MeSH
- Tachycardia, Ventricular drug therapy therapy MeSH
- Humans MeSH
- Death, Sudden, Cardiac MeSH
- Treatment Failure MeSH
- Arrhythmias, Cardiac * drug therapy therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
The current study was designed to investigate the effect of berbamine (BBM) on isoproterenol (ISO) induced changes in cardiac marker enzymes, myocardial oxidative stress, lipid profile and expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in male Wistar rats. Rats were pretreated with BBM (25 mg/kg) through intraperitoneal injection for 7 days followed by induction of myocardial infarction (MI) by subcutaneous injection of ISO (85 mg/kg) for last two days. Key findings: In the present study, the histopathological findings of the heart tissue showed that BBM treatment significantly minimized the damage induced by ISO. BBM pretreatment showed a significant decrease in heart weight, serum marker enzymes, lipid peroxidation and significant increase in cardiac endogenous enzymatic and non-enzymatic antioxidants compared to the ISO-treated group. In addition, we observed significantly upregulated eNOS expression and downregulated iNOS expression in BBM pretreated group. Thus, BBM protected the rat’s heart from ISO-induced myocardial infarction by its antioxidant, and antilipidemic properties. Significance: The results of the present investigation suggested that BBM efficiently ameliorated the ISO-induced myocardial infarction in rats.
- MeSH
- Benzylisoquinolines administration & dosage pharmacology MeSH
- Myocardial Infarction drug therapy chemically induced physiopathology MeSH
- Isoproterenol administration & dosage adverse effects MeSH
- Cardiotonic Agents MeSH
- Disease Models, Animal MeSH
- Nitrosative Stress drug effects MeSH
- Polymerase Chain Reaction methods MeSH
- Rats, Wistar MeSH
- Nitric Oxide Synthase Type II drug effects MeSH
- Nitric Oxide Synthase Type III drug effects MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
