sr-59230a and Heart-Failure

The β

Topics: Adenosine Triphosphate; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Fatty Acids; Gene Expression; Glucose; Heart; Heart Failure; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Myocardium; Nitric Oxide Synthase Type II; Propanolamines

Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of β3-adrenergic receptors (β3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the β3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson's trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of β3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of β3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the β3-AR-nNOS-NO pathway.

Topics: Animals; Cardiomegaly, Exercise-Induced; Catecholamines; Cell Size; Fibrosis; Heart Failure; Male; Mice; Myocardium; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Synthase Type I; Physical Conditioning, Animal; Propanolamines; Reactive Oxygen Species; Receptors, Adrenergic, beta-3; Signal Transduction; Superoxide Dismutase

To investigate the effects of β3-adrenoceptors(β3-AR) inhibitor SR 59230A on MicroRNAs expression in rat myocardium with chronic heart failure and the related mechanisms.. One hundred male SD rats were randomly divided into sham operated group(40)and chronic heart failure(CHF)group(60). Coronary artery ligation was used to induce CHF. Then the rats in CHF group were further randomly divided into CHF control group and CHF+SR 59230A group (CHF+SR). Rats in the sham group were divided into sham control group and sham+SR 59230A group (Sham+SR). The rats in Sham+SR group and CHF+SR group were treated with 1 ml SR 59230A(85 mmoL/L in 0.9% saline)twice a day for seven weeks by intraperitoneal injection, while the rats in control groups were injected with the same amount of saline for seven weeks separately. miScript miRNA PCR Arrays were used to determine the expression profile of MicroRNAs. Immunohistochemistry was used to evaluate the distribution of the related proteins in the heart tissue sections. Western blot was used to detect the expressions of nuclear factor-kappaB(NF-κB),p53 and p53-Phospho-Serine 15 in the heart.. ①After. Blocking of β3-AR improved the damaged heart in CHF rats; β3-AR caused the change of MicroRNAs expression, and it related to NF-κB signal pathway.

Topics: Adrenergic beta-3 Receptor Antagonists; Animals; Heart; Heart Failure; Male; MicroRNAs; Myocardium; NF-kappa B; Propanolamines; Random Allocation; Rats; Rats, Sprague-Dawley; Tumor Suppressor Protein p53

To investigate the association between beta(3)-adrenergic receptor (beta(3)-AR) and oxidative stress in isoproterenol (ISO)-induced chronic heart failure (HF) rats.. Seven weight-matched normal adult rats (control), 18 ISO induced heart failure rats and 21 ISO induced heart failure rats treated with specific beta(3)-AR inhibitor, SR59230A for 6 weeks were included in this study. Echocardiography was performed at the end of the study and the myocardial levels of total superoxide dismutase (T-SOD) and lipid peroxidation (LPO) were measured by colorimetry, myocardial expression of beta(3)-AR was detected by reverse transcription-polymerase chain reaction (RT-PCR).. Compared with control group, the cardiac function was significantly reduced and myocardial beta(3)-AR mRNA expression was significantly increased, LPO level was also significantly enhanced while T-SOD level was significantly reduced in ISO group and these changes could be significantly attenuated by treatment with SR59230A.. Our results showed that myocardial upregulation of beta(3)-AR is associated with increased oxidative stress in this model and beta(3)-AR inhibitor may be a new therapeutic agent for heart failure treatment.

Topics: Animals; Gene Expression Regulation; Heart Failure; Lipid Peroxidation; Male; Myocardium; Oxidative Stress; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Superoxide Dismutase; Up-Regulation

Ventricular arrhythmia in chronic heart failure (CHF) is considered to be associated with stimulation of β-adrenergic receptors (β-ARs). Three classes of β-ARs have been identified; importantly, distinct from β1 and β2 subtypes, β3-AR could inhibit arrhythmia. Intracellular Ca2+ is considered as a predominant effecter of arrhythmia during heart failure. However, the exact role of β3-AR in arrhythmia and Ca2+ regulation in CHF is not clear yet. Therefore, we studied the effect of BRL37344, a specific β3-AR activator, on CHF-related ventricular arrhythmia and cellular Ca2+ transport. Rabbits with CHF induced by combined aortic insufficiency and aortic constriction were treated with BRL37344 in the presence or absence of β1-AR and β2-AR stimulation. We then evaluated the current produced by sodium calcium exchanger (INCX), an electrical marker of abnormal Ca2+ removal through ion transporter protein sodium calcium exchanger (NCX), Ca2+ transient, a sign of Ca2+ entering the cell, concentration of Ca2+ in sarcoplasmic reticulum (SR) (SR Ca2+ load) and its abnormal release (SR Ca2+ leak). After treatment with BRL37344, the incidence of ventricular arrhythmias induced by infusion of a β1-AR or β2-AR activator decreased significantly. Similarly, β3-AR stimulation remarkably inhibited increase of INCX, Ca2+ transient, SR Ca2+ load and leak induced by activation of β1-AR or β2-AR. SR59230A, a specific β3-AR blocker, abolished the inhibitory effects of BRL37344. These results suggest that β3-AR activation could inhibit ventricular arrhythmia through regulating intracellular Ca2+. Thus, β3-AR is a feasible therapeutic target that holds promise in the treatment of ventricular arrhythmias in CHF.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Arrhythmias, Cardiac; Biological Transport; Calcium; Electrophysiology; Ethanolamines; Heart Failure; Microscopy, Fluorescence; Propanolamines; Rabbits; Receptors, Adrenergic, beta-3; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger

To investigate the effect of beta(3)-adrenoceptor (beta(3)-AR) antagonist (SR59230A) on the cardiac function and left ventricular remodeling in a rat model of heart failure induced by isoproterenol (ISO), and to probe into its mechanism.. Eight rats were randomly selected to serve as controls from 85 male adult Wistar rats. After a heart failure model was reproduced, twenty remain rats were randomly divided into ISO group (n = 10) and SR59230A group (SR group, n = 10). ISO group received intraperitoneal injection of 1 ml saline twice a day; SR group received intraperitoneal injection of 85 nmol SR59230A in 1 ml saline twice a day; control group received no treatment. The parameters determined included echocardiogram, the expression of nitric oxide synthase (eNOS) of left ventricle by the technique of reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, cyclic guanosine monophosphate (cGMP) level by enzyme linked immunosorbent assay (ELISA), the ratio of left ventricular weight and body weight (LVW/BW), and the ratio of lung weight and body weight (PW/BW).. Compared with control group, the left ventricular end systolic pressure (LVESP), the maximum and minimum first derivative of left ventricular pressure (+/-dp/dtmax) were significantly decreased (all P<0.01), while heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) were significantly increased (both P<0.01) in ISO group. Compared with ISO group, LVESP, +/-dp/dtmax were markedly higher (P<0.05 or P<0.01) respectively, whereas HR and LVEDP were markedly lower (P<0.05 and P<0.01) in SR group, and there was no difference in HR between SR group and control group (P>0.05), while LVEDP was higher in RS group than control group (P<0.01). The levels of eNOS mRNA, protein and cGMP were significantly lower in SR group compared with ISO group (all P<0.01). In addition, when compared with ISO group, LVW/BW ratio and PW/BW ratio in SR group were also decreased (both P<0.05).. beta(3)-AR antagonist SR59230A can block the beta(3)-AR-NOS-cGMP pathway and improve cardiac function in heart failure in rat when if is administered for a long term. SR59230A can also improve left ventricular remodeling in a certain degree.

Topics: Adrenergic beta-3 Receptor Antagonists; Animals; Disease Models, Animal; Heart Failure; Male; Nitric Oxide Synthase Type III; Propanolamines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Ventricular Function, Left; Ventricular Remodeling

Stimulation of the heart beta 3-adrenoceptor (AR) may result in a negative inotropic effect. Being up-regulated, beta 3-AR plays a more important role in the regulation of cardiac function during heart failure. However, the effect of chronic blocking of beta 3-AR on heart failure has not been fully elucidated. In this study, we used a selective beta 3-AR antagonist SR59230A to treat a well defined heart failure rat model chronically, then evaluated its effect on cardiac function and investigated the mechanism.. Male Wistar rats were chosen randomly as controls (n = 8). Isoproterenol induced heart failure rats were randomly divided into ISO group (n = 10) and SR group (n = 10). The ISO group received intraperitoneal injection of 1 ml saline twice a day; the SR group received intraperitoneal injection of SR59230A 85 nmol in 1 ml saline twice a day; and the control group received no treatment. The treatment was started 24 hours after the last isoproterenol injection and continued for 7 weeks. Then we measured the following indexes: the ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW), collagen volume fraction (CVF), left ventricular end diastolic dimension (LVEDd), left ventricular end systolic dimension (LVESd), ejection fraction (EF), fractional shortening (FS) and the ratio of E wave to A wave (E/A), the mRNA and protein expression of beta 3-AR and eNOS, and cGMP level in the heart.. The ratios HW/BW and LVW/BW were significantly increased in the ISO group compared with the control group (P < 0.01), but they were limited in the SR group (P < 0.05 compared with the ISO group). CVF increased in the ISO group and the SR group (P < 0.01), but it was significantly attenuated in the SR group (P < 0.01). LVEDd, LVESd and E/A ratio were significantly increased in the ISO group compared with the control group (P < 0.01), while EF and FS were significantly decreased (P < 0.01). Compared with the ISO group, the SR group showed that LVEDd, LVESd and E/A ratio were significantly decreased (P < 0.01), whereas EF and FS were significantly increased (P < 0.01). beta(3)-AR and eNOS mRNA and protein in the ISO group were significantly increased when compared with the control group (P < 0.01). These increases were all attenuated in the SR group compared with the ISO group (P < 0.01). The level of cGMP in myocardial tissue was significantly increased in the ISO group compared with the control group (P < 0.01), whereas SR59230A treatment normalized this increment (P < 0.01).. Chronic blocking of beta 3-AR could ameliorate cardiac function in heart failure rats and its mechanism involves inhibition of the negative inotropic effect and attenuation of cardiac remodeling.

Topics: Adrenergic beta-3 Receptor Antagonists; Adrenergic beta-Antagonists; Animals; Blotting, Western; Disease Models, Animal; Echocardiography; Enzyme-Linked Immunosorbent Assay; Heart Failure; Male; Myocardium; Nitric Oxide Synthase Type III; Propanolamines; Rats; Rats, Wistar; Receptors, Adrenergic, beta-3; Reverse Transcriptase Polymerase Chain Reaction; Ventricular Function, Left