OBJECTIVETo observe the effects of combined beta(1) adrenergic receptor (AR) antagonist with beta(2)AR agonist therapy on cardiac function and cardiomyocyte apoptosis in heart failure rats.

METHODSHeart failure was induced by isoproterenol and rats were randomly divided into metoprolol group (50 mg/kg twice daily/gavage, n = 11), combined treatment group (fenoterol 125 microg/kg and metoprolol 50 mg/kg twice daily/gavage, n = 11) and placebo group (saline, n = 10), another normal 9 male Wistar rats served as control group. After 8 weeks' treatment, cardiac function, apoptosis index (AI), Caspase-3 activity, expression levels of bcl-2 and bax protein, organ weight/body weight and collagen volume fraction (CVF) were evaluated.

RESULTS(1) Left ventricular end diastolic dimension, left ventricular end systolic dimension and E/A ratio were significantly increased and fractional shortening, ejection fraction significantly reduced post isoproterenol (all P < 0.05 vs. control) and these changes were significantly attenuated by metoprolol alone (all P < 0.05 vs. placebo) and further attenuated by the metoprolol and fenoterol combination therapy (all P < 0.05 vs. placebo and metoprolol). (2) Left ventricular weight to body weight ratio, lung weight to body weight ratio and CVF were also significantly reduced in metoprolol and combined treatment group than those in placebo group (all P < 0.01). (3) Compared with placebo group, AI and Caspase-3 activity were significantly lower in metoprolol group (all P < 0.01 vs. placebo) and further reduced in combined treatment group (all P < 0.01 vs. metoprolol). (4) The expression level of bax protein was significantly lower in metoprolol group while bcl-2/bax significantly higher than those in placebo group. These changes were more significant in combined treatment group (all P < 0.01 vs. metoprolol).

CONCLUSIONSbeta(1)AR antagonist in combination with beta(2)AR agonist further improved the cardiac function and prevented cardiac remodeling compared with using beta(1)AR antagonist alone in heart failure rats. Downregulated bax and upregulated bcl-2/bax expressions might contribute to the observed beneficial therapy effects by reducing cardiomyocyte apoptosis in these animals.

Adrenergic beta-1 Receptor Antagonists ; Adrenergic beta-2 Receptor Agonists ; Adrenergic beta-Agonists ; pharmacology ; therapeutic use ; Adrenergic beta-Antagonists ; pharmacology ; therapeutic use ; Animals ; Apoptosis ; drug effects ; Drug Therapy, Combination ; Heart Failure ; drug therapy ; Male ; Myocytes, Cardiac ; cytology ; Rats ; Rats, Wistar ; Ventricular Remodeling

OBJECTIVETo demonstrate the inhibitory effect of kappa-opioid receptor activation by U50488H on hypertrophy induced by NE in cultured neonatal rat cardiac myocytes and compare its effect with that of prazosin and propranolol.

METHODSThe cellular proliferation was determined with crystal violet staining. The protein content was assayed with Lowry's method. The cardiomyocytes volumes were measured by computer photograph analysis system. The protein synthesis was assayed with [3H]-lencine incorporation method.

RESULTS(1) NE significantly induced the increase of protein content, [3H]-leucine incorporation and cell size without a concomitant increase in cell number in low serum medium. OThese responses were partially suppressed by prazosin or propranolol alone and completely abolished by both in combination. U50488H significantly inhibited the NE-induced increase of protein content, [3H]-leucine incorporation and cell size. The inhibitory effects of U50488H on NE-induced cardiac hypertrophy were greater than either prazosin or propranolol, but comparable to combination of both.

CONCLUSIONNE, acting via both alpha1- and beta-adrenergic pathway, stimulates myocyte hypertrophy. Stimulating kappa-opioid receptor significantly inhibits NE-induced cardiac hypertrophy, which may be related with alpha1- and beta1-adrenergic pathway.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer ; pharmacology ; Adrenergic alpha-1 Receptor Antagonists ; pharmacology ; Adrenergic beta-Antagonists ; pharmacology ; Animals ; Animals, Newborn ; Cardiomegaly ; chemically induced ; pathology ; prevention & control ; Cell Enlargement ; drug effects ; Cells, Cultured ; Female ; Male ; Myocytes, Cardiac ; cytology ; Norepinephrine ; Prazosin ; pharmacology ; Propranolol ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, kappa ; agonists

No abstract available.
Adrenergic beta-3 Receptor Agonists/therapeutic use ; Humans ; Muscarinic Antagonists/therapeutic use ; Precision Medicine/methods/*trends ; Urinary Bladder, Overactive/*therapy

BackgroundSerum soluble ST2 (sST2) levels are elevated early after acute myocardial infarction and are related to adverse left ventricular (LV) remodeling and cardiovascular outcomes in ST-segment elevation myocardial infarction (STEMI). Beta-blockers (BB) have been shown to improve LV remodeling and survival. However, the relationship between sST2, final therapeutic BB dose, and cardiovascular outcomes in STEMI patients remains unknown.

MethodsA total of 186 STEMI patients were enrolled at the Wuhan Asia Heart Hospital between January 2015 and June 2015. All patients received standard treatment and were followed up for 1 year. Serum sST2 was measured at baseline. Patients were divided into four groups according to their baseline sST2 values (high >56 ng/ml vs. low ≤56 ng/ml) and final therapeutic BB dose (high ≥47.5 mg/d vs. low <47.5 mg/d). Cox regression analyses were performed to determine whether sST2 and BB were independent risk factors for cardiovascular events in STEMI.

ResultsBaseline sST2 levels were positively correlated with heart rate (r = 0.327, P = 0.002), Killip class (r = 0.408, P = 0.000), lg N-terminal prohormone B-type natriuretic peptide (r = 0.467, P = 0.000), lg troponin I (r = 0.331, P = 0.000), and lg C-reactive protein (r = 0.307, P = 0.000) and negatively correlated to systolic blood pressure (r = -0.243, P = 0.009) and LV ejection fraction (r = -0.402, P = 0.000). Patients with higher baseline sST2 concentrations who were not titrated to high-dose BB therapy (P < 0.0001) had worse outcomes. Baseline high sST2 (hazard ratio [HR]: 2.653; 95% confidence interval [CI]: 1.201-8.929; P = 0.041) and final low BB dosage (HR: 1.904; 95% CI, 1.084-3.053; P = 0.035) were independent predictors of cardiovascular events in STEMI.

ConclusionsHigh baseline sST2 levels and final low BB dosage predicted cardiovascular events in STEMI. Hence, sST2 may be a useful biomarker in cardiac pathophysiology.

Adrenergic beta-Antagonists ; administration & dosage ; therapeutic use ; Adult ; Aged ; Biomarkers ; blood ; Female ; Humans ; Interleukin-1 Receptor-Like 1 Protein ; blood ; Male ; Middle Aged ; Prognosis ; Prospective Studies ; ST Elevation Myocardial Infarction ; blood ; drug therapy ; pathology

BACKGROUNDStimulation 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.

METHODSMale 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.

RESULTSThe 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).

CONCLUSIONSChronic 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.

Adrenergic beta-3 Receptor Antagonists ; Adrenergic beta-Antagonists ; pharmacology ; therapeutic use ; Animals ; Blotting, Western ; Disease Models, Animal ; Echocardiography ; Enzyme-Linked Immunosorbent Assay ; Heart Failure ; drug therapy ; physiopathology ; Male ; Myocardium ; pathology ; Nitric Oxide Synthase Type III ; genetics ; Propanolamines ; pharmacology ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta-3 ; physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Ventricular Function, Left ; drug effects

Adrenergic beta-Antagonists ; therapeutic use ; Consensus ; Humans ; Receptors, Adrenergic, beta

BACKGROUNDPrevious studies have suggested that &beta;1-receptor blockers benefit septic shock patients. This study aimed to determine whether &beta;1-receptor blockers benefit tissue perfusion in sepsis and to identify parameters to reduce the risk of this drug in sepsis.

METHODSConsecutive septic shock patients were recruited from the Intensive Care Unit of Peking Union Medical College Hospital within 48 h of diagnosis. All patients were hemodynamically stable and satisfactorily sedated with a heart rate (HR) ≥100 beats/min. Esmolol therapy achieved the target HR of 10-15% lower than the baseline HR. Clinical and physiological data of patients were collected prospectively within 1 h prior to esmolol therapy and 2 h after achieving the targeted HR.

RESULTSSixty-three patients were recruited. After esmolol therapy, blood pressure was unaltered, whereas stroke volume (SV) was increased compared with before esmolol therapy (43.6 ± 22.7 vs. 49.9 ± 23.7 ml, t = -2.3, P = 0.047). Tissue perfusion, including lactate levels (1.4 ± 0.8 vs. 1.1 ± 0.6 mmol/L, t = 2.6, P = 0.015) and the central venous-to-arterial carbon dioxide difference (5.6 ± 3.3 vs. 4.3 ± 2.2 mmHg, t = 2.6 P = 0.016), was also significantly decreased after esmolol therapy. For patients with increased SV (n = 42), cardiac efficiency improved, and esmolol therapy had a lower risk for a decrease in cardiac output (CO). Therefore, pretreatment cardiac systolic and diastolic parameters with (n = 42)/without (n = 21) an increase in SV were compared. Mitral lateral annular plane systolic excursion (MAPSElat) in patients with increased SV was significantly higher than that in those without increased SV (1.3 ± 0.3 vs. 1.1 ± 0.2 cm, t = 2.4, P = 0.034).

CONCLUSIONSSV of septic shock patients is increased following esmolol therapy. Although CO is also decreased with HR, tissue perfusion is not worse. MAPSElat can be used to predict an increase in SV before esmolol use.

TRIAL REGISTRATIONClinicalTrials.gov, NCT01920776; https://clinicaltrials.gov/ct2/show/NCT01920776?term=NCT01920776&rank=1.

Adrenergic beta-1 Receptor Antagonists ; therapeutic use ; Adult ; Aged ; Cardiac Output ; drug effects ; Echocardiography ; Female ; Heart Rate ; drug effects ; Hemodynamics ; drug effects ; Humans ; Male ; Middle Aged ; Myocardium ; metabolism ; Propanolamines ; therapeutic use ; Shock, Septic ; drug therapy ; Stroke Volume ; drug effects

Adrenergic beta-1 Receptor Antagonists ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Cardiomyopathy, Hypertrophic ; diagnosis ; drug therapy ; Electrocardiography ; Female ; Glycogen Storage Disease ; diagnosis ; drug therapy ; Humans ; Young Adult

Adrenergic beta-Antagonists ; Arrhythmias, Cardiac ; Humans

Adrenergic beta-Antagonists ; therapeutic use ; Genomics