The effects of glucagon and epinephrine on gluconeogenesis in young (4 month) and old (24 month) Fisher 344 rat hepatocytes were compared. In contrast to glucagon, which had a similar effect on gluconeogenesis in both young and old cells, epinephrine caused a smaller increase in gluconeogenesis in old rat hepatocytes than in young hepatocytes. beta2 adrenergic receptor (beta2-AR) expression slightly decreased in aged rat liver, and there were differences between young and old hepatocytes in their patterns of G protein coupled receptor kinases, which are involved in the activation of beta2-AR receptor signal desensitization. The major isoform of the kinase changed from GRK2 to GRK3 and the expression of beta-arrestin, which is recruited by the phosphorylated beta2-AR for internalization and degradation, increased in aged rat liver. GRK3 overexpression also decreased the glucose output from young rat hepatocytes. We conclude that an age-associated reduction in epinephrine-induced gluconeogenesis occurs through the epinephrine receptor desensitizing system.
Adrenergic beta-Agonists/*pharmacology ; Aging/*drug effects ; Animals ; Epinephrine/*pharmacology ; G-Protein-Coupled Receptor Kinase 2/metabolism ; G-Protein-Coupled Receptor Kinase 3/metabolism ; Glucagon/pharmacology ; *Gluconeogenesis/drug effects ; Male ; Models, Biological ; Phosphorylation ; Rats ; Rats, Inbred F344 ; Receptors, Adrenergic, beta-2/agonists/metabolism

The effects of glucagon and epinephrine on gluconeogenesis in young (4 month) and old (24 month) Fisher 344 rat hepatocytes were compared. In contrast to glucagon, which had a similar effect on gluconeogenesis in both young and old cells, epinephrine caused a smaller increase in gluconeogenesis in old rat hepatocytes than in young hepatocytes. beta2 adrenergic receptor (beta2-AR) expression slightly decreased in aged rat liver, and there were differences between young and old hepatocytes in their patterns of G protein coupled receptor kinases, which are involved in the activation of beta2-AR receptor signal desensitization. The major isoform of the kinase changed from GRK2 to GRK3 and the expression of beta-arrestin, which is recruited by the phosphorylated beta2-AR for internalization and degradation, increased in aged rat liver. GRK3 overexpression also decreased the glucose output from young rat hepatocytes. We conclude that an age-associated reduction in epinephrine-induced gluconeogenesis occurs through the epinephrine receptor desensitizing system.
Adrenergic beta-Agonists/*pharmacology ; Aging/*drug effects ; Animals ; Epinephrine/*pharmacology ; G-Protein-Coupled Receptor Kinase 2/metabolism ; G-Protein-Coupled Receptor Kinase 3/metabolism ; Glucagon/pharmacology ; *Gluconeogenesis/drug effects ; Male ; Models, Biological ; Phosphorylation ; Rats ; Rats, Inbred F344 ; Receptors, Adrenergic, beta-2/agonists/metabolism

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

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

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

OBJECTIVETo observe the effect of beta(3)-adrenoceptor (AR) in regulating resting intracellular Ca(2+) concentration of the ventricular myocytes and investigate the signaling pathway in rats with experimental heart failure.

METHODSRat models of experimental heart failure were established by ligation of the anterior descending artery, and the myocytes were isolated by enzymatic digestion. The resting intracellular Ca(2+) concentration was determined using laser scanning confocal microscopy (LSCM) in the cells stimulated with 1 micromol/L BRL37344 (a selective beta(3)-AR agonist) alone or in combination with PTX, L-NAME, or methylene blue.

RESULTSIn the ventricular myocytes from normal control rats, BRL373444 reduced the resting intracellular Ca(2+) concentration of by 45.5%, while the reduction increased to 59.4% in the cells from rats with heart failure. In combination with L-NAME (10 micromol/L), methylene blue (10 micromol/L), and PTX (2 microg/ml), BRL373444 caused a reduction in resting intracellular Ca(2+) concentration of the ventricle myocytes from normal control rats by 10.1%, 16.9%, and 15.4%, respectively in control group, while the rate was 16.9%, 19.3%, and 11.7% in the heart failure group.

CONCLUSIONSBeta(3)-AR agonist can decrease the resting intracellular Ca(2+) concentration of the ventricular myocytes, but the reduction is smaller in cells from rats with heart failure than in cells of normal rats. This effect is mediated through the PTX-NOS-NO pathway.

Adrenergic Agonists ; pharmacology ; Adrenergic beta-3 Receptor Agonists ; Animals ; Calcium ; metabolism ; Heart Failure ; chemically induced ; metabolism ; pathology ; Heart Ventricles ; pathology ; In Vitro Techniques ; Intracellular Space ; drug effects ; metabolism ; Male ; Myocytes, Cardiac ; drug effects ; metabolism ; pathology ; Rats ; Rats, Wistar ; Receptors, Adrenergic, beta-3 ; metabolism ; Rest ; Signal Transduction ; drug effects

Adrenal Cortex Hormones ; administration & dosage ; Adrenergic beta-2 Receptor Agonists ; Adrenergic beta-Agonists ; administration & dosage ; Asthma ; drug therapy ; Clinical Trials as Topic ; Drug Therapy, Combination ; Humans ; Patient Compliance ; Practice Guidelines as Topic ; Pulmonary Disease, Chronic Obstructive ; drug therapy

AIMTo study the effects of beta 2-adrenergic receptor-selective agonist clenbuterol on nitrogen metabolism and glucose-6-phosphate dehydrogenase activity of rat hepatocyte and its pharmacological mechanism.

METHODSBiochemical methods were used to study the influence of clenbuterol on urea-nitrogen concentration of hepatocyte culture medium, 3H-leucine incorporation into hepatocyte, insulin-like growth factor I (IGF-I) production and glucose-6-phosphate dehydrogenase (G6PDH) activity of rat hepatocyte.

RESULTSThe results showed that urea-nitrogen production by cultured rat hepatocytes was markedly affected with clenbuterol treatment (1 x 10(-6) mol.L-1), urea-nitrogen concentration of culture medium was decreased by 25.51% (P < 0.05) compared with control. The inhibitory effect of hepatocyte urea-nitrogen production of clenbuterol was blocked by propranolol, a beta-adrenoreceptor antagonist (1 x 10(-6) mol.L-1), but hepatocyte urea-nitrogen level was not affected with propranolol treatment only (P > 0.05). The content of 3H-leucine incorporation in rat hepatocyte was significantly increased by 23.35% (P < 0.05) with clenbuterol-treatment (1 x 10(-6) mol.L-1), and the enhanced effect of 3H-leucine incorporation into hepatocyte was antagonized by propranolol (1 x 10(-6) mol.L-1. The level of 3H-leucine incorporation of rat hepatocyte was not influenced by propranolol alone. IGF-I production of rat hepatocyte might be affected by clenbuterol. IGF-I concentration of culture medium was increased by 39.46% with clenbuterol (1 x 10(-6) mol.L-1), but no significant difference was found compared with the control (P > 0.05). Moreover, G6PDH activity of rat hepatocyte was significantly decreased by 43.36% (P < 0.05) with clenbuterol treatment (1 x 10(-6) mol.L-1), and the declined effect of clenbuterol was antagonized by propranolol. G6PDH activity of rat hepatocyte was not affected on condition that propranolol was administered alone (P > 0.05).

CONCLUSIONIt is suggested that clenbuterol may regulate nitrogen and fat metabolism by means of increasing nitrogen retention and protein synthesis, and decreasing G6PDH activity of rat hepatocyte for pharmacological effects.

Adrenergic beta-2 Receptor Agonists ; Animals ; Cells, Cultured ; Clenbuterol ; pharmacology ; Glucosephosphate Dehydrogenase ; metabolism ; Hepatocytes ; drug effects ; enzymology ; metabolism ; Nitrogen ; metabolism ; Rats ; Rats, Sprague-Dawley

A novel rapid method for detection of the illicit beta2-agonist additives in health foods and traditional Chinese patent medicines was developed with the desorption corona beam ionization mass spectrometry (DCBI-MS) technique. The DCBI conditions including temperature and sample volume were optimized according to the resulting mass spectra intensity. Matrix effect on 9 beta2-agonists additives was not significant in the proposed rapid determination procedure. All of the 9 target molecules were detected within 1 min. Quantification was achieved based on the typical fragment ion in MS2 spectra of each analyte. The method showed good linear coefficients in the range of 1-100 mg x L(-1) for all analytes. The relative deviation values were between 14.29% and 25.13%. Ten claimed antitussive and antiasthmatic health foods and traditional Chinese patent medicines from local pharmacies were analyzed. All of them were negative with the proposed DCBI-MS method. Without tedious sample pretreatments, the developed DCBI-MS is simple, rapid and sensitive for rapid qualification and semi-quantification of the illicit beta2-agonist additives in health foods and traditional Chinese patent medicines.
Adrenergic beta-2 Receptor Agonists ; analysis ; Drugs, Chinese Herbal ; chemistry ; Food, Organic ; analysis ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Substance Abuse Detection ; methods ; Tandem Mass Spectrometry

The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are &beta;2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.
Adrenergic beta-2 Receptor Agonists ; therapeutic use ; Asthma ; drug therapy ; genetics ; Glucocorticoids ; therapeutic use ; Leukotrienes ; genetics ; therapeutic use ; Metabolic Networks and Pathways ; Pharmacogenetics ; Polymorphism, Single Nucleotide ; Precision Medicine