Sympathetic cues via the adrenergic signaling critically regulate bone homeostasis and contribute to neurostress-induced bone loss, but the mechanisms and therapeutics remain incompletely elucidated. Here, we reveal an osteoclastogenesis-centered functionally important osteopenic pathogenesis under sympatho-adrenergic activation with characterized microRNA response and efficient therapeutics. We discovered that osteoclastic miR-21 was tightly regulated by sympatho-adrenergic cues downstream the β2-adrenergic receptor (β₂AR) signaling, critically modulated osteoclastogenesis in vivo by inhibiting programmed cell death 4 (Pdcd4), and mediated detrimental effects of both isoproterenol (ISO) and chronic variable stress (CVS) on bone. Intriguingly, without affecting osteoblastic bone formation, bone protection against ISO and CVS was sufficiently achieved by a (D-Asp₈)-lipid nanoparticle-mediated targeted inhibition of osteoclastic miR-21 or by clinically relevant drugs to suppress osteoclastogenesis. Collectively, these results unravel a previously underdetermined molecular and functional paradigm that osteoclastogenesis crucially contributes to sympatho-adrenergic regulation of bone and establish multiple targeted therapeutic strategies to counteract osteopenias under stresses.
Adrenergic Agents/pharmacology* ; Apoptosis Regulatory Proteins/pharmacology* ; Bone Diseases, Metabolic/metabolism* ; Humans ; Liposomes ; MicroRNAs/genetics* ; Nanoparticles ; Osteoclasts ; Osteogenesis/physiology* ; RNA-Binding Proteins/pharmacology*

The pathophysiology of visceral pain in patients with irritable bowel syndrome remains largely unknown. Our previous study showed that neonatal maternal deprivation (NMD) does not induce visceral hypersensitivity at the age of 6 weeks in rats. The aim of this study was to determine whether NMD followed by adult stress at the age of 6 weeks induces visceral pain in rats and to investigate the roles of adrenergic signaling in visceral pain. Here we showed that NMD rats exhibited visceral hypersensitivity 6 h and 24 h after the termination of adult multiple stressors (AMSs). The plasma level of norepinephrine was significantly increased in NMD rats after AMSs. Whole-cell patch-clamp recording showed that the excitability of dorsal root ganglion (DRG) neurons from NMD rats with AMSs was remarkably increased. The expression of β adrenergic receptors at the protein and mRNA levels was markedly higher in NMD rats with AMSs than in rats with NMD alone. Inhibition of β adrenergic receptors with propranolol or butoxamine enhanced the colorectal distention threshold and application of butoxamine also reversed the enhanced hypersensitivity of DRG neurons. Overall, our data demonstrate that AMS induces visceral hypersensitivity in NMD rats, in part due to enhanced NE-β adrenergic signaling in DRGs.
Adrenergic Agents ; pharmacology ; Animals ; Ganglia, Spinal ; drug effects ; Hyperalgesia ; drug therapy ; physiopathology ; Hypersensitivity ; drug therapy ; Male ; Maternal Deprivation ; Neurons ; drug effects ; Patch-Clamp Techniques ; methods ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects ; Stress, Physiological ; physiology ; Visceral Pain ; chemically induced ; metabolism

Previous studies have shown that electroacupuncture (EA) promotes recovery of motor function in Parkinson's disease (PD). However the mechanisms are not completely understood. Clinically, the subthalamic nucleus (STN) is a critical target for deep brain stimulation treatment of PD, and vesicular glutamate transporter 1 (VGluT1) plays an important role in the modulation of glutamate in the STN derived from the cortex. In this study, a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD was treated with 100 Hz EA for 4 weeks. Immunohistochemical analysis of tyrosine hydroxylase (TH) showed that EA treatment had no effect on TH expression in the ipsilateral striatum or substantia nigra pars compacta, though it alleviated several of the parkinsonian motor symptoms. Compared with the hemi-parkinsonian rats without EA treatment, the 100 Hz EA treatment significantly decreased apomorphine-induced rotation and increased the latency in the Rotarod test. Notably, the EA treatment reversed the 6-OHDA-induced down-regulation of VGluT1 in the STN. The results demonstrated that EA alleviated motor symptoms and up-regulated VGluT1 in the ipsilateral STN of hemi-parkinsonian rats, suggesting that up-regulation of VGluT1 in the STN may be related to the effects of EA on parkinsonian motor symptoms via restoration of function in the cortico-STN pathway.
Adrenergic Agents ; toxicity ; Animals ; Apomorphine ; pharmacology ; Disease Models, Animal ; Dopamine Agonists ; pharmacology ; Electroacupuncture ; methods ; Functional Laterality ; drug effects ; Male ; Medial Forebrain Bundle ; injuries ; Motor Activity ; drug effects ; physiology ; Neurons ; drug effects ; metabolism ; Oxidopamine ; toxicity ; Parkinson Disease, Secondary ; chemically induced ; physiopathology ; therapy ; Rats ; Rats, Sprague-Dawley ; Subthalamic Nucleus ; drug effects ; metabolism ; pathology ; Tyrosine 3-Monooxygenase ; metabolism ; Up-Regulation ; drug effects ; physiology ; Vesicular Glutamate Transport Protein 1 ; metabolism

This paper is aimed to study the effect of ADL on expression of β1-AR and M2-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect the expression of β1-AR and M2-AchR in myocardial cells at 7 and 14 d after microwave exposure. The results show that the expression level was higher in microwave exposure group and 0.75 g/(kg•d) ADL group than in sham operation group and significantly lower in 1.5 and 3.0 g/(kg•d) ADL groups than in microwave group. So we have a conclusion that the expression of β1-AR and M2-AchR is down-regulated in myocardial cells of rats exposed to microwave radiation. ADL can protect rats against microwave-induced heart tissue injury.
Animals ; Down-Regulation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Heart ; drug effects ; Male ; Microwaves ; adverse effects ; Myocardium ; cytology ; metabolism ; Protective Agents ; pharmacology ; Rats, Wistar ; Receptor, Muscarinic M2 ; metabolism ; Receptors, Adrenergic, beta-1 ; metabolism

To study the antiarrhythmic effect of the newly developed alpha/beta-blocker TJ0711, a variety of animal models of arrhythmia were induced by CaCl2, ouabain and ischemia/reperfusion. Glass microelectrode technique was used to observe action potentials of right ventricular papillary muscle of guinea pig. The onset time of arrhythmia induced by CaCl2 was significantly prolonged by TJ0711 at 0.75, 1.5 and 3 mg x kg(-1) doses. TJ0711 (1.5 and 3 mg x kg(-1)) can significantly shorten the ventricular tachycardia (VT) and ventricular fibrillation (VF) duration, the incidence of VF and mortality were significantly reduced. On ischemia-reperfusion-induced arrhythmic model, TJ0711 (0.25, 0.5, 1 and 2 mg x kg(-1)) can significantly reduce the ventricular premature contraction (PVC), VT, VF incidence, mortality, arrhythmia score with a dose-dependent manner. At the same time, rats serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities decreased significantly by TJ0711 (1 and 2 mg x kg(-1)). Ouabain could cause arrhythmia in guinea pigs, when TJ0711 (0.375, 0.75, 1.5 and 3 mg x kg(-1)) was given, the doses of ouabain inducing a variety of arrhythmia PVC, VT, VF, cardiac arrest (CA) were significantly increased with a dose-dependent manner. In the TJ0711 0.1-30 micromol x L(-1) concentration range, guinea pig right ventricular papillary muscle action potential RP (rest potential), APA (action potential amplitude) and V(max) (maximum velocity of depolarization) were not significantly affected. APD20, APD50 and APD90 had a shortening trend but no statistical difference with the increase of TJ0711 concentration. TJ0711 has antiarrhythmic effect on the sympathetic nerve excitement and myocardial cell high calcium animal arrhythmia model. Myocardial action potential zero phase conduction velocity and resting membrane potential were not inhibited by TJ0711. APD20, APD50 and APD90 were shortened by TJ0711 at high concentration. Its antiarrhythmic action mechanism may be besides the action of blocking beta1 receptor, may also have a strong selective blocking action on alpha1 receptor and reducing intracellular calcium concentration.
Action Potentials ; drug effects ; Adrenergic alpha-Antagonists ; administration & dosage ; pharmacology ; Adrenergic beta-Antagonists ; administration & dosage ; pharmacology ; Animals ; Anti-Arrhythmia Agents ; administration & dosage ; pharmacology ; Arrhythmias, Cardiac ; blood ; chemically induced ; etiology ; pathology ; physiopathology ; Calcium Chloride ; Creatine Kinase ; blood ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; Heart Ventricles ; cytology ; Lactate Dehydrogenases ; blood ; Male ; Myocardial Reperfusion Injury ; complications ; Myocytes, Cardiac ; drug effects ; physiology ; Ouabain ; Papillary Muscles ; cytology ; Phenoxypropanolamines ; administration & dosage ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the relaxant effect of Aike Mixture (AKM) on isolated bladder and prostatic urethral smooth muscle of rabbits.

METHODSThe isolated bladder and prostatic urethral smooth muscle from male rabbits were placed in a Magnus bath and smooth muscle contraction was measured using a biological signal acquisition and analysis system. The effects of AKM in combination with methoxyamine, carbachol and CaCl2 on the contractile tension of muscle strips were determined by cumulative dosing.

RESULTSAKM dose-dependently reduced contractile tension of bladder trigone smooth muscle (r=0.831, P<0.05), reduced contractile wave amplitude (r=0.837, P<0.05) and decreased contractile frequency (r=-0.917, P<0.01). AKM significantly inhibited the increases in smooth muscle contraction induced by methoxyamine, carbachol and CaCl2.

CONCLUSIONAKM dose-dependently inhibited the contraction of rabbit isolated bladder and prostatic urethral smooth muscle by antagonizing α1-adrenergic receptors and M-cholinergic receptors.

Animals ; Calcium Chloride ; pharmacology ; Carbachol ; pharmacology ; Drugs, Chinese Herbal ; pharmacology ; Hydroxylamines ; pharmacology ; In Vitro Techniques ; Male ; Muscle Contraction ; drug effects ; Muscle, Smooth ; drug effects ; physiology ; Neuromuscular Agents ; pharmacology ; Prostate ; drug effects ; physiology ; Rabbits ; Receptors, Adrenergic, alpha-1 ; metabolism ; Receptors, Muscarinic ; metabolism ; Urethra ; drug effects ; physiology ; Urinary Bladder ; drug effects ; physiology

AIM: In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD: Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one (XJP), were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, β1-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS: Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising compound Ic exhibited β1-adrenoceptor blocking activity (inhibition: 52.2%) at 10(-7) mol·L(-1), which was superior to that of propranolol (inhibition: 49.7%). CONCLUSION The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.
Adrenergic beta-Antagonists ; chemical synthesis ; chemistry ; pharmacology ; Animals ; Antihypertensive Agents ; chemical synthesis ; chemistry ; pharmacology ; Benzopyrans ; chemical synthesis ; chemistry ; pharmacology ; Drugs, Chinese Herbal ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Hypertension ; drug therapy ; physiopathology ; Male ; Molecular Structure ; Oximes ; chemistry ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship

OBJECTIVEWe used the individual patient data from clinical trials, pooled in the INDANA data set, to explore whether blood pressure reduction was related to the baseline individual characteristics, and quantify the potential associations.

METHODSWe used the data from 31 140 patients with essential hypertension recruited in four randomized placebo-controlled clinical trials, MRC35-64, MRC65-74, STEP and SYST-EU. Thiazide diuretics, β-blocker, and calcium channel blocker, three of six major BP lowering drugs were analyzed. Patients were all with the same first dosage of the drug in each trial. Age, body weight, height, level of total cholesterin (TC), systolic blood pressure (SBP) and diastolic blood pressure (DBP) when initialed and at first visit of follow-up, pharmacological treatment, gender, status of smoking, history of myocardium infarction were factors taken into model. Data were managed by software SAS(®). Statistical analyses were performed with SAS(®) and R. Model was developed to evaluate the relationship between decrease of SBP and characteristics of patients.

RESULTSInitial SBP is the only modifier of treatment effect on SBP response in the 3 BP lowering drug classes (β = 0.09, 0.37 and 0.18, respectively). Age and initial DBP were factors significantly correlated with SBP fall for diuretic (β = 0.17 and 0.14), and age was one of factors significantly correlated with SBP fall for β-blocker (β = -0.17). Smokers would receive less SBP fall compare to non-smokers in β-blocker active treated group (β = -2.07). There is converse effect of age between the diuretic and β-blocker; older people seem sensitive to diuretic, while young people are sensitive to β-blocker. As to calcium channel antagonist class, body weight is another modifier (β = 0.06) (All P value are 0.000 except 0.050 for body weight in calcium channel antagonist class).

CONCLUSIONWe identified 5 significant modifiers (baseline SBP and DBP, age, smoking status and body weight) for SBP response to treatment effect, while gender, TC and history of myocardial infarction are not modifiers for SBP response to treatment effect.

Adrenergic beta-Antagonists ; pharmacology ; therapeutic use ; Adult ; Age Factors ; Aged ; Antihypertensive Agents ; pharmacology ; therapeutic use ; Blood Pressure ; Body Weight ; Calcium Channel Blockers ; pharmacology ; therapeutic use ; Female ; Humans ; Hypertension ; drug therapy ; physiopathology ; Male ; Middle Aged ; Models, Theoretical ; Randomized Controlled Trials as Topic ; Smoking ; Sodium Chloride Symporter Inhibitors ; pharmacology ; therapeutic use ; Systole

Adrenergic beta-2 Receptor Agonists ; pharmacology ; Anti-Inflammatory Agents ; pharmacology ; Asthma ; drug therapy ; physiopathology ; Chloroquine ; pharmacology ; Humans ; Myocytes, Smooth Muscle ; cytology ; drug effects ; metabolism ; Quaternary Ammonium Compounds ; pharmacology ; Receptors, Adrenergic, beta-2 ; metabolism ; Receptors, G-Protein-Coupled ; agonists ; metabolism ; Receptors, Interleukin-4 ; antagonists & inhibitors ; metabolism ; Respiratory System ; drug effects ; metabolism ; physiopathology

OBJECTIVETo evaluate the effect of dexmedetomidine (Dex) on bispectral index (BIS) and auditory evoked potential index (AAI) during anesthesia with target controlled infusion (TCI) of propofol and remifentanyl.

METHODSThirty adult patients (ASA I approximate, equalsII) who were scheduled for elective thyroidectomy were monitored with BIS, AAI, ECG, blood pressure, end-tidal CO(2), and pulse oximeter before and during anesthesia. Anesthesia was induced by TCI with propofol 4 mg/L and remifentanyl 1 mu g/kg. After loss of consciousness the patients were intubated after rocuronium 0.6 mg/kg intravenous injection, remifentanyl was then infused at 0.2 microg/(kg x min)(-1) and propofol infusion (Ct) was titrated to maintain a BIS value at 50 +/- 3. At 10 min after stabilization of anesthesia the patients were randomly and double-blindly divided into 2 groups: Group D (n=15) received Dex 0.4 mu g/kg iv administered over 5 min and Group C (n=15) received equal volume of normal saline. Values of BIS, AAI, MAP, HR were recorded every 2 min within 20 min after the administration of the drugs.

RESULTSBefore anesthesia the BIS index was 90 +/- 2 in Group D and 92 +/- 2 in Group C, AAI was 81 +/- 1 in Group D and 78 +/- 1 in Group C. In anesthesia with target controlled infusion of propofol, BIS index showed a significant decrease with the i.v. administration of Dex 0.4 microg/kg, while AAI remained unchanged. In Group C, both of BIS and AAI remained unchanged after saline injection.

CONCLUSIONDuring propofol and remifentanyl anesthesia, after the administration of Dex, BIS value demonstrates a predominant decrease, whereas AAI shows no changes.

Adrenergic alpha-Agonists ; administration & dosage ; Adult ; Androstanols ; administration & dosage ; Anesthetics, Combined ; administration & dosage ; Anesthetics, Intravenous ; administration & dosage ; Dexmedetomidine ; administration & dosage ; pharmacology ; Double-Blind Method ; Evoked Potentials, Auditory ; drug effects ; Female ; Humans ; Infusions, Intravenous ; methods ; Male ; Medetomidine ; pharmacology ; Middle Aged ; Monitoring, Intraoperative ; methods ; Neuromuscular Nondepolarizing Agents ; administration & dosage ; Piperidines ; administration & dosage ; pharmacology ; Propofol ; administration & dosage ; pharmacology ; Thyroidectomy