Regulation ofβ2-adrenoceptors in brain glia:implications for neuroinflammatory and degenerative disorders

Noradrenaline:Within the central nervous system(CNS),the primary source of the catecholamine neurotransmitter noradrenaline is the locus coeruleus(LC)in the pontine tegmentum,with LC neurons projecting to almost all regions of the brain and spinal cord.Following its release from LC neurons,noradrenaline has wide ranging effects.For example,noradrenaline is the endogenous agonist for G-coupledα-andβ-adrenoceptors that are expressed on many cell types,including neurons and glia,in both the peripheral nervous system and CNS.It is via these receptors that noradrenaline exerts its anti-inflammatory and neurotrophic effects in the brain.Noradrenaline additionally has adrenoceptor-independent neuroprotective actions,and as such plays a role in free radical scavenging and reducing oxidative stress(Feinstein et al.,2016).

THE PLASMA CATECHOLAMINE AND MYOCARDIAL ADRENOCEPTORS OF SUSCEPTIBLE STRAIN OF RAT DURING CHRONIC HYPOXIA

Hilltop Sprague Dawley (HT) rats were considered as a good model to investigate the mechanism of mountain sickness. They showed severe pulmonary hypertension, right ventricular hypertrophy, polycythemia and even right ventricular fail-

PGE₂Generation in Myocardium from Isolated Rat Atrium under Hypoxia and Reoxygenation Conditions. Effect of Anti-<i>β</i>₁IgG from Patients with Chronic Severe Periodontitis

Background: Hypoxia is one of the most frequently encountered stresses in health and disease. Methods: We compared the effects of an anti-β1 periodontal IgG (pIgG) and an authentic β1 adrenergic agonist, xamoterol, on isolated myocardium from rat atria contractility. We used an ELISA assay to measure the generation of PGE2 in vitro after the addition of either the antibody or the adrenergic agonist. We analyzed the myocardium histopathologically in the presence of both the antibody and/or the adrenergic agonist drug during normoxia, hypoxia and reperfusion conditions. Results: PGE2 generation increased during the hypoxia and was unchanged during reoxygenation period compared with the production of this prostanoid in atria during normoxia condition. A β1 specific adrenoceptor antagonist atenolol and the β1 synthetic peptide abrogated the increment of the prostanoid in the presence of pIgG but only atenolol due to it in the presence of xamoterol. The increment of PGE2 was dependent on the activation of cox-1 and cox-2 isoforms. Moreover, cox-2 was more active and produced more increments in the production of PGE2 in the presence of the pIgG than cox-1 activation. Histopathologically, studies of myocardium specimens during these different periods of the experimental protocol: basal (B), hypoxia (H) and reoxygenation (R), were also performed and showed tissue necrosis and edematization at the myocardium level. Conclusion: The phenomenon studied here supports the notion that PGE2 may be responsible for tissue edematization. PGE2 maybe acts as a beneficial modulator in the myocardium and prevents a major injury of it. The inflammation damage to the heart organ and cardiomyocytes caused by the actions of the antibodies in the course of heart lesions provoked by cardiovascular autoimmune disease, explains some of these results obtained in the present experiments. Further studies will be needed to establish the real role of PGE2 during hypoxia injury of the heart in the course of autoimmune diseases.

Antipsychotics cardiotoxicity:What's known and what's next

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling,sometimes lifeshortening adverse effects.Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns.These cardiotoxic effects range from arrhythmia to heart failure in the clinic,with myocarditis/cardiomyopathy,ischemic injuries,and unexplained cardiac lesions as the pathological bases.Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity.This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level.We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity.We propose that third-generation antipsychotics or drug adjuvant therapy,such as cannabinoid receptor modulators that confer dual benefits—i.e.,alleviating cardiotoxicity and improving metabolic disorders—deserve further clinical evaluation and marketing.

Reducing sympathetic nervous tone in aged rats bettered cardiomyocyte contraction by improving the response of β_2-adrenoceptor

The study was to investigate the effect of reducing central sympathetic nervous tone with clonidine on cardiomyocyte contraction,and further to analyze the influence of reducing the central sympathetic nervous tone on response of β1 and β2-AR in aged ventricular myocytes.Sprague-Dawley rats were randomly divided into three groups:adult group,aged group and aged group with clonidine.

The effect of nebivolol on the production of nitric oxide induced by bacterial lipopolysaccharide and peptidoglycan in mice

Nitric oxide (NO) plays a pivotal role in main- taining balance of physiological events in many systems including the autonomic, cardiovas- cular, hematological, and pulmonary systems. Lipopolysaccharide (LPS) and peptidoglycan (PGN), components of the outer cell membranes of Gram-negative bacteria and cell walls of Gram-positive bacteria respectively, are in- criminated in NO-induced septic shock. Ne- bivolol is a third generation β1- adrenoceptor blocker with a vasodilatory property attributed to enhanced availability of nitric oxide and re- duction of cellular oxidative stress through an unknown mechanism. The current study ex- plored the hypothesis that if nebivolol enhances the availability of NO, pretreatment with ne- bivolol may enhance production of NO in re- sponse to subsequent treatment with LPS and PGN, an observation that may have relevance in clinical septic shock. Groups of female BALB/c mice each containing 12 mice (6-8 weeks old) were injected intraperitoneally with LPS (30 μg/mouse), PGN (100 μg/mouse), nebivolol (0.25 μg/g, 0.35 μg/g, 0.7 μg/g), LPS and nebivolol (0.25 μg/g), LPS and nebivolol (0.35 μg/g), LPS and nebivolol (0.7 μg/g), PGN and nebivolol (0.25 μg/g), PGN and nebivolol (0.35μg/g). One group of mice was injected with saline and an- other served as control. Three mice from each group were bled 1, 3, 6 and 9 hours post-injec- tion, the blood was pooled and the nitrite serum levels, reflecting NO concentration, were de- termined using Greiss reagent. The following results were obtained: 1) Treatment with saline did not induce NO production;2) LPS induced NO production to a maximal limit of 545% at 9 hours as compared to treatment with saline;3) PGN did not induce NO production;4) nebivolol at most doses and periods (7 out of 10 deter- minations) increased NO production over a range of 18-110% as compared to treatment with saline;5) Nebivolol enhanced LPS-induced production of NO by 58% at a dose of 0.7 μg/gm at 9 hours. It is concluded that nebivolol in- duces NO production. At low doses nebivolol initially appeared to have a suppressive or no effect on NO production induced by LPS. In- crease in the dose of nebivolol resulted in augmentation of LPS-induced production of NO. PGN, in the dose tested, did not have an effect on NO production.

Alpha1B adrenoceptor expression is a marker of reduced survival and increased tumor recurrence in patients with endometrioid ovarian cancer

AIM: To investigate the expression patterns of different adrenoceptor isoforms in ovarian cancer and their association with survival and tumor recurrence. METHODS: The protein expression levels of a1 B, a2 C and b2 adrenoceptor were assessed in unselected ovarian cancer using immunohistochemistry on microarrayed archival tissue samples. A database containing clinical and pathology parameters and follow-up was usedto investigate the association between adrenoceptor isoform expression with ovarian specific survival and tumor recurrence, using univariate and multivariate statistical analysis. RESULTS: Expression of a1 B showed an association with reduced ovarian specific survival(P = 0.05; CI: 1.00-1.49) and increased tumor recurrence(P = 0.021, CI: 1.04-1.69) in the whole patient group. On subanalysis the expression of a1 B in endometrioid cancers(χ2 = 5.867, P = 0.015) was found to predict reduced ovarian specific survival and increased tumor recurrence independently of tumor grade, clinical stage and chemotherapy. An association with clinical outcome was not seen for a2 C or b2 AR.CONCLUSION: Alpha1 B adrenoceptor protein was found to predict increased risk of tumor recurrence and reduced mortality in patients with endometrioid type ovarian cancer and should be investigated as a biomarker for identifying patients at increased risk of disease progression. Furthermore, a adrenergic receptor antagonists with a1 B selectivity should be investigated as a possible adjuvant therapy for treating patients with endometrioid cancer. Proof of principle could be tested in a retrospective population study.

Chronic blocking of β_3-adrenoceptor ameliorates cardiac function in rat model of heart failure

Background Stimulation of the heart β3-adrenoceptor （AR） may result in a negative inotropic effect. Being up-regulated, β3-AR plays a more important role in the regulation of cardiac function during heart failure. However, the effect of chronic blocking of β3-AR on heart failure has not been fully elucidated. In this study, we used a selective β3-AR antagonist SR59230A to treat a well defined heart failure rat model chronically, then evaluated its effect on cardiac function and investigated the mechanism. Methods 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 β3-AR and eNOS, and cGMP level in the heart. Results 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）. β3-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）. Conclusions Chronic blocking of β3-AR could ameliorate cardiac function in heart failure rats and its mechanism involves inhibition of the negative inotropic effect and attenuation of cardiac remodeling.

Referred Somatic Hyperalgesia Mediates Cardiac Regulation by the Activation of Sympathetic Nerves in a Rat Model of Myocardial Ischemia

Myocardial ischemia(MI)causes somatic referred pain and sympathetic hyperactivity,and the role of sensory inputs from referred areas in cardiac function and sympathetic hyperactivity remain unclear.Here,in a rat model,we showed that MI not only led to referred mechanical hypersensitivity on the forelimbs and upper back,but also elicited sympathetic sprouting in the skin of the referred area and C8–T6 dorsal root ganglia,and increased cardiac sympathetic tone,indicating sympathetic-sensory coupling.Moreover,intensifying referred hyperalgesic inputs with noxious mechanical,thermal,and electro-stimulation(ES)of the forearm augmented sympathetic hyperactivity and regulated cardiac function,whereas deafferentation of the left brachial plexus diminished sympathoexcitation.Intradermal injection of the α_(2) adrenoceptor(α_(2)AR)antagonist yohimbine and agonist dexmedetomidine in the forearm attenuated the cardiac adjustment by ES.Overall,these findings suggest that sensory inputs from the referred pain area contribute to cardiac functional adjustment via peripheral α_(2)AR-mediated sympathetic-sensory coupling.

Effect of electroacpuncture of Neiguan(PC 6)and Tianquan(PC 2)on skin temperature,blood perfusion,and adrenoceptor response in rats with acute myocardial ischemia

OBJECTIVE: To investigate the effect of electroacupuncture(EA) of acupoints Neiguan(PC 6) and Tianquan(PC 2) on the skin temperature, blood perfusion, and alpha1-and beta2-adrenoreceptor(α1-AR and β2-AR) protein and m RNA level in rats with acute myocardial ischemia.METHODS: Thirty male adult Wistar rats [(230 ±20) g] were randomly assigned into five groups(n = 6 each): a control group, sham operation group, model group, model group treated with EA at low frequency(L-EA, 2 Hz, 1 m A) and model group treated with EA at high frequency(H-EA, 100 Hz, 1 m A). The rat model was prepared by ligating the left anterior descending coronary artery. Electroacupuncture was performed at the left Neiguan(PC 6) for 20 min daily for 3 d. After the 3 rd time of the treatment, measurements of skin blood perfusion and temperature in Neiguan(PC 6) and Tianquan(PC 2) in all groups were made by laser speckle contrast imaging and infrared thermal image instrument. Real-time PCR and ELISA were used to measure m RNA level and protein level of α1-AR andβ2-AR in the skin tissues of Neiguan(PC 6) and Tianquan(PC 2), respectively. Serum levels of c Tn T and electrocardiogram were used to identify the state of myocardium.RESULTS: In the group receiving electroacupunture at Neiguan(PC 6), compared with control group,the skin temperature, blood perfusion, and β2-AR m RNA and protein level of model group significantly decreased(P < 0.05), α1-AR m RNA and protein level of model group significantly increased(P < 0.05);compared with model group, the skin temperature,blood perfusion, and β2-AR m RNA and protein level of L-EA significantly increased(P < 0.05), α1-AR m RNA and protein level of L-EA and H-EA significantly decreased(P < 0.05). The same trend has taken place in the former four groups of the Tianquan(PC 2).CONCLUSION: Low-or high-frequency electroacupuncture can improve the skin temperature and blood perfusion which may be induced by decreasingthelevelofα1-ARandincreasingthelevelofβ2-AR of the Neiguan(PC 6) and Tianquan(PC 2) in the rat with acute myocaidial ischemia.

EffectofElectroacupunctureonPulmonaryβ－AdrenoceptorinAllergicAsthmaGuinea－Pigs

Twenty four male guinea-pigs were randomly divided into 3 groups: Group A, allergic asthmaguinea-pigs prepared by peritoneal injection and spraying inhalation of albumin; Group B, allergic asthmaguinea-pigs treated with electroacupuncture through stimulating the acupoint Feishu (UB13 ) and Group C, thecontrol group. With[3H] -DHA as a radioligand, pulmonary adrenoceptor ( AC) in the 3 groups of guinea-pigs were detrermined by radioligand binding assay technique. The results showed that: ( 1 ) The maximumbinding volume of receptor ligand ( Bmax, fmol/mg prot. ) of pulmonary AC in Group A (123. 86 42. 91 )was significantly lower than that in group C (199 . 54 37. 03 , P< 0. 05) , while the difference between groupB ( 142. 00 42. 91 ) and group C was not significant ( P > 0. 05 ) . ( 2 ) The Kd ( nM) of pulmonary AC ingroup A, B and C were 5 . 10 1 . 39 , 6. 53 2 . 41 and 8. 72 2 . 02 respectively, and the differences amongthe three groups were not significant ( P >0. 05) . The results indicated that the decrease of the content anddysfunction of pulmonary AC in allergic asthma guinea-pigs might be regulated by electroacupuncture thera-py.

Expressions of α_1 adrenoceptor subtypes mRNA in hepatic tissues of cirrhotic patients with portal hypertension

Objective To investigate the expression of mRNA of α 1 adrenoceptor in hepatic tissues of cirrhotic patients with portal hypertension Methods Semi quantitative reverse transcription and polymerase chain reaction (RT PCR) were used in 12 hepatic virus B related cirrhotic patients with portal hypertension and 15 controls from routine liver cutting biopsy for gallstone patients undergoing cholecystectomy who have no history of hypertension Special α 1 adrenoceptor subtype product and internal standard GAPDH product were amplified in the same RT PCR system simultaneously The ratio of their integral optical density (IOD) was calculated to stand for the relative expression of the α 1 adrenoceptor subtypes Results The relative mRNA expression of α 1a adrenoceptor subtype in hepatic tissues of cirrhotic patients Department of Surgery, People's Hospital, Beijing Medical University, Beijing 100044, China (Zhu JY, Chen L, Leng XS and Du RY) This work was supported by the National Natural Science Foundation and the Scientific Research Foundation of the Ministry of Health.(0 26±0 12) was significantly lower than that of controls (0 86±0 38, P <0 01) The relative mRNA expression of α 1b adrenoceptor subtype in hepatic tissues of cirrhotic patients (0 03±0 01) was significantly lower than that of controls (0 23±0 10, P <0 01) There was no expression of α 1d adrenoceptor subtype in hepatic tissues of either cirrhotic patients or controls The relative mRNA expression of α 1a adrenoceptor subtype is significantly higher than that of α 1b adrenoceptor subtype in hepatic tissues of both cirrhotic patients and controls ( P <0 01) Conclusion α 1a adrenoceptor mRNA expression predominated in both normal and cirrhotic hepatic tissues, came in second the expression of α 1b adrenoceptor and no expression of α 1d adrenoceptor The decreased expression of mRNA of α 1a and α 1b adrenoceptor may underlie the decrease of α 1 adrenoceptor proteins often seen in the hepatic tissues of cirrhotic patients, and may play an important role in the pathogenesis and maintenance of portal hypertension