title: Chronic blocking of beta 3-adrenoceptor ameliorates cardiac function in rat model of heart failure.
abstract: BACKGROUND
  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.
  
  
  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 beta 3-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). 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, First Clinical Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Run-tao
authors.initials: RT
authors.lastname: Gan
authors.forename: Wei-min
authors.initials: WM
authors.lastname: Li
authors.forename: Chun-hong
authors.initials: CH
authors.lastname: Xiu
authors.forename: Jing-xia
authors.initials: JX
authors.lastname: Shen
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wu
authors.forename: Yi-hui
authors.initials: YH
authors.lastname: Kong
mesh_terms: D058673:Adrenergic beta-3 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058673:Adrenergic beta-3 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D052250:Nitric Oxide Synthase Type III