title: Functional and molecular effects of imidazoline receptor activation in heart failure.
abstract: OBJECTIVE
  Heart failure is a progressive deterioration in heart function associated with overactivity of the sympathetic nervous system. The benefit of inhibition of sympathetic activity by moxonidine, a centrally acting imidazoline receptor agonist, was questioned based on the outcome of a failing clinical trial. The following studies measured cardiac structure and hemodynamics and mechanisms underlying moxonidine-induced changes, in cardiomyopathic hamsters, where the stage of the disease, dose, and compliance were controlled.
  
  
  METHODS
  Male BIO 14.6 hamsters (6 and 10 months old, with moderate and advanced heart failure, respectively) received moxonidine at 2 concentrations: low (2.4 mg/kg/day) and high (9.6 mg/kg/day), or vehicle, subcutaneously, for 1month. Cardiac function was measured by echocardiography, plasma and hearts were collected for histological determination of fibrosis and apoptosis, as well as for measurement cytokines by Elisa and cardiac proteins by Western blotting.
  
  
  RESULTS
  Compared to age-matched vehicle-treated BIO 14.6, moxonidine did not reduce blood pressure but significantly reduced heart rate and improved cardiac performance. Moxonidine exerted anti-apoptotic effect with differential inflammatory/anti-inflammatory responses that culminate in attenuated cardiac apoptosis and fibrosis and altered protein expression of collagen types. Some effects were observed regardless of treatment onset, although the changes were more significant in the younger group. Interestingly, moxonidine resulted in upregulation of cardiac imidazoline receptors.
  
  
  CONCLUSIONS
  These studies imply that in addition to centrally mediated sympathetic inhibition, the effects of moxonidine may, at least in part, be mediated by direct actions on the heart. Further investigation of imidazolines/imidazoline receptors in cardiovascular diseases is warranted.
authors.affiliation: Centre Hospitalier de L'Université de Montréal Research Center (CRCHUM), Montreal, QC, Canada.
authors.forename: Angelita Maria
authors.initials: AM
authors.lastname: Stabile
authors.forename: Henry
authors.initials: H
authors.lastname: Aceros
authors.forename: Kim
authors.initials: K
authors.lastname: Stockmeyer
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel Rahman
authors.forename: Nicolas
authors.initials: N
authors.lastname: Noiseux
authors.forename: Suhayla
authors.initials: S
authors.lastname: Mukaddam-Daher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D006224:Cricetinae; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D054755:Imidazoline Receptors / Q000819:agonists*; D008297:Male; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D007093:Imidazoles; D054755:Imidazoline Receptors; D003094:Collagen; C043482:moxonidine