title: Angiotensin receptor blockade improves myocardial beta-adrenergic receptor signaling in postinfarction left ventricular remodeling: a possible link between beta-adrenergic receptor kinase-1 and protein kinase C epsilon isoform.
abstract: OBJECTIVE
  We tested the hypothesis that angiotensin II type 1 receptor blocker (ARB) may improve beta-adrenergic receptor (AR) coupling in heart failure (HF) after myocardial infarction (MI).
  
  
  BACKGROUND
  Beta-AR desensitization is one of the mechanisms underlying the transition from compensated to decompensated HF. Beta-adrenergic receptor kinase-1 (ARK1), which can be induced by protein kinase C (PKC) in vitro, is activated in the failing myocardium, resulting in beta-AR uncoupling.
  
  
  METHODS
  Models of MI in rats were produced by ligation of left coronary artery. Four weeks after surgery, they were randomized to vehicle (MI/control [C]) or candesartan (10 mg/kg/day) treatment (MI/ARB). Sham-operated rats, or shams, served as controls.
  
  
  RESULTS
  After two weeks of treatment, echocardiography and hemodynamics showed that the left ventricular (LV) dimension increased and that the percent of fractional shortening and maximum rate of rise in left ventricular pressure (dP/dt) decreased in MI rats compared with shams. There were no differences in these indexes between MI/C and MI/ARB. An increase in maximum dP/dt under isoproterenol (ISO) stimulation was attenuated in MI/C but improved in MI/ARB. Reductions in the percentage of high-affinity sites of beta-AR and ISO-stimulated cyclic adenosine monophosphate production in noninfarcted myocardium were also improved by ARB treatment. Up-regulation of beta-ARK1 and PKC-epsilon isoform protein levels and activation of PKC in noninfarcted myocardium from MI/C were both inhibited by ARB treatment.
  
  
  CONCLUSIONS
  Treatment with ARB during the chronic phase of MI improved beta-AR coupling in noninfarcted myocardium without affecting basal LV function. Cross-talk between beta-AR and angiotensin signaling through beta-ARK1 and PKC-epsilon may be responsible for the phenomenon.
authors.affiliation: Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Keitaro
authors.initials: K
authors.lastname: Mahara
authors.forename: Michikado
authors.initials: M
authors.lastname: Iwata
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D011493:Protein Kinase C / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D047228:Angiotensin II Type 1 Receptor Blockers; D011943:Receptors, Adrenergic, beta; D011493:Protein Kinase C; D007545:Isoproterenol