title: Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol.
abstract: OBJECTIVE
  The purpose of this study was to determine whether carvedilol's alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF).
  
  
  BACKGROUND
  Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain.
  
  
  METHODS
  We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation.
  
  
  RESULTS
  Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol.
  
  
  CONCLUSIONS
  Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.
authors.affiliation: Division of Cardiology, Mount Sinai Hospital and the University of Toronto, Toronto, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Kubo
authors.forename: E R
authors.initials: ER
authors.lastname: Azevedo
authors.forename: G E
authors.initials: GE
authors.lastname: Newton
authors.forename: J D
authors.initials: JD
authors.lastname: Parker
authors.forename: J S
authors.initials: JS
authors.lastname: Floras
mesh_terms: D000320:Adrenergic Fibers / Q000187:drug effects; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D004311:Double-Blind Method; D016903:Drug Monitoring; D019317:Evidence-Based Medicine; D005080:Exercise Test / Q000187:drug effects; D005260:Female; D005583:Fourier Analysis; D018737:Hand Strength; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007537:Isometric Contraction / Q000187:drug effects; D008134:Long-Term Care; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects; D009451:Neuroeffector Junction / Q000187:drug effects; D011379:Prognosis; D011412:Propanolamines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol; D008790:Metoprolol