title: Randomized, double-blind, placebo-controlled study of carvedilol on the prevention of nitrate tolerance in patients with chronic heart failure.
abstract: OBJECTIVE
  This study was designed to evaluate the effect of carvedilol on nitrate tolerance in patients with chronic heart failure.
  
  
  BACKGROUND
  The attenuation of cyclic guanosine 5'-monophosphate (cGMP) production due to inactivation of guanylate cyclase by increased superoxide has been reported as a mechanism of nitrate tolerance. Carvedilol has been known to combine alpha/beta-blockade with antioxidant properties.
  
  
  METHODS
  To evaluate the effect of carvedilol on nitrate tolerance, 40 patients with chronic heart failure were randomized to four groups that received either carvedilol (2.5 mg once a day [carvedilol group, n=10]), metoprolol (30 mg once a day [metoprolol group, n=10]), doxazosin (0.5 mg once a day [doxazosin group, n=10]) or placebo (placebo group, n=10). Vasodilatory response to nitroglycerin (NTG) was assessed with forearm plethysmography by measuring the change in forearm blood flow (FBF) before and 5 min after sublingual administration of 0.3 mg NTG, and at the same time blood samples were taken from veins on the opposite side to measure platelet cGMP. Plethysmography and blood sampling were obtained serially at baseline (day 0); 3 days after carvedilol, metoprolol, doxazosin or placebo administration (day 3); and 3 days after application of a 10-mg/24-h NTG tape concomitantly with carvedilol, metoprolol, doxazosin or placebo (day 6).
  
  
  RESULTS
  There was no significant difference in the response of FBF (%FBF) and cGMP (%cGMP) to sublingual NTG on day 0 and day 3 among the four groups. On day 6, %FBF and %cGMP were significantly lower in the metoprolol, doxazosin and placebo groups than on day 0 and day 3, but these parameters in the carvedilol group were maintained.
  
  
  CONCLUSIONS
  These results indicated that carvedilol may prevent nitrate tolerance in patients with chronic heart failure during continuous therapy with NTG.
authors.affiliation: Department of Cardiology, KINU Medical Association Hospital, Mitsukaido, Ibaraki, Japan. wata-h@xa2.so-net.ne.jp
authors.forename: H
authors.initials: H
authors.lastname: Watanabe
authors.forename: M
authors.initials: M
authors.lastname: Kakihana
authors.forename: S
authors.initials: S
authors.lastname: Ohtsuka
authors.forename: Y
authors.initials: Y
authors.lastname: Sugishita
mesh_terms: D018674:Adrenergic Antagonists / Q000627:therapeutic use*; D000368:Aged; D001783:Blood Flow Velocity / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D006152:Cyclic GMP / Q000096:biosynthesis / Q000097:blood; D004311:Double-Blind Method; D017292:Doxazosin / Q000627:therapeutic use; D004342:Drug Hypersensitivity / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005542:Forearm / Q000098:blood supply; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D008875:Middle Aged; D005996:Nitroglycerin / Q000009:adverse effects*; D011412:Propanolamines / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000009:adverse effects*
chemical_list: D018674:Adrenergic Antagonists; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol; D005996:Nitroglycerin; D008790:Metoprolol; D006152:Cyclic GMP; D017292:Doxazosin