title: Long-term nitroglycerin treatment is associated with supersensitivity to vasoconstrictors in men with stable coronary artery disease: prevention by concomitant treatment with captopril.
abstract: OBJECTIVE
  We examined whether long-term nitroglycerin (NTG) treatment leads to an increase in sensitivity to vasoconstrictors. To assess a potential role of the renin-angiotensin system in mediating this phenomenon, we treated patients concomitantly with the angiotensin-converting enzyme (ACE) inhibitor captopril.
  
  
  BACKGROUND
  The anti-ischemic efficacy of organic nitrates is rapidly blunted by the development of nitrate tolerance. The underlying mechanisms are most likely multifactorial and may involve increased vasoconstrictor responsiveness.
  
  
  METHODS
  Forearm blood flow and vascular resistance were determined by using strain gauge plethysmography. The short-term responses to intraarterial angiotensin II (1, 3, 9 and 27 ng/min) and phenylephrine (an alpha-adrenergic agonist drug, 0.03, 0.1, 0.3 and 1 microg/min) were studied in 40 male patients with stable coronary artery disease. These patients were randomized into four groups receiving 48 h of treatment with NTG (0.5 microg/kg body weight per min) or placebo with or without the ACE inhibitor captopril (25 mg three times daily).
  
  
  RESULTS
  In patients treated with NTG alone, the maximal reductions in forearm blood flow in response to angiotensin II and phenylephrine were markedly greater (-64 +/- 3% and -53 +/- 4%, respectively) than those in patients receiving placebo (-41 +/- 2% and -42 +/- 2%, respectively). Captopril treatment completely prevented the NTG-induced hypersensitivity to angiotensin II and phenylephrine (-33 +/- 3% and -35 +/- 3%, respectively) but had no significant effect on blood flow responses in patients without NTG treatment (-34 +/- 2% and -37 +/- 3%, respectively).
  
  
  CONCLUSIONS
  We conclude that continuous administration of NTG is associated with an increased sensitivity to phenylephrine and angiotensin II that is prevented by concomitant treatment with captopril. The prevention of NTG-induced hypersensitivity to vasoconstrictors by ACE inhibition indicates an involvement of the renin-angiotensin system in mediating this phenomenon.
authors.affiliation: Department of Medical Statistics, University of Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heitzer
authors.forename: H
authors.initials: H
authors.lastname: Just
authors.forename: C
authors.initials: C
authors.lastname: Brockhoff
authors.forename: T
authors.initials: T
authors.lastname: Meinertz
authors.forename: M
authors.initials: M
authors.lastname: Olschewski
authors.forename: T
authors.initials: T
authors.lastname: Münzel
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D002216:Captopril / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000008:administration & dosage / Q000627:therapeutic use*; D010656:Phenylephrine / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000502:physiology; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D010656:Phenylephrine; D002216:Captopril; D005996:Nitroglycerin