title: Dissociation of coronary vascular tolerance and neurohormonal adjustments during long-term nitroglycerin therapy in patients with stable coronary artery disease.
abstract: OBJECTIVE
  We sought to examine whether long-term nitroglycerin treatment causes tolerance in large coronary arteries and whether the loss of vascular effects parallels neurohormonal adjustments.
  
  
  BACKGROUND
  Nitroglycerin therapy is associated with increased plasma renin activity and aldosterone levels and a decrease in hematocrit. It is assumed that nitroglycerin tolerance results in part from these neurohormonal adjustments and intravascular volume expansion.
  
  
  METHODS
  Three groups were studied: group I (n = 10), no prior nitroglycerin therapy; and group II (n = 10) and group III (n = 8), 24- and 72-h long-term nitroglycerin infusion (0.5 micrograms/kg body weight per min), respectively. Coronary artery dimensions were assessed using quantitative angiography. Plasma renin activity, plasma aldosterone and vasopressin levels and hematocrit were monitored before and during nitroglycerin infusions.
  
  
  RESULTS
  In group I, increasing intravenous concentrations of nitroglycerin caused a dose-dependent increase of the midportion of the left anterior descending coronary artery (baseline diameter 2.13 +/- 0.07 mm [mean +/- SEM], maximally by 22 +/- 2%) and left circumflex coronary artery (baseline diameter 2.08 +/- 0.07) mm, maximally by 22 +/- 3%). An intracoronary nitroglycerin bolus (0.2 mg) caused no further significant increase in diameter, indicating maximal dilation. In group II (n = 10), the baseline large coronary artery diameter under ongoing nitroglycerin was significantly larger than that in group I (left anterior descending artery 2.61 +/- 0.08 mm, left circumflex artery 2.57 +/- 0.08 mm). Additional intravenous and intracoronary nitroglycerin challenges did not cause further dilation, indicating maximally dilated vessels. At the same time, plasma renin activity, plasma aldosterone and vasopressin levels were significantly increased, and hematocrit significantly decreased. In group III patients, the baseline diameter of the left anterior descending artery and the left circumflex artery did not differ from that in patients without nitroglycerin pretreatment, indicating a complete loss of nitroglycerin coronary vasodilative effects. These patients showed no significant increase in circulating neurohormonal levels but a significant decrease in hematocrit.
  
  
  CONCLUSIONS
  Within 24 h of continuous nitroglycerin treatment, the coronary arteries were maximally dilated despite neurohormonal adjustments and signs of intravascular volume expansion. Within 3 days of nitroglycerin infusion, tolerance developed in the absence of neurohormonal activation. The dissociation of neurohormonal adjustments and tolerance in large coronary arteries indicates that after long-term nitroglycerin treatment, true vascular tolerance, perhaps from an intracellular tolerance step, may have developed.
authors.affiliation: Medizinische Klinik III, Division of Cardiology, University of Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Münzel
authors.forename: T
authors.initials: T
authors.lastname: Heitzer
authors.forename: S
authors.initials: S
authors.lastname: Kurz
authors.forename: D G
authors.initials: DG
authors.lastname: Harrison
authors.forename: C
authors.initials: C
authors.lastname: Luhman
authors.forename: L
authors.initials: L
authors.lastname: Pape
authors.forename: M
authors.initials: M
authors.lastname: Olschewski
authors.forename: H
authors.initials: H
authors.lastname: Just
mesh_terms: D000450:Aldosterone / Q000097:blood; D016022:Case-Control Studies; D017023:Coronary Angiography; D003327:Coronary Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006400:Hematocrit; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000627:therapeutic use*; D012083:Renin / Q000097:blood; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*; D014667:Vasopressins / Q000097:blood
chemical_list: D014665:Vasodilator Agents; D014667:Vasopressins; D000450:Aldosterone; D012083:Renin; D005996:Nitroglycerin