Thromboxane antagonism and cough induced by angiotensin-converting-enzyme inhibitor

Lancet. 1997 Jul 5;350(9070):15-8. doi: 10.1016/S0140-6736(96)12045-6.

Abstract

Background: The increased prostaglandin synthesis that might follow stimulation of the arachidonic acid cascade by angiotensin-converting-enzyme inhibition (ACE-I) has been suggested to underlie the appearance of cough on ACE-I treatment. We investigated whether the prostanoid thromboxane was involved.

Methods: Nine patients with essential hypertension who had cough after enalapril 20 mg once a day (coughers) were treated, while continuing the enalapril, in a double-blind crossover study with placebo or picotamide, 600 mg twice daily. Picotamide is a platelet antiaggregant that acts through both inhibition of thromboxane synthase and thromboxane-receptor antagonism. Thirteen hypertensive patients with no history of ACE-I-induced cough were also treated with enalapril and served as controls. Cough frequency was measured by a visual analogue scale and by a daily cough diary. 24 h urinary recovery of 11-dehydro-thromboxane-B2 and 6-keto-PGF1 alpha were measured to assess any changes in endoperoxide metabolism during the study periods.

Findings: 11-dehydro-thromboxane-B2 (TXB2) recovery was significantly reduced by picotamide, which led to the disappearance of cough in eight patients within 72 h. Picotamide urinary recovery data suggested incomplete absorption in the non-responder. At baseline and after rechallenge with enalapril, 11-dehydro-TXB2 excretion was in the same range in the controls and in the coughers, but the latter showed significantly lower excretion of 6-keto-PGF1 alpha, and their ratio of 11-dehydroTXB2 to 6-keto-PGF1 alpha was twice that of the controls (1.40 [95% CI 0.86-1.95] vs 0.61 [0.37-0.84]).

Interpretation: A thromboxane antagonist is effective in ACE-I-induced cough. An imbalance between thromboxane and prostacyclin may represent a marker of patients susceptible to ACE-I-induced cough.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / urine
  • Angiotensin-Converting Enzyme Inhibitors / adverse effects*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Cough / chemically induced*
  • Cough / metabolism
  • Cough / prevention & control*
  • Cross-Over Studies
  • Double-Blind Method
  • Enalapril / adverse effects*
  • Enalapril / therapeutic use
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / metabolism
  • Middle Aged
  • Phthalic Acids / pharmacology*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Thromboxane B2 / analogs & derivatives
  • Thromboxane B2 / urine
  • Thromboxanes / antagonists & inhibitors*

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Phthalic Acids
  • Platelet Aggregation Inhibitors
  • Thromboxanes
  • Thromboxane B2
  • 6-Ketoprostaglandin F1 alpha
  • picotamide
  • 11-dehydro-thromboxane B2
  • Enalapril