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


RESULTS
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]).


CONCLUSIONS
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.
Malini
P L
PL
Clinica Medica III, S Orsola University Hospital, Bologna, Italy.
Strocchi
E
E
Zanardi
M
M
Milani
M
M
Ambrosioni
E
E
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D003371:Cough / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004656:Enalapril / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008875:Middle Aged; D010795:Phthalic Acids / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D000806:Angiotensin-Converting Enzyme Inhibitors; D010795:Phthalic Acids; D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C011581:picotamide; C049235:11-dehydro-thromboxane B2; D004656:Enalapril