Am. J. Respir. Crit. Care Med., Vol 153, No. 2, Feb 1996, 812-819.
Angiotensin-converting enzyme inhibitor and danazol increase sensitivity of cough reflex in female guinea pigs
T Ebihara, K Sekizawa, T Ohrui, H Nakazawa and H Sasaki
Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Japan.
To examine the mechanisms of an angiotensin-converting enzyme (ACE)
inhibitor-induced cough in perimenopausal and postmenopausal women, cough
responses to aerosols of capsaicin and citric acid were examined in four
groups of female guinea pigs treated orally with danazol (D) (an agent
decreasing plasma estrogen levels), cilazapril (C) (an inhibitor of ACE),
both danazol and cilazapril (C+D), or without either drug (control group)
for 4 to 5 wk. Capsaicin caused dose-dependent increases in the number of
coughs in all four groups. C or D alone shifted dose-response curves to
capsaicin (from 10(-7) M to 10(-3) M) to lower concentrations compared with
the control, and C+D further shifted them. Likewise, the number of coughs
induced by citric acid (3 x 10(-1) M; 2 min) was highest in animals treated
with C+D and significantly higher in animals treated with C or D than in
the control group. Aerosols of a selective substance P (SP) receptor
antagonist FK 888 (10(-5) M; 2 min) inhibited capsaicin-induced cough in
all four groups, and dose-response curves to capsaicin did not differ
significantly at any concentrations among the four groups in the presence
of FK 888 (p > 0.10). D decreased cyclic AMP levels in the trachea,
irrespective of the combination of C. A beta 2-adrenoceptor agonist,
procaterol, which is thought to inhibit SP release by elevation of cyclic
AMP in sensory nerves, dose-dependently inhibited the number of coughs
induced by capsaicin (10(-3) M) in animals treated with D. The present
study suggests that SP is a common mechanism mediating increases in the
sensitivity of cough reflex induced by both ACE inhibition and a decrease
in plasma estrogen levels, and the additive effects of the two events may
explain the high incidence of cough during ACE inhibitor therapy in
perimenopausal and postmenopausal women.
