We examined whether inhaled frusemide could reduce the potentiation of capsaicin-induced cough by prostaglandin (PG) F2 alpha. Eight non-smoking normal subjects, after a baseline capsaicin challenge were given inhaled frusemide or saline followed by capsaicin challenge, then PGF2 alpha and finally capsaicin challenge again. PGF2 alpha-induced coughs were reduced after frusemide to 3.6 +/- 1.0 compared with 5.7 +/- 1.2 after saline (P less than 0.05). PGF2 alpha increased capsaicin-induced coughs by 11.1 +/- 3.7 and 7.9 +/- 3.4 after placebo and frusemide, respectively (P less than 0.05). Frusemide had no effect on capsaicin-induced cough alone. Changes in local ionic concentrations by frusemide, particularly chloride ions within the vicinity of epithelial cough receptors, may determine the cough response to low chloride solutions and to PGF2 alpha, but not to capsaicin which acts directly on the cough receptors, and alter the sensitivity of the receptors to capsaicin.