Cysteinyl leukotriene D4 increases human detrusor muscle responsiveness to histamine

Leukotriene D(4) and histamine are proinflammatory mediators that are released concomitantly by activated mast cells. There is the possibility of mutual potentiation of their actions in inflammatory diseases such as interstitial cystitis. We investigated whether human detrusor smooth muscle cells showed increased responsiveness to histamine in the presence of leukotriene D(4).

Cold cup detrusor biopsies were obtained from patients undergoing cystoscopy for benign noninvasive bladder diseases. Human detrusor smooth muscle cells in culture were obtained using an explantation technique and subcultivated for a maximum of 3 passages. The cytosolic free Ca(2+) concentration and contractile force were measured by spectrofluorometry and myograph techniques, respectively.

Low doses of leukotriene D(4) (10 nM or less), which usually do not produce a significant effect on the free Ca(2+) concentration or on muscle contraction when administered 30 to 60 seconds beforehand, significantly enhanced the transient increase in the free Ca(2+) concentration and isometric force induced by 50 to 200 nM histamine. Increased histamine responses were associated with an upward shift in the fura-2 fluorescence ratio, suggesting that histamine hyperresponsiveness was due to the appearance of additional histamine receptors on the sarcolemma or to more efficient signaling per receptor. Leukotriene D(4) concentrations greater than 10 nM had no potentiating effects.

To our knowledge this is the first demonstration in the human detrusor that leukotriene D(4) potentiates the effect of histamine. These inflammatory mediators, which are often released concomitantly from mast cells, may interact mutually to potentiate the spasmogenic effect of histamine. These results suggest that the combination of leukotriene D(4) and histamine H1 receptor antagonists may be more effective for the treatment of interstitial cystitis than when given alone.