Effect of Bradykinin on Airway Ciliary Motility and Its Modulation by Neutral Endopeptidase

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Abstract
We studied the effect of bradykinin on ciliary activity and its modulation by peptidases in cultured rabbit epithelium in vitro. Bradykinin (10-7 M) elicited a rapid, transient increase in ciliary beat frequency (CBF) from the baseline values of 1,031 .+-. 25 to 1,388 .+-. beats/min (mean .+-. SE, p < 0.001), followed by a decline to a steady-state value of 1,180 .+-. 30 beats/min, which was still greater than the baseline CBF. The ciliostimulation was dose-dependently inhibited by the B2-receptor antagonist (D-Arg-Hyp3,Thi5.8,D-Phe1)-bradykinin but not by the B1-receptor antagonist (Des-Arg9,Leu8)-bradykinin. Nifedipine, Ca2+-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change of CBF. Involvement of tachykinins, leukotrienes, prostaglandin D2, or thromboxane A2 was ruled out because bradykinins action was not affected by (D-Pro2,D-Trp7.9)-substance P71 nondihydroguaiaretic acid, or SQ29548, an antagonist for prostaglandin D2 and thromboxane A2. Bradykinin also increased prostaglandin E2 release (p < 0.01), an effect that was abolished by indomethacin and Ca2+ deficiency. The CBF dose-response curve for bradykinin was shifted to lower concentratons by 1 log U by the neutral endopeptidase inhibitor phosphoramidon (p < 0.01), whereas the angiotensin-converting enzyme inhibitor captopril was without effect. These results suggest that bradykinin interacts with B2-type receptors and stimulates ciliary activity throgh Ca2+-dependent prostaglandin E2 release, and that neutral endopeptidase may play a role in modulating the effect of bradykinin on airway mucociliary transport.