Regulation of bradykinin sensitivity in peripheral sensory fibres of the neonatal rat by nitric oxide and cyclic GMP.

ABSTRACT

Bradykinin-induced activation of peripheral sensory fibres was studied using an in vitro preparation of the neonatal rat spinal cord with attached tail. Noxious heat stimulation, as well as the applications of bradykinin and capsaicin, to the tail evoked reproducible responses recorded as a depolarization of a lumbar ventral root. Prolonged administration of a supramaximal concentration of bradykinin invariably induced a complete but selective desensitization to a subsequent bradykinin challenge. Bradykinin-induced desensitization was significantly attenuated by concanavalin-A and the effect of concanavalin-A was prevented by alpha-methyl mannoside. Both cyclic GMP and sodium nitroprusside induced a long lasting reduction of bradykinin responsiveness in peripheral fibres. The effect of nitroprusside was prevented by concanavalin-A, and by methylene blue, an inhibitor of guanylyl cyclase. Methylene blue also reduced bradykinin-induced desensitization. L-arginine, but not D-arginine, induced a desensitization to bradykinin. On the other hand, 7-nitroindazole (7-NI, 200-500 nM), an inhibitor of NOS, reduced the desensitization of bradykinin responses but higher concentrations of 7-NI (IC50 = 6.7 +/- 0.9 microM) selectively attenuated responses to bradykinin. The effects of 7-NI were attenuated by L-arginine pretreatment. These data suggest that bradykinin-induced desensitization of peripheral sensory fibres is mediated in part via NO and cyclic GMP dependent mechanisms possibly NO production is required for guanylate cyclase activation.