INVOLVEMENT OF THE NITRIC-OXIDE CYCLIC-GMP PATHWAY IN THE DESENSITIZATION OF BRADYKININ RESPONSES OF CULTURED RAT SENSORY NEURONS

Bradykinin (BK) excites a subset of dorsal root ganglion neurons by inducing an inward cation current (I(BK)) that strongly desensitizes and is accompanied by elevations in cGMP. We have examined the links between cGMP metabolism and I(BK). The BK dose dependencies of I(BK) activation, desensitization, and cGMP production are comparable. Stimulation (with sodium nitroprusside [NP] or 8-bromo-cGMP [8Br-cGMP]) or inhibition (with methylene blue, hemoglobin, and nitric oxide synthase [NOS] inhibitors) of cGMP levels did not mimic or diminish I(BK). However, desensitization was affected by the following agents: first, desensitization was enhanced by NP and reduced by NOS inhibitors. Second, the effects of NOS inhibitors could be overcome by 8Br-cGMP or L-arginine. Third, 8Br-cGMP modification of desensitization required receptor occupancy. We conclude that the NO-cGMP pathway affects a component of I(BK) desensitization at the receptor or G protein level.