BIOASSAY AND PHARMACOLOGICAL CHARACTERIZATION OF THE NITRERGIC NEUROTRANSMITTER

Based on organ bath experiments illustrating nitric oxide (NO) or an N O-releasing substance as mediator of the nonadrenergic noncholinergic (NANC) nerve-induced relaxations in the canine ileocolonic junction an d rat gastric fundus, a bioassay superfusion technique was developed t o detect and characterize the inhibitory NANC neurotransmitter. Eviden ce is provided that NANC nerve stimulation results in the release of a vasorelaxant factor with pharmacological properties similar to NO: it s release is blocked by inhibition of the NO biosynthesis and tetrodot oxin, but enhanced by L-arginine. Its half-life is comparable to that of NO, and its biological activity is enhanced by superoxide dismutase , but abolished by hemoglobin. In addition, the nitrergic transferable factor is similarly affected as authentic NO by pyrogallol, hydroquin one, hydroxocobalamin and L-cysteine. Nitrosothiols, like S-nitroso-L- cysteine, S-nitroso glutathione and S-nitroso-N-acetyl-D,L-penicillami ne, on the other hand, have a different pharmacological profile compar ed to NO and the nitrergic factor, indicating that NO, and not a nitro sothiol, is released from inhibitory NANC nerves in the canine ileocol onic junction. This nerve-induced release is Ca2+-dependent and prejun ctionally regulated by K+ channels and alpha(2)-adrenoceptors: blockad e of K+ channels enhances the release, whereas alpha(2)-adrenoceptor a ctivation reduces the release of the nitrergic factor, possibly by act ivating K+ channels.