The effects of neuropeptide Y and its fragments upon basal and electrically stimulated ion secretion in rat jejunum mucosa.

1. The effects of neuropeptide Y (NPY) and a range of C terminal fragments were investigated both on basal short circuit current (s.c.c.) and electrical field stimulated responses in voltage clamped preparations in rat jejunal mucosa. 2. Most of the NPY fragments tested had direct effects upon the mucosa, reducing baseline s.c.c. with EC50 values of 1 micron or more. NPY was 30 times more effective than any of the fragments tested and the order of potency was: NPY much greater than NPY (11-36) greater than or equal to (12-36) greater than or equal to (13-36) greater than or equal to (14-36). NPY (15-36), (16-36), (20-36) and (22-36) were still less effective and complete concentration-response curves could not be constructed. NPY (26-36), des amido NPY and the C-terminal flanking peptide of NPY (CPON) were all inactive and did not significantly alter responses to NPY. 3. Electrical field stimulation (EFS) of mucosal preparations elicited rapid transient secretory responses in the presence of hexamethonium and atropine. NPY and fragments attenuated these secretory responses and where concentration-response relationships could be compared at a given time point the following order of potency was obtained: NPY much greater than NPY (11-36) greater than NPY (13-36). Again NPY (26-36), des amido NPY and CPON were ineffective, while at single concentrations (300 nM) a graded attenuation of EFS responses was obtained with NPY (14-36) greater than or equal to NPY (15-36) greater than NPY (16-36) greater than or equal to NPY (20-36) greater than NPY (22-36). 4. The attenuation of EFS responses by these peptides was not dependent upon the basal secretory state. Pretreatment of tissues with piroxicam reduced s.c.c. and attenuated further reductions in s.c.c. by NPY, but had no effect upon NPY-mediated inhibition of electrically-stimulated secretory responses. 5. NPY fragments attenuated both basal and EFS generated secretion. Since fragments are effective these receptors must, by definition be Y2-like. NPY (11-36) and NPY (13-36) at 300nm and 1 microM did not significantly attenuate secretory responses to either carbachol (CCh) or substance P (SP). A 1 microM concentration of either fragment was equivalent in effect to 30nm NPY upon basal current, but NPY at this concentration significantly reduced both CCh- and SP-induced secretion. The reduced spectrum of fragment activity together with the different order and potency ratios obtained with these three peptides indicates a presynaptic action for NPY and the fragments.