Comparison of the antisecretory effect of endogenous forms of peptide YY on fed and fasted rat jejunum.

It is intriguing that the antisecretory peptide YY is present in plasma in two forms: PYY1-36 and PYY3-36. PYY3-36 has been found in human and rabbit blood within 30 min of the beginning of the meal, when the peak of water and electrolyte secretion occurs in the duodeno-jejunum. The aim of this study was therefore to compare the antisecretory effect of PYY1-36 and PYY3-36 in fed and fasted rat jejunum. The variations in electrolyte secretion were assessed by measuring the variations in short-circuit current (delta Isc) and transepithelial isotopic chloride fluxes in jejunal mucosa isolated from fed and fasted animal, and mounted in Ussing Chambers. In fasted animals, 2 x 10(-7) M PYY3-36 induced a reduction in Isc of -0.50 +/- 0.01 microEq/hr.cm2, which was not statistically different from that induced by 2 x 10(-7) M PYY1-36 (-0.60 +/- 0.01 microEq/h cm2). In contrast, in fed animals, 2 x 10(-7) M PYY3-36 did not trigger a significant response on Isc and net chloride flux, while the response to PYY1-36 was present but blunted. The absence of response was probably not related to the presence of secretory peptides because PYY3-36 was still able to induce a reduction in Isc after stimulation by a series of 10 different secretory peptides. After 10(-8) M PYY3-36 addition to an epithelium from the fasted animal, response to 10(-7) M PYY3-36 was blunted for 30 min and returned to control value after 60 min. Plasma concentration of PYY was higher in the fed rats compared to fasted (213.78 +/- 38 vs. 53.62 +/- 11.47 pg/ml p < 0.01). After incubation of crypt cells with or without 0.1 microM of unlabeled PYY for 60 min, Scatchard analysis of equilibrium binding data show that binding capacity (Bmax) of receptors was reduced when crypt cells were previously incubated with unlabeled PYY without significant modification of dissociation constants. Bmax were 183 +/- 27 in control vs. 56 +/- 11 fmol/mg protein. These results confirm the antisecretory activity of PYY1-36 in the jejunum of fasted and fed rats. They further indicate that PYY3-36 displays similar activity to PYY1-36 in fasted animals, but lack of activity in fed animals. These results suggest that the two circulating forms of PYY act as antisecretory peptides by two different mechanisms, implying a C-terminal specificity.