Effects of peptide YY and its analogues on chloride ion secretion in fed and fasted rat jejunum

Abstract

The aim of our study was to determine whether a meal modifies the antisecretory response induced by PYY and the structural requirements to elicit antisecretory effects of analogue PYY(22-36) for potential antidiarrhea therapy. The variations in short-circuit current (Isc) due to the modification of ionic transport across the rat intestine were assessed in vitro, using Ussing chambers. In fasted rats, PYY induced a dose- and time-dependent reduction in Isc, with a sensitivity threshold at 5 x 10(-11) M (delta Isc -2 +/- 0.5 microA/cm2). The reduction was maximal at 10(-7) M (Isc -23 +/- 2 microA/cm2), and the concentration producing half-maximal inhibition was 10(-9) M. At 10(-7) M, reduction of 1sc by PYY reached 90% of response to 5 x 10(-5) M bumetanide. The PYY effect was partly reversed by 10(-5) M forskolin (Isc + 13.43 +/- 2.91 microA/h.cm2, p < 0.05) or 10(-5) M dibutyryl adenosine 3',5' cyclic monophosphate (Isc + 12 +/- 1.69 microA/cm2, p < 0.05). Naloxone and tetrodotoxin did not alter the effect of PYY. In addition, PYY and its analogue P915 reduced net chloride ion secretion to 2.85 and 2.29 microEq/cm2 (p < 0.05), respectively. The antisecretory effect of PYY was accompanied by dose- and time-dependent desensitization when jejunum was prestimulated by a lower dose of peptide. The antisecretory potencies exhibited by PYY analogues required both a C-terminal fragment (22-36) and an aromatic amino acid residue (Trp or Phe) at position 27. At 10(-7) M the biological activity of PYY was lower in fed than fasted rats (p < 0.001). Our results confirm the antisecretory effect of PYY, but show that the fed period is accompanied by desensitization, similar to the transient desensitization observed in the fasted period with cumulative doses. This suggests that PYY may act as a physiological mediator that reduces intestinal secretion.