Wade P.R.,Enterology Research Team |
Palmer J.M.,Enterology Research Team |
Mabus J.,Enterology Research Team |
Saunders P.R.,Enterology Research Team |
And 5 more authors.
Neurogastroenterology and Motility | Year: 2010
Background Prokineticins 1 and 2 (PROK1 and PROK2) are so named because they contract gastrointestinal smooth muscle, yet little else is known about their role in gastrointestinal function. Therefore, we used a combination of approaches to elucidate the mechanisms by which PROK1 alters ileal contractility and secretion in rats. Methods RT-PCR and immunofluorescence were used to determine PROK and receptor (PK-R) mRNA levels and PK-R1 localization, respectively. Upper GI transit and fluid secretion were determined in vivo. Contractility and intestinal epithelial ion transport were assessed in isolated ileal segments. Key Results In the gastric fundus, PROK1 mRNA is highly expressed (70-fold >PROK2 mRNA) whereas the ileum has the highest mRNA expression of its receptor. PK-R1 immunoreactivity is visualized in ileal crypt cells, and in submucosal and myenteric neurons. In ileal segments, PROK1 evokes biphasic contractile responses consisting of an early, TTX-sensitive response (EC50 = 87.8 nmol L-1) followed by a late, TTX-insensitive (EC50 = 72.4 nmol L-1) component that is abolished in mucosa-free preparations. Oral administration of PROK1 enhances small bowel transit (111 ± 3% of control) and fluid secretion (340 ± 90% of control) and in muscle-stripped ileal preparations increases short-circuit current (EC50 = 8.2 nmol L-1) in a TTX-insensitive manner. The PROK1-evoked Cl- secretion is reduced by piroxicam (non-selective cyclooxygenase inhibitor), and a prostaglandin EP4 receptor antagonist (AH23848), but not a thromboxane receptor antagonist (GR32191B). Conclusions & Inferences These results demonstrate that PROK1 has oral prokinetic and secretogogue activity and that it acts on the intestinal mucosa via PK-R1 and prostaglandin receptors to mediate these effects. © 2009 Blackwell Publishing Ltd.