Effects of exendin-4 on colonic motility in rats and its underlying mechanism

Background: Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists modulate gastrointestinal motility; however, the effects of GLP-1R agonists on colonic motility are still controversial, and the molecular mechanism is unclear. Exendin-4 shares 53% homology with GLP-1 and is a full agonist of GLP-1R. In this study, our aims were to explore the role and mechanism of exendin-4 in isolated rat colonic tissues and cells.

Methods: An organ bath system was used to examine the spontaneous contractions of smooth muscle strips. The whole-cell patch-clamp technique was used to investigate the currents of L-type voltage-dependent calcium channels and large conductance Ca²⁺ -activated K⁺ (BK_Ca ) channels in smooth muscle cells.

Key results: Exendin-4 decreased both the amplitude and frequency of spontaneous contractions of smooth muscle strips in a concentration-dependent manner. The inhibitory effect was completely blocked by exendin-4(9-39), a GLP-1R antagonist. Moreover, this effect was partially abolished by tetrodotoxin (TTX), a blocker of neuronal voltage-dependent Na⁺ channels, Nω-Nitro-l-arginine (L-NNA), a nitric oxide synthase (NOS) inhibitor, apamin, an inhibitor of small-conductance Ca²⁺ -activated K⁺ (SK) channels. Whole-cell patch-clamp recordings revealed that exendin-4 inhibited the peak current of L-type calcium channels in colonic smooth muscle cells, but did not change the shape of the current-voltage (I-V) curves. The steady-state activation and steady-state inactivation of L-type calcium channels were not affected. Likewise, BK_Ca currents were significantly inhibited by exendin-4.

Conclusions: Exendin-4 indirectly inhibits colonic muscle activity via a nitrergic and a purinergic neural pathway through NO and ATP release and inhibits L-type voltage-dependent calcium channels and BK_Ca channels in smooth muscle cells.