Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine

The tachykinin NK1 receptor agonist substance P methyl ester (SPOME) impede s intestinal peristalsis by releasing nitric oxide (NO) from inhibitory mot or neurones. Since NK1 receptor agonists differ in their receptor interacti on, we set out to compare a range of NK1 receptor agonists including SPOME, septide and GR-73 632 in their effects on propulsive peristalsis and circu lar muscle activity in the guinea-pig isolated small intestine. SPOME (100- 300 nM) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR-73 632 (30-300 nM) interrupted peristalsis by causing circular muscle spasms. Separate experi ments showed that all three NK1 receptor agonists caused contraction of the circular muscle, which was enhanced by the NO synthase inhibitor N-G-nitro -L-arginine methyl ester (300 mu M) and the P2X purinoceptor antagonist sur amin (300 mu M). In contrast, tetrodotoxin (300 nM) augmented the contracti le effect of septide and GR-73 632 but not that of SPOME. It is concluded t hat the motor response to NK1 receptor agonists involves release of NO and adenosine triphosphate from inhibitory motor neurones. However, the NK1 rec eptor agonists differ in the mechanism by which they cause inhibitory trans mitter release, which corresponds to differences in their antiperistaltic a ction.