Contribution of NK3 tachykinin receptors to propulsion in the rabbit isolated distal colon

The role of NK3 receptors in rabbit colonic propulsion has been investigated in vitro with the selective agonist, senktide, and two selective antagonists, SR142801 and SB222200. Peristalsis was elicited by distending a rubber balloon with 0.3 and 1.0 mL of water leading to a velocity of 2.2 and 2.8 mm s(-1), respectively. At concentrations of 1 nM, senktide inhibited propulsion evoked by both distensions (range 25-40%), whereas at 6 and 60 nmol L-1 facilitated 'submaximal' propulsion by 30%. In the presence of N omega -nitro-L-arginine (L-NNA, 200 mu mol L-1), which per se caused a slight prokinetic effect, 1 nmol L-1 senktide markedly accelerated propulsion (range 35-50%). Hexamethonium (200 mu mol L-1) had minor effects on propulsion. In its presence, 60 nmol L-1 senktide significantly inhibited propulsion induced by both stimuli (range 20-50%). SR142801 (0.3, 3 nmol L-1) and SB222200 (30, 300 nmol L-1) facilitated 'submaximal' propulsion (range 20-40%). Conversely, higher antagonist concentrations (SR142801: 30, 300 nM; SB222200: 1, 10 mu mol L-1) inhibited propulsion to both distensions by 20%. A combination of SR142801 (300 nmol L-1) plus hexamethonium (200 mu mol L-1) induced an approximately four-fold greater inhibition of propulsion than that induced by SR142801 alone. In conclusion, in the rabbit-isolated distal colon, a subset of NK3 receptors located on descending pathways mediates an inhibitory effect on propulsion by activating a NO-dependent mechanism. Another subset of NK3 receptors, located on ascen ding pathways mediates a facilitative effect involving a synergistic interaction with cholinergic nicotinic receptors.