Neurotensin inhibition of canine intestinal motility in vivo via alpha-adrenoceptors.

Neurotensin given intra-arterially in bolus doses to the canine small intestine inhibited field-stimulated, atropine-sensitive contractile responses in the duodenum (mean effective dose (ED50) = 3.2 X 10(-11) mol) and in the ileum (mean ED50 = 2.1 X 10(-11) mol). Norepinephrine (ED50 = 3 X 10(-9) mol) also inhibited these contractile responses. Phenylephrine (ED50 = 1.3 X 10(-8) mol) was one-fourth as potent as norepinephrine and clonidine (ED50 = 8 X 10(-10) mol) was at least as potent as norepinephrine, while isoproterenol (up to 8 X 10(-8) mol) failed to show any inhibitory effects. Phentolamine (2 mg/kg) increased significantly the ED50 of neurotensin and norepinephrine. Prazosin (2 mg/kg) increased significantly the ED50 of norepinephrine in the duodenum but had no effect on the ED50 of neurotensin. Yohimbine (2 mg/kg) increased the ED50 values of neurotensin and adrenergic agonists. Both neurotensin and norepinephrine in doses causing maximal inhibition of field-stimulated responses decreased (by 40 to 60%) contractile responses to 9 X 10(-10) mol (approximately the intra-arterial ED50 dose) of acetylcholine. Reserpine pretreatment markedly diminished the inhibition of spontaneous or field-stimulated phasic contractions by distention or field stimulation of a distal site. Reserpine also diminished the ED50 for neurotensin from 1 X 10(-11) to 2 X 10(-11) mol (p less than 0.02), but did not abolish neurotensin's inhibitory effect. Tetrodotoxin (10-15 micrograms, intra-arterially) increased the dose of neurotensin required to inhibit spontaneous activity in the ileum but after this toxin, as after adrenergic antagonists or reserpine, maximal inhibition could still be obtained. These results suggested that neurotensin inhibited contractile activity of canine intestine by acting on neural receptors to release norepinephrine. Norepinephrine activated primarily alpha 2-adrenoceptors and ultimately inhibited acetylcholine release. Neurotensin also inhibited contractions by activating a second, less sensitive receptor on smooth muscle.