Enhanced nerve-stimulated muscarinic and neurokinin contractions of ileum from streptozotocin guinea-pigs.
Diabetes mellitus can lead to neuropathy of enteric neurons, resulting in abnormal gut motility. These studies investigated voltage-dependent contributions of muscarinic M₃ receptor activation by acetylcholine and neurokinin NK₁ receptor activation by neurokinins to nerve-stimulated contractions of longitudinal ileal strips from STZ guinea-pigs, a type 1 diabetic model with insulin deficiency, but mild hyperglycaemia. Contractions to bethanechol, substance P methyl ester, and nerve stimulation were greater in diabetic as compared to control ileum. The muscarinic M₃ receptor antagonist 4-DAMP at lower voltages and the neurokinin NK₁ receptor antagonist SR140333 at higher voltages, but not the neurokinin NK₁ receptor antagonist CP-96,345, were more effective at inhibiting nerve-stimulated immediate peak contractions and total areas of contraction of ileum from diabetic as compared to control animals. For diabetic ileum, voltage-dependent increases in the areas of nerve-stimulated contraction were observed in the presence of 4-DAMP and CP-96,345 but not SR140333. At low voltages only, nerve-stimulated release of acetylcholine was greater from diabetic as compared to control ileum. Fluorescence intensity of tachykinin-like immunoreactivity was increased in ileal myenteric ganglia from diabetic as compared to control animals. In diabetic guinea-pigs, stronger ileal nerve-stimulated contractions reflected increased release of acetylcholine at lower voltages and tachykinins at higher voltages, as well as increased sensitivity of smooth muscle M₃ and NK₁ receptors to acetylcholine and tachykinins. Hypoinsulinaemia may be a primary contributor to intestinal motility dysfunction in type 1 diabetes mellitus.
Department of Physiology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, USA.
J
J
Cellini
R
R
Pommier
R
R
Porter
K J
KJ
LePard
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000150:complications; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology*; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005725:Ganglia, Autonomic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D013311:Streptozocin; D015320:Tachykinins / Q000378:metabolism
D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D018377:Neurotransmitter Agents; D043587:Receptor, Muscarinic M3; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D013311:Streptozocin; D000109:Acetylcholine