Effect of N-methyl-d-aspartate receptor blockade on neuronal plasticity and gastrointestinal transit delay induced by ischemia/reperfusion in rats.
Intestinal ischemia impairs gastrointestinal motility. The aims of this study were to investigate the effect of intestinal ischemia on gastrointestinal transit and on the expression of enteric transmitters in the rat, and whether the glutamate N-methyl-d-aspartate receptors influence these effects. Ischemia (1 h), induced by occluding the superior mesenteric artery, was followed by 0 or 24 h of reperfusion. Normal and sham-operated rats served as controls. Serosal blood flow was measured with laser Doppler flow meter. Gastrointestinal transit was measured as time of appearance of a marker in fecal pellets. Immunohistochemistry was used to evaluate the number of neurons immunoreactive for neuronal nitric oxide synthase (NOS) or vasoactive intestinal polypeptide and the density of substance P immunoreactive fibers in the myenteric plexus. The N-methyl-d-aspartate receptors antagonist, (+)-5-methyl-10,11-dihydro-5HT-[a,b] cyclohepten-5,10-imine (MK-801) (1 mg/kg i.v.) or the NOS inhibitor, N-nitro-l-arginine (10 mg/kg i.v.) was administered prior to ischemia. Serosal blood flow was decreased by 70% during ischemia, but it was not altered in sham-operated rats. Gastrointestinal transit was significantly prolonged in ischemic/reperfused rats compared with controls. There was a significant increase in the number of vasoactive intestinal polypeptide and neuronal nitric oxide synthase immunoreactive neurons, and a marked decrease of substance P immunoreactive fibers in ischemia followed by 24 h of reperfusion animals compared with controls. These alterations were not observed in ischemia without reperfusion. A significant delay of gastrointestinal transit and increase of vasoactive intestinal polypeptide neurons were also observed in sham-operated rats. The changes in transmitter expression and gastrointestinal transit in ischemic/reperfused rats were prevented by pre-treatment with the NOS inhibitor, N-nitro-l-arginine or the N-methyl-d-aspartate receptors antagonist, MK-801. This study suggests an involvement of the glutamatergic system and its interaction with nitric oxide in intestinal ischemia/reperfusion. Ischemia/reperfusion might induce local release of glutamate that activates N-methyl-d-aspartate receptors leading to increased production of nitric oxide and adaptive changes in enteric transmitters that might contribute to gastrointestinal dysmotility.
Calcina
F
F
CURE Digestive Diseases Research Center, Division of Digestive Diseases, Building 115, Room 224, Veterans Administration Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.
Barocelli
E
E
Bertoni
S
S
Furukawa
O
O
Kaunitz
J
J
Impicciatore
M
M
Sternini
C
C
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014660:Vasoactive Intestinal Peptide; D016291:Dizocilpine Maleate; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester