Effect of radiation on cAMP, cGMP and Ca(2+)(i) pathways and their interactions in rat distal colon.
The secretory response implicated in the intestinal response to luminal attack is altered by radiation. The cAMP, cGMP and Ca(2+)(i) pathways leading to secretion as well as the interactions between the cAMP pathway and the cGMP or Ca(2+)(i) pathway were studied in the rat distal colon 4 days after a 9-Gy abdominal X irradiation, when modifications mainly occurred. The secretory response in Ussing chambers and cAMP and cGMP accumulation in single isolated crypts were measured. The muscarinic receptor characteristics were determined in mucosal membrane preparations. The secretory response by the cAMP pathway (stimulated by vasoactive intestinal peptide or forskolin) and the cAMP accumulation in crypts were decreased (P < 0.05) after irradiation. The weak secretory response induced by the cGMP pathway (stimulated by nitric oxide or guanylin) was unaltered by radiation, and the small amount of cGMP determined in isolated crypts from the control group became undetectable in the irradiated group. Inducible NOS was not involved in the hyporesponsiveness to VIP after irradiation (there was no effect of an iNOS inhibitor). The secretory response by the Ca(2+)(i) pathway (stimulated by carbachol) was unaffected despite a decreased number and increased affinity of muscarinic receptors. The non-additivity of VIP and carbachol co-stimulated responses was unmodified. In contrast, VIP and SNP co-stimulation showed that NO enhanced the radiation-induced hyporesponsiveness to VIP through a reduced accumulation of cAMP in crypts. This study provides further understanding of the effect of ionizing radiation on the intracellular signaling pathways.
Morel
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Institut de Radioprotection et de Sûreté Nucléaire, Département de Protection de la santé de l'Homme et de Dosimétrie, Section Autonome de Radiobiologie Appliquée à la Médecine, IRSN, Fontenay aux Roses Cedex, France.
Dublineau
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I
Griffiths
N M
NM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D018679:Cholinergic Agonists / Q000494:pharmacology; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005768:Gastrointestinal Hormones / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009092:Mucous Membrane / Q000378:metabolism; D045265:Natriuretic Peptides; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; C072685:guanylin; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D002217:Carbachol; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP; D002118:Calcium