Modulation of heme oxygenase/carbon monoxide system affects the inhibitory neurotransmission involved in gastrointestinal motility of streptozotocin-treated diabetic rats.
Alterations in gastrointestinal motility of diabetic patients have been linked to degenerative changes induced by glucose abnormalities in the peripheral nervous system. The heme oxygenase/carbon monoxide (HO/CO) signalling represents one of the non-adrenergic/non-cholinergic (NANC) neurotransmission pathways involved in regulation of physiological peristalsis. To investigate the role of HO/CO system in intestinal motility under diabetic conditions, the response to electrical field stimulation (EFS) and western blot analysis of HO/CO pathway components were studied on duodenum longitudinal smooth muscle strips isolated from streptozotocin (STZ)-treated diabetic rats (65 mg kg(-1), i.p.) and respective controls (CTRL), 6 weeks after the onset of diabetes. When compared to CTRL, the ability of CO releasing molecule (CORM-3) (100-400 micromol L(-1)) to enhance NANC relaxation was significantly impaired in STZ-treated rats (P < 0.05). Conversely, in vitro incubation with the HO inhibitor ZnPPIX (10 micromol L(-1), 60 min) significantly reduced EFS-induced relaxation in CTRL (P < 0.05), but not in STZ-treated rats. Interestingly, the ability of ZnPPIX to inhibit EFS-induced relaxation was partially restored in STZ-treated rats co-administered in vivo with the HO-1 inducer cobalt protoporphyrin IX (CoPPIX) (0.5 mg per 100 g body weight weekly). Expression of inducible HO-1 protein was increased in homogenates from STZ-treated rats (vs CTRL, P < 0.01), and further increased in STZ-treated rats receiving CoPPIX (P < 0.05). Taken together, our data underline the essential role of HO/CO system in regulation of inhibitory NANC neurotransmission in the duodenum and suggest that dysregulation of HO/CO activity may represent one mechanism by which gastrointestinal motility is altered in diabetes.
Piepoli
A L
AL
Department of Pharmacology and Human Physiology, Medical School, University of Bari, Bari, Italy.
de Salvatore
G
G
Lemoli
M
M
de Benedictis
L
L
Mitolo-Chieppa
D
D
de Salvia
M A
MA
D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism*; D048909:Diabetes Complications / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)