Influence of soluble guanylate cyclase inhibition on inflammation and motility disturbances in DSS-induced colitis.
Nitric oxide (NO) has been associated with a spectrum of harmful to protective roles in inflammatory bowel disease. The involvement of soluble guanylate cyclase (sGC)--the downstream effector of NO--in the negative effect of NO in inflammatory models has been proposed but this has not been evaluated in inflammatory bowel diseases. The present study investigates therefore the influence of colonic inflammation on sGC activity, as well as the effect of in vivo sGC inhibition on colonic inflammation and on in vitro changes in colonic motility in the dextran sulfate sodium (DSS)-model of colitis in rat. Administration of 7% DSS in the drinking water for 6 days resulted in colonic inflammation as judged from histology and myeloperoxidase activity, accompanied by weight loss and bloody stools. Plasma and colonic tissue cyclic guanosine 3',5'-monophosphate (cGMP) levels were decreased in DSS-treated rats. Colonic levels of neuronal NO synthase (nNOS) mRNA and immunoreactivity were not influenced, while those of inducible NO synthase (iNOS) and colonic nitrite/nitrate levels were increased by DSS exposure. Circular muscle strips from inflamed distal colon showed decreased inhibitory responses towards electrical field stimulation and exogenous NO, while methacholine-induced phasic activity was suppressed. Inhibition of sGC by in vivo treatment with ODQ further reduced cGMP levels but did not prevent the inflammation and motility alterations. These results suggest that DSS-induced colitis in rats is accompanied by a reduced sensitivity of sGC, leading to reduced basal cGMP levels and decreased colonic responsiveness towards nitrergic stimuli, but pharmacological reduction of cGMP generation does not prevent the development of DSS-induced colitis.
Van Crombruggen
Koen
K
Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 900 Ghent, Belgium.
Van Nassauw
Luc
L
Demetter
Pieter
P
Cuvelier
Claude
C
Timmermans
Jean-Pierre
JP
Lefebvre
Romain A
RA
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000503:physiopathology*; D006152:Cyclic GMP / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D000071756:Soluble Guanylyl Cyclase
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D010069:Oxadiazoles; D011810:Quinoxalines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D016264:Dextran Sulfate; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP