Role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage in rats.
OBJECTIVE
Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy. Activation of ATP-sensitive potassium channels (K(ATP)) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage.


METHODS
Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.


RESULTS
Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.


CONCLUSIONS
Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/K(ATP) pathway.
Medeiros
J V R
JV
Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceara, Brazil.
Gadelha
G G
GG
Lima
S J
SJ
Garcia
J A
JA
Soares
P M G
PM
Santos
A A
AA
Brito
G A C
GA
Ribeiro
R A
RA
Souza
M H L P
MH
D000818:Animals; D001120:Arginine / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D003981:Diazoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010438:Peptic Ulcer Hemorrhage / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013276:Stomach Ulcer / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D054086:KATP Channels; D010069:Oxadiazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D011687:Purines; D011810:Quinoxalines; D013450:Sulfones; D009569:Nitric Oxide; D000431:Ethanol; D001120:Arginine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D005978:Glutathione; D006152:Cyclic GMP; D003981:Diazoxide; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester