Late, but not early, inhibition of soluble guanylate cyclase decreases mortality in a rat sepsis model.
Overproduction of nitric oxide and activation of soluble guanylate cyclase (sGC) are important in sepsis-induced hypotension and hyporesponsiveness to vasoconstrictors. A time course of the expression and activity of sGC in a sepsis model [cecal ligation and puncture (CLP)] was evaluated in rats. Soluble GC alpha-1 and beta-1 subunit mRNA levels increased in the lungs, but not in the aorta. However, in both tissues, the protein levels increased 24 h after sepsis and remained high for up to 48 h. Sodium nitroprusside-stimulated cGMP accumulation was higher 48 h after CLP in the lung and aorta. NOS-2 protein expression peaked 24 h after CLP, decreasing thereafter. The impact of inhibiting the expression of sGC early (8 h) or late (20 h) on vascular reactivity and the indexes of organ damage and mortality were also studied. Late administration of methylene blue (MB) or ODQ (1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one) restored the blood pressure and vascular responsiveness to vasoconstrictors to normal levels but was ineffective in early sepsis. Late MB injection reduced the plasma levels of urea, creatinine, and lactate. MB improved the survival if administered late, but it increased the mortality when administrated early after sepsis onset. The increased sGC expression/activity may be relevant for the late hypotension and hyporesponsiveness to vasoconstrictors in sepsis. In accordance, MB increased survival if administered in late sepsis, but not in early sepsis. Therefore, differential responsiveness to sGC during the course of sepsis may determine the success or failure of treatment with sGC inhibitors.
Fernandes
Daniel
D
Department of Pharmacology, University Campus, Trindade, Biological Sciences Centre, Block "D," Florianopolis, Santa Catarina 88049-900, Brazil.
Sordi
Regina
R
Pacheco
Letícia Kramer
LK
Nardi
Geisson Marcos
GM
Heckert
Bettina Tomio
BT
Villela
Christina Gaspar
CG
Lobo
Amanda Revoredo
AR
Barja-Fidalgo
Christina
C
Assreuy
Jamil
J
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002432:Cecum / Q000473:pathology / Q000601:surgery; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000235:genetics; D008751:Methylene Blue / Q000627:therapeutic use; D009026:Mortality; D010069:Oxadiazoles / Q000627:therapeutic use; D011810:Quinoxalines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000201:enzymology* / Q000401:mortality; D014661:Vasoconstriction / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D012333:RNA, Messenger; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue