Nitric oxide-cyclic GMP contributes to abnormal activation of Na+-K+-ATPase in the aorta from rats with endotoxic shock.
We examined pharmacologically the influence of nitric oxide (NO), guanosine 3':5'-cyclic monophosphate (cyclic GMP), adenine 3':5'-cyclic monophosphate (cyclic AMP), and protein kinase C-linked signaling pathways on relaxation to potassium in aortic segments isolated from rats treated for 6 h with bacterial endotoxin (lipopolysaccharide). Endotoxemia for 6 h was associated with a severe hypotension and vascular hyporeactivity to norepinephrine (NE), and an increase in plasma NO in vivo and aortic NO ex vivo. The NE-induced contraction was attenuated and the potassium-induced relaxation was accentuated in the aorta of rats with endotoxic shock. Ouabain inhibited the potassium-induced relaxation in aortae from normal and endotoxemic rats. 8-Bromo-cyclic GMP significantly enhanced the potassium-induced relaxation in control aortae, whereas 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) abolished this difference between normal and endotoxemic rats. In contrast, inhibition of potassium-induced relaxation was observed in aortae from normal and endotoxemic rats treated with 8-bromo-cyclic AMP or phorbol 12-myristate 13-acetate. Individually, inhibitors of protein kinase A or protein kinase C did not significantly alter relaxation to potassium; however, in combination, these inhibitors significantly potentiated relaxation in aortae from control rats. These results suggest that activity of Na(+)-K(+)-ATPase is enhanced in the vascular bed of animals with endotoxic shock and that this elevation in activity is mediated by NO-cyclic GMP, but not by cyclic AMP-protein kinase A or protein kinase C.
Chen
Shiu-Jen
SJ
Departments of Physiology, National Defense Medical Center, Taipei, Republic of China, Taiwan. ccwu@mail.ndmctsgh.edu.tw
Chen
Kao-Hsiang
KH
Wu
Chin-Chen
CC
D000818:Animals; D001011:Aorta / Q000201:enzymology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000378:metabolism; D004731:Endotoxins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011188:Potassium / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D012772:Shock, Septic; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004731:Endotoxins; D004791:Enzyme Inhibitors; D009566:Nitrates; D010069:Oxadiazoles; D011810:Quinoxalines; D009569:Nitric Oxide; D010042:Ouabain; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium