Hippocampal mitochondrial dysfunction with decreased mtNOS activity in prehepatic portal hypertensive rats.
Portal hypertension is a major complication of human cirrhosis that frequently leads to central nervous system dysfunction. In our study, rats with prehepatic portal hypertension developed hippocampal mitochondrial dysfunction as indicated by decreased respiratory rates, respiratory control and mitochondrial nitric oxide synthase (mtNOS) activity in mitochondria isolated from the whole hippocampus. Succinate-dependent respiratory rates decreased by 29% in controlled state 4 and by 42% in active state 3, and respiratory control diminished by 20%. Portal hypertensive rats showed a decreased mtNOS activity of 46%. Hippocampal mitochondrial dysfunction was associated with ultrastructural damage in the mitochondria of hippocampal astrocytes and endothelial cells. Swollen mitochondria, loss of cristae and rupture of outer and inner membrane was observed in astrocytes and endothelial cells of the blood-brain barrier in parallel with the ammonia gradient. It is concluded that the moderate increase in plasma ammonia that followed portal hypertension was the potential primary cause of the observed alterations.
Lores-Arnaiz
Silvia
S
Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina. slarnaiz@ffyb.uba.ar
Perazzo
Juan Carlos
JC
Prestifilippo
Juan Pablo
JP
Lago
Néstor
N
D'Amico
Gabriela
G
Czerniczyniec
Analía
A
Bustamante
Juanita
J
Boveris
Alberto
A
Lemberg
Abraham
A
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D006975:Hypertension, Portal / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D010101:Oxygen Consumption / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000097:blood / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D009419:Nerve Tissue Proteins; D000644:Quaternary Ammonium Compounds; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat