title: Tacrolimus ameliorates cerebral vasodilatation and intracranial hypertension in the rat with portacaval anastomosis and hyperammonemia.
abstract: Arterial hyperammonemia and cerebral vasodilatation correlate with cerebral herniation in patients with fulminant hepatic failure (FHF). Tacrolimus is a calcineurin inhibitor that passes the blood-brain barrier and may increase cerebrovascular tone and restrict cerebral ammonia influx. In this study, we determined if tacrolimus prevents cerebral vasodilatation and high intracranial pressure (ICP) in the rat with portacaval anastomosis (PCA) challenged to high arterial ammonia (NH4+) concentration. Seven groups of mechanically ventilated rats, with 6-9 rats in each group, were investigated within 48 hours after construction of a PCA (4 groups) or after sham operation (3 groups). Three groups of the rats received infusion of NH4+ and 4 groups received saline for approximately 180 minutes. Two groups of the PCA rats receiving either NH4+ or saline had an i.v. injection of tacrolimus (0.4 mg/kg) or vehicle before start of NH4+ or saline infusion. Cerebral blood flow (CBF) was monitored by a laser Doppler probe in brain cortex. ICP was monitored by placement of a catheter in the cerebrospinal fluid. CBF and ICP increased in PCA rats receiving NH4+ infusion compared to PCA controls and to all groups of sham-operated animals (P <.05). In the group of PCA rats pre-treated with tacrolimus before receiving ammonia infusion, the increase in ICP was ameliorated compared to the ammonia infused group receiving vehicle (P <.03). Tacrolimus also prevented an increase in CBF in the PCA group receiving NH4+ (P <.05) compared to the control groups. In conclusion, Tacrolimus prevents cerebral vasodilatation and ameliorates intracranial hypertension in PCA rats receiving NH4+ infusion. These findings indicate that tacrolimus could be of clinical value in the prevention of cerebral hyperemia, high ICP, and serious brain damage in patients with FHF.
authors.affiliation: Department of Hepatology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dethloff
authors.forename: Bent Adel
authors.initials: BA
authors.lastname: Hansen
authors.forename: Fin Stolze
authors.initials: FS
authors.lastname: Larsen
mesh_terms: D000714:Anastomosis, Surgical; D000818:Animals; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000097:blood; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D019586:Intracranial Hypertension / Q000188:drug therapy*; D008297:Male; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D011169:Portal Vein / Q000601:surgery*; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000627:therapeutic use*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014682:Vena Cava, Inferior / Q000601:surgery*
chemical_list: D000644:Quaternary Ammonium Compounds; D002245:Carbon Dioxide; D010100:Oxygen; D016559:Tacrolimus