Figure 4

P-glycoprotein activity regulation at the blood–brain barrier through activation of endothelin-1 signaling. Twenty-hours after endothelin-1 (ET-1) intracerebroventricular (icv) treatment, digoxin, a P-glycoprotein (P-gp) substrate, was administered intravenously in adult brain (A) and juvenile brain (B) during four hours (steady state (ss) achievement) at a concentration of 1 mg/kg/h. At the end of the infusion period, blood was sampled, brain was isolated and the administered substrate was quantified using mass spectrometry. P-gp transport activity was estimated by the ratio between the substrates’ unbound brain concentrations and unbound plasma concentrations_. Unbound plasma digoxin concentration in adult (C) and juvenile rat (D) was also calculated. ET-1 induces an enhanced transporter activity of P-gp at the adult blood–brain barrier (BBB), whereas no significant change occurred in P-gp activity at the juvenile BBB. Data represent the mean concentration for five rat brains/plasma. Variability is given by bars ± S.E.M. Data were analyzed using Student’s t-test. Statistical comparisons: *P <0.05.