Increased brain uptake and brain to blood efflux transport of 14C-GABA in spontaneously hypertensive rats

Abstract

The brain uptake and brain to blood efflux transport of 14C-GABA were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats using 20 min bilateral in situ brain perfusion in rats anesthetized using urethane. The volume of distribution (Vd) of 14C-GABA into cerebrospinal fluid (CSF) and brain regions (cortex, diencephalon, cerebellum, and brain stem) was significantly greater in SHR than in the corresponding regions in WKY rats ( p < 0.05). The estimated Vd value of 14C-GABA in CSF of SHR was 3.4 fold greater than that in WKY. Also compared to WKY, the Vd of 14C-GABA into cerebellum and cortex of SHR was 15.3 fold and 19.4 fold greater, respectively. Although the study of blood–brain barrier (BBB) integrity using 3H-mannitol revealed increased paracellular permeability at the brain capillaries of SHR when compared to WKY rats, this was found to be only partially responsible for the increased 14C-GABA uptake. The study of brain to blood efflux transport of 14C-GABA (after loading of brain with 14C-GABA by vascular perfusion) revealed that the half-time of elimination was significantly shorter in SHR (5.35 ± 0.66 min) than in WKY rats (14.83 ± 1.94 min), ( p < 0.001). HPLC analysis revealed that GABA concentrations in brain extracts and CSF of SHR were similar to those in WKY rats ( p > 0.05). The faster efflux in SHR might be, at least partially, responsible to compensate for increased uptake of this neurotransmitter and to preserve the protective function of BBB towards GABA. The protective function of the BCSFB towards GABA appears to be also preserved, since systemic infusion of GABA within a wide range of administered doses (0.004–5.00 mg/kg) produced an increase in GABA CSF concentration from around 0.5 μM to only 11 μM, and the obtained pattern of CSF GABA concentrations under these conditions did not differ between SHR and WKY rats, as revealed by HPLC.