Experimental uremia affects hypothalamic amino acid neurotransmitter milieu

Chronic renal failure is associated with delayed puberty and hypogonadism. To investigate the mechanisms subserving the reported reduced pulsatile rel ease of gonadotropin-releasing hormone (GnRH) in chronic renal failure, thi s study examined the amino acid neurotransmitter milieu in the medial preop tic area (MPOA), the hypothalamic region where the GnRH-secreting neurons r eside, in 5/6-nephrectomized male rats and in ad libitum-fed or pair-fed co ntrols. All rats were castrated and received either a testosterone or a veh icle implant to evaluate additional effects of the prevailing sex steroid m ilieu. Local excitatory (essential amino acids: aspartate, glutamate) and i nhibitory (gamma -aminobutyric acid [GABA], taurine) amino acid transmitter outflow in the MPOA was measured by microdialysis via stereotactically imp lanted cannulae in the awake, freely moving rats. In addition to basal extr acellular concentrations, the neurosecretory capacity was assessed by the a ddition of 100 mM KCl to the dialysis fluid. The mechanisms of neurosecreti on were evaluated further by inhibition vesicular release with the use of C a2+-free, Mg2+-enriched dialysis fluid and by local perfusion with inhibito rs of voltage-dependent synaptic release(1 muM tetrodotoxin) and of GABA re uptake (0.5 mM nipecotic acid). In the uremic rats, basal outflow of GABA, glutamate and aspartate, and K+-stimulated aspartate outflow were increased . K+-stimulated GABA and glutamate release was less sensitive to Ca2+ deple tion in the uremic than in the control rats. The elevated basal GABA and es sential amino acid outflow in the uremic rats was due to a voltage- and Ca2 +-independent mechanism. GABA reuptake was inhibited proportionately by nip ecotic acid in uremic and pair-fed control rats. Testosterone supplementati on had no independent effects on neurotransmitter outflow. In summary, the amino acid neurotransmitter milieu is altered in the MPOA of uremic rats by a nonsynaptic, nonvesicular mechanism. These abnormalities may contribute to the impaired function of the GnRH pulse generator.