Impaired autofeedback regulation of hypothalamic norepinephrine release in experimental uremia.
Chronic renal failure (CRF) is associated with multiple hypothalamic dysfunctions, including reduced secretion of gonadotropin-releasing hormone (GnRH). Because GnRH release is tightly controlled by sympathetic neuronal input, a possible alteration of local noradrenergic neurotransmission in experimental CRF was evaluated. Basal, stimulated, and autoinhibited norepinephrine (NE) release was assessed in hypothalamic and hippocampal tissue slices obtained from 5/6-nephrectomized and control rats. Autoinhibition-free NE release from brain slices, prelabeled with [3H]NE and superfused with physiologic buffer, was stimulated by six electrical pulses, 100 Hz (pseudo-one-pulse stimulation). Autoinhibited NE release was induced by 90 pulses at 3 Hz. The release of tritiated NE was measured upon addition of increasing concentrations of unlabeled NE to exogenously activate the inhibitory alpha2-autoreceptor. Although neither basal nor stimulated NE release differed between the groups, significantly lower pIC50 and Imax estimates of the concentration-response curves of exogenous NE on [3H]NE release were observed in CRF rats, suggesting a diminished autoinhibition of hypothalamic noradrenergic terminals in CRF. Western blotting of tissue homogenates disclosed a significantly reduced abundance of alpha2-autoreceptor protein in hypothalamic tissue from CRF rats. These abnormalities were selectively observed in the hypothalamus, whereas noradrenergic autoinhibition seemed unaltered in the hippocampus. The results suggest a diminished autoinhibition of hypothalamic NE release in CRF. Although impaired hypothalamic NE autoinhibition does not explain reduced GnRH secretion in CRF, it may be involved in the pathogenesis of sympathetic hyperactivity associated with this condition.
Klein
Katrin
K
University Children's Hospital, Im Neuenheimer Feld 150, Heidelberg 69120, Germany.
Daschner
Markus
M
Vogel
Marcel
M
Oh
Jun
J
Feuerstein
Thomas J
TJ
Schaefer
Franz
F
D000818:Animals; D025461:Feedback, Physiological / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009638:Norepinephrine / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000503:physiopathology*
D009638:Norepinephrine