Impaired autofeedback regulation of hypothalamic norepinephrine release in experimental uremia

TY - JOUR

T1 - Impaired autofeedback regulation of hypothalamic norepinephrine release in experimental uremia

AU - Klein, Katrin

AU - Daschner, Markus

AU - Vogel, Marcel

AU - Oh, Jun

AU - Feuerstein, Thomas J

AU - Schaefer, Franz

PY - 2005/7

Y1 - 2005/7

N2 - 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.

AB - 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.

KW - Animals

KW - Feedback, Physiological/physiology

KW - Homeostasis/physiology

KW - Hypothalamus/metabolism

KW - Male

KW - Norepinephrine/biosynthesis

KW - Rats

KW - Rats, Sprague-Dawley

KW - Uremia/physiopathology

U2 - 10.1681/ASN.2004100830

DO - 10.1681/ASN.2004100830

M3 - SCORING: Journal article

C2 - 15829712

VL - 16

SP - 2081

EP - 2087

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 7

ER -