Steven L. Bealer - US grants

The along objectives of this research project are to understand the mechanisms through which dietary sodium modifies baroreflex sensitivity. Increasing sodium ingestion reverse facilitation of cardiac and neural baroreflex responses induced by acute, moderate sodium loading. The hypothesis to be tested is that: Increased sodium ingestion sensitizes central sympathoadrenal circuits, so acute increases in plasma sodium, acting at or through neurons and alpha-adrenoreceptors in the median preoptic nucleus, increases cardiac and neural sympathetic tone, overrides the sympathoinhibitor effects of vasopressin, and reduces baroreflex sensitivity. The specific aims addressed will determine the effects of increased sodium ingestion on; 1) the contribution of the sympathetic and parasympathetic systems to cardiac baroreflex responses during acute sodium loading, 2) sympathoadrenal activation and neural baroreflex responses during acute sodium loading, 3) the sympathoinhibitory effects of vasopressin on baroreflex function, and the role of 4) neurons and 5) alpha-adrenergic receptors in the median preoptic nucleus in mediating baroreflex sensitivity during acute, moderate sodium loading, 3) the sympathoinhibitory effects of vasopressin on baroreflex function, and the role of 4) neurons, and 5) alpha-adrenergic receptors in the median preoptic nucleus in mediating baroreflex sensitivity during acute, moderate sodium loading. These studies will directly measure blood pressure, heart rate, renal sympathetic nerve activity, and lumbar nerve activity in conscious, unrestrained rats during baroreflex testing before and following acute, moderate sodium loading. In addition, plasma concentrations of vasopressin and norepinephrine will be measured before and following acute sodium loading. Data from animals on a normal sodium diet will be compared to rats provided isotonic saline as the sole drinking fluid to increase dietary sodium for three weeks. The role of neurons and alpha-adrenergic receptors in the median preoptic nucleus will be evaluated by comparing responses of control animals to responses from rats given neurotoxic lesions of this brain area, or treated with selective alpha-adrenergic antagonists prior to testing. Defining these mechanisms will add to our understanding of some cardiovascular pathologies. For example, diminished baroreflex buffering may directly contribute to, or at least by permissive in, the establishment of chronic, salt-induced hypertension in experimental animals and in susceptible humans. In addition, reduced cardiac baroreflex responses, characterized by increased sympathetic dominance, as an independent risk factor for sudden death and cardiac arrhythmias. Therefore, increased sodium ingestion may increase risk for arrhythmias by decreasing baroreflex sensitivity and increasing cardiac sympathetic function. The work will be performed in the Department of Physiology, University of Tennessee, Memphis, TN 38163.

DESCRIPTION (provided by applicant): The overall objective of this research project is to characterize the autoregulatory functions of central oxytocin (OT) on systemic OT release during reproductive states. OT is released during parturition to aid in uterine contraction, and OT secretion during nursing is essential for milk delivery and normal growth of the offspring. Recent studies find that the central OT system is activated during gestation, and participates in behavioral, anatomical, and physiological adaptations, which contribute to successful lactation. We have found that OT receptor (OTR) binding increases during gestation, and that blockade of OTR, only during gestation, decreases milk delivery to suckling offspring, resulting in reduced weight gain. However, the mechanism(s) by which OTR blockade during gestation diminishes lactational efficiency is unknown. We will test the HYPOTHESIS that OTR stimulation during gestation is required for genetic and electrophysiological adaptations necessary for 1) increased OT synthesis and 2) OT neuron sensitivity required for adequate milk delivery in response to suckling. To test this proposal, the SPECIFIC AIMS are to determine the effects of OTR blockade DURING GESTATION on; 1) OT binding in magnocellular nuclei, 2) OT mRNA in magnocellular nuclei and OT content in the neural lobe during gestation and mid-lactation, 3) development of OT neuron membrane and synaptic adaptations characteristic of lactation, and 4) response sensitivity of OT neurons to suckling and administration of excitatory neurotransmitters. These Aims will be addressed using receptor autoradiography, biochemical measures of OT mRNA, radioimmunoassay of OT in neural lobe, dialysate, and plasma, microdialysis, electrophysiological evaluation of isolated OT cells and in hypothalamic slices, and activation of c-fos in OT neurons. These measures will be performed on virgin animals, and pregnant animals following central administration of an OT antagonist or vehicle during mid-late gestation. Increasing efficiency of lactation to ensure adequate infant growth will increase the number of breast fed infants to recommended levels, which will decrease the incidence and severity of a wide range of illnesses and pathologies.