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Effect of standing on neurohumoral responses and plasma volume in healthy subjects

Upright posture leads to rapid pooling of blood in the lower extremities and shifts plasma fluid into surrounding tissues. This results in a decrease in plasma volume (PV) and in hemoconcentration. There has been no integrative evaluation of concomitant neurohumoral and PV shifts with upright posture in normal subjects. We studied 10 healthy subjects after 3 days of stable Na+ and K+ intake. PV was assessed by the Evans blue dye method and by changes in hematocrit. Norepinephrine (NE), NE spillover, epinephrine (Epi), vasopressin, plasma renin activity, aldosterone, osmolarity, and kidney response expressed by urine osmolality and by Na+ and K+ excretion of the subjects in the supine and standing postures were all measured. We found that PV fell by 13% (375 +/- 35 ml plasma) over approximately 14 min, after which time it remained relatively stable. There was a concomitant decrease in systolic blood pressure and an increase in heart rate that peaked at the time of maximal decrease in PV. Plasma Epi and NE increased rapidly to this point. Epi approached baseline by 20 min of standing. NE spillover increased 80% and clearance decreased 30% with 30 min of standing. The increase in plasma renin activity correlated with an increase in aldosterone. Vasopressin increased progressively, but there was no change in plasma osmolarity. The kidney response showed a significant decrease in Na+ and an increase in K+ excretion with upright posture. We conclude that a cascade of neurohumoral events occurs with upright posture, some of which particularly coincide with the decrease in PV. Plasma Epi levels may contribute to the increment in heart rate with maintained upright posture.

Non-NASA Center

Kinetics, Ca2+ dependence, and biophysical properties of integrin-mediated mechanical modulation of transmitter release from frog motor nerve terminals

Neurotransmitter release from frog motor nerve terminals is strongly modulated by change in muscle length. Over the physiological range, there is an approximately 10% increase in spontaneous and evoked release per 1% muscle stretch. Because many muscle fibers do not receive suprathreshold synaptic inputs at rest length, this stretch-induced enhancement of release constitutes a strong peripheral amplifier of the spinal stretch reflex. The stretch modulation of release is inhibited by peptides that block integrin binding of natural ligands. The modulation varies linearly with length, with a delay of no more than approximately 1-2 msec and is maintained constant at the new length. Moreover, the stretch modulation persists in a zero Ca2+ Ringer and, hence, is not dependent on Ca2+ influx through stretch activated channels. Eliminating transmembrane Ca2+ gradients and buffering intraterminal Ca2+ to approximately normal resting levels does not eliminate the modulation, suggesting that it is not the result of release of Ca2+ from internal stores. Finally, changes in temperature have no detectable effect on the kinetics of stretch-induced changes in endplate potential (EPP) amplitude or miniature EPP (mEPP) frequency. We conclude, therefore, that stretch does not act via second messenger pathways or a chemical modification of molecules involved in the release pathway. Instead, there is direct mechanical modulation of release. We postulate that tension on integrins in the presynaptic membrane is transduced mechanically into changes in the position or conformation of one or more molecules involved in neurotransmitter release, altering sensitivity to Ca2+ or the equilibrium for a critical reaction leading to vesicle fusion.

Non-NASA Center

Afferent projections to the mammillary complex of the rat, with special reference to those from surrounding hypothalamic regions

To better understand the functional organization of the mammillary nuclei, we investigated the afferents to this nuclear complex in the rat with iontophoretically injected wheat germ agglutinin conjugated to horseradish peroxidase. Particular attention was paid to tracing local hypothalamic afferents to these nuclei. Injections into the medial mammillary nucleus (MMN) revealed strong projections from the subicular region, and weaker projections from the prefrontal cortex, medial septum, and the nucleus of the diagonal band of Broca. Other descending subcortical projections to the MMN arise from the anterior and the lateral hypothalamic area, the medial preoptic area, and the bed nucleus of the stria terminalis. Ascending afferents to the MMN were found to originate in the raphe and various tegmental nuclei. Following all injections into the MMN, labelled neurons were found in nuclei surrounding the mammillary body. The lateral and posterior subdivisions of the tuberomammillary nucleus projected mainly to the pars medianus and pars medialis of the MMN. The dorsal and ventral premammillary nuclei projected to the pars lateralis of the MMN. The supramammillary nucleus at rostral level had a small projection to the pars medialis and lateralis of the MMN. However, the most obvious projection from this nucleus was to the pars posterior of the MMN, chiefly from the lateral part of the caudal supramammillary nucleus. Injections into the lateral mammillary nucleus revealed inputs from the presubiculum, parasubiculum, septal region, dorsal tegmental nucleus, dorsal raphe nucleus, and periaqueductal gray. In addition, the lateral mammillary nucleus was found to receive a moderate projection from the medial part of the supramammillary nucleus and stronger projections from the lateral part of the caudal supramammillary nucleus. A very light projection was also seen from the lateral and posterior subdivisions of the tuberomammillary nucleus. These findings add to our knowledge of the extensive and complex connectivity of the mammillary nuclei. In particular, the local connections we have demonstrated with the supramammillary and tuberomammillary nuclei indicate the existence of significant local circuits as well as circuits involving more distant brain regions such as the septal nuclei, subiculum, prefrontal cortex, and brain stem tegmentum.

Non-NASA Center