Mechanisms regulating spinal sympathetic output to the heart and vessels have been examined using the technique of intrathecal administration of neuroactive agents at T2 and/or T9 in the rat. Antagonists and/or agonists of glycine, GABA$ sb{ rm A},$ GABA$ sb{ rm B}$ and excitatory amino acid receptors have been studied to determine how the respective amino acids mechanisms function at the spinal level to regulate sympathetic output. The results indicated that glycine, GABA$ sb{ rm A},$ GABA$ sb{ rm B},$ novel GABA, D-baclofen-sensitive, NMDA and non-NMDA receptors are involved in regulation of sympathetic output at the spinal level. Glycine, GABA$ sb{ rm A},$ GABA$ sb{ rm B},$ NMDA and non-NMDA receptors also participate in regulation of arterial pressure and heart rate under basal conditions. As D-baclofen increases only arterial pressure, it is proposed that there is a differential distribution of some receptors on the sympathetic neurons innervating different end organs. In addition, as the antagonists strychnine and APV alter either heart rate or arterial pressure, it is proposed that different receptors differ in their degree of tonic activation.

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The effects of various steroid hormones on human chorionic gonadotropin (hCG) production and placental viability were investigated using an explant culture model of human placenta. / Placental hCG production was assessed using two different methods: (a) hCG concentrations in media recovered from cultures were measured by radioimmunoassay and (b) tissue levels of hCG in cultured placentae were determined immunohistochemically; both were evaluated before and after exposure to steroid hormones. In first trimester placentae, progesterone and dehydroepiandrosterone (DHEA) increased hCG concentrations both in collected medium and levels in cultured placentae. Estradiol increased the levels of hCG in tissues but not in media. Cortisol increased concentrations in media but did not alter tissue levels. Testosterone decreased hCG levels in media, but had no effect on hCG placental content. In third trimester cultures, progesterone and DHEA were the only hormones studied which increased concentrations of hCG in media; estradiol, cortisol and testosterone had no effect. Progesterone, estradiol and DHEA, alone or in combination, extended the viability of first trimester placental explant cultures from approximately 7 to 30 days. There was a significant relationship between placental viability and tissue hCG levels (r = 0.73, P $<$ 0.001). The concentrations of hCG, progesterone and estradiol in human placentae were determined at various times through gestation. These studies suggest that a temporal relationship exists between the placental levels of hCG and these steroids, and that they may be significant determinants of growth and differentiation of the placenta in vivo. Furthermore, these investigations support the hypothesis that hCG production by the placenta is subject to paracrine regulation by steroid hormones.

This thesis describes the modulatory effects of acetylcholine (ACh) on neuronal responsiveness in the primary somatosensory cortex of cats. In 52 anesthetized animals, the responses of 440 cells were studied in three series of experiments. In series 1, iontophoretic administration of various doses (7-200 nA) of ACh produced increased firing rates in 16% (33/203) of the neurons tested. Responses to somatic stimuli were modulated by ACh in 29% of the cases. These modulatory effects were predominantly excitatory, with only 5% of the cells being depressed by ACh. In series 2 and 3, 50 nA of ACh applied in the absence of other overt stimula altered the responsiveness of a cell to subsequent tactile stimulation or iontophoretically-applied glutamate. This occurred in 21% (13/61) of the cells. In contrast, when 50 nA of ACh was administered simultaneously with glutamate and/or receptive field stimulation, altered responsiveness occurred in 77% (76/99) of the cases. One-third (32/99) of these cells displayed prolonged changes in responsiveness, lasting from 7 min to over 1 h. / Cells modulated by ACh were found in all cortical layers. The percentage of cholinoceptive cells was highest in layer VI (78%), and was not less than 50% in any layer. Both long and short-term potentiating effects of ACh on responses to somatic stimulation and responses to glutamate administration could be reversibly blocked by low iontophoretic doses of atropine.

Quantal nicotinic transmission, from about half of the preganglionic inputs to the perfused rat superior cervical ganglion, was more potent and better sustained when activity was in short, high frequency bursts, rather than in continuous trains, regardless of train frequency. The advantage of short bursts was in producing post-tetanic potentiation, while limiting both depression of synaptic potential amplitude and increases in failure rate that were evident during long trains. Presynaptic bursting was also more effective in suppressing, via muscarinic and non-cholinergic mechanisms, the postganglionic cell afterhyperpolarization. This suppression allowed cells to fire at higher frequencies during bursts of depolarizing current pulses used to simulate nicotinic epsps. Burst patterning of activity was concluded to enhance ganglionic transmission via both pre and postsynaptic mechanisms. Presynaptic conduction block, possibly associated with accumulation of extracellular K$ sp+$, appeared to be partly responsible for the depression of quantal transmitter release during long trains.

Human subjects were asked to "fixate" an earth-stationary target, in complete darkness, either during or after a brief passive head rotation. During head rotation saccadic eye movements synergistically improved compensatory slow-phase vestibulo-ocular reflex (VOR) stabilization. Visual-vestibular conflict that adaptively attenuated VOR gain caused the combined saccadic and slow-phase response to undercompensate for head rotation. Saccades volitionally generated after the cessation of head rotation (Vestibular Memory-Contingent Saccades, VMCS), successfully acquired the earth-fixed target, indicating that perceived vestibular information has access to the saccade generating mechanism. The above adaptive stimulus contracted the amplitude of VMCSs, suggesting a commensurate modification of the percept of self-movement relative to space. VMCSs displayed a "range effect", slightly biasing all results towards the mid-range amplitude. A schema is proposed implicating the posterior parietal cortex in the perception of vestibular input, the control of gaze and their adaptive modification.

The aim of the study was to investigate the mechanisms of bronchoconstriction induced by dry gas hyperpnea challenge in the rat. The interaction of airway hyperresponsiveness to contractile agonists and the atopic constitution of the animals with responsiveness to hyperpnea challenge was also evaluated. A hyperresponsive strain, Fisher 344, two control normoresponsive strains, Lewis and ACI, and an atopic but normoresponsive rat, Brown Norway (BN) to dry gas hyperpnea challenge were studied. The effects of the NK1 (CP-99994), the NK2 (SR-48968) receptor antagonists, and the selective LTD4 receptor antagonist pranlukast on responses to hyperpnea challenge were examined in BN rats. The animals were anesthetized with xylazine and pentobarbital sodium intraperitoneally and mechanically ventilated with a tidal volume of 8 ml/kg and a frequency of 150 breaths/min for hyperpnea challenge. Pulmonary responses to challenge were measured in spontaneously breathing animals. Dry gas hyperpnea challenge was performed with a dry mixture of 5% CO2-95% O2 for 5 min whereas wet gas was humidified prior to administration. Bronchovascular leakage was assessed by quantitating Evans blue in bronchoalveolar lavage (BAL) fluid. (Abstract shortened by UMI.)

Platelet aggregation is mediated primarily by the binding of fibrinogen to its membrane receptor, GPIIb-IIIa, but such an interaction may not be sufficient to support aggregation. This question could potentially be resolved by reconstituting GPIIb-IIIa into a model membrane system. / A protocol was developed for the generation of liposomes containing purified GPIIb-IIIa. Flow cytometric techniques confirmed that the receptor was present in the lipid bilayer and were used to evaluate the characteristics of fibrinogen binding to the liposomes, which like fibrinogen-platelet interactions exhibited specificity, saturability, time-dependence, and calcium-dependence. / No fibrinogen-specific aggregation of GPIIb-IIIa-liposomes with stir or shear was observed, as determined by flow cytometric cell counting and microscopic examination of particles. In contrast, platelets rapidly formed large aggregates in the presence of fibrinogen. It thus appears that elements other than fibrinogen and GPIIb-IIIa play an important role in platelet aggregation.

$ beta$-Hexosaminidase (Hex) is an essential lysosomal enzyme whose absence in man results in a group of disorders, the G$ sb{ rm M2}$ gangliosidoses which includes Tay-Sachs and Sandhoff diseases. There are two major isoenzymes of Hex, Hex A ($ alpha beta$) and Hex B ($ beta beta$). / Two cell types, apical and narrow cells, in the initial segment of the rat epididymis immunolocalized Hex. Principal cells of the epididymis were intensely reactive for Hex only in the intermediate zone, caput and proximal corpus regions. Clear cells were reactive in the regions of the epididymis where they were found. Electron microscopic immunocytochemistry confirmed the presence of Hex in lysosomes of all reactive cells in the epididymis and of those in Sertoli cells and interstitial macrophages of the testis. / The regulation of Hex in the male reproductive tract was examined in the epididymides of rats at various ages after birth and of adult rats which were orchidectomized and treated with or without testosterone. / To study the impact of absence of Hex in the male reproductive tract, mouse models of human Tay-Sachs (Hexa $-$/$-$) and Sandhoff (Hexb $-$/$-$) diseases, created through gene targeted disruption of the $Hexa ( alpha$-subunit) and $Hexb ( beta$-subunit) genes respectively, were examined. (Abstract shortened by UMI.)

Neural, humoral and mechanical factors affecting cardiac function and the peripheral vasculature were examined to assess the relative importance of peripheral vs cardiac factors in the control of cardiac output during exercise. First, I examined neural vs local regulation of humoral vasoconstrictors endothelin-1 (ET) and NPY, in anesthetized dogs, and showed that plasma ET levels, in contrast to NPY, increase in response to systemic hypotension but not carotid sinus baroreceptor activation. This did not occur with intact vagi suggesting an interaction of neural and humoral factors. In the next two studies I separated peripheral vascular and cardiac neural influences on cardiac output (CO) and right atrial pressure (Pra) responses during graded exercise by comparing cardiac denervated heart transplant patients (HT) with normally innervated subjects. The increase in Pra was higher in HT than normals but stabilized as the CO increased at peak effort. Stimulation of the heart with dobutamine in 2 patients did not increase exercise capacity, suggesting that peripheral not cardiac factors limit exercise in HT patients. The rise in central venous pressure at exercise onset was similar in both groups which demonstrates the importance of the mechanical effect of muscle contraction vs reflex changes in mobilizing blood from the peripheral vasculature at exercise onset. In the fourth study I assessed whether large changes in human body mass, induced by isolated gastric bypass surgery, would affect the heart rate (HR)/oxygen consumption (VO2) relationship during exercise. Peak absolute VO2 was significantly lower in the previously obese group vs obese and control groups despite similar normalized 24-hour energy expenditure. HR was higher in the previously obese at a given submaximal VO2 due to the higher relative VO2, suggesting a significant loss of muscle mass and supporting the idea that HR is a function of the relative VO2. In the fifth study I assessed the influence of