Yuki Niimi

Effect of heat stress on muscle sympathetic nerve activity in humans.

To elucidate the effect of heat stress on the sympathetic nervous system, we evaluated changes in muscle sympathetic nerve activity (MSNA), plasma arginine vasopressin (AVP), tympanic temperature, skin blood flow, cardiac output, mean blood pressure, and heart rate in 9 subjects in response to acute heat stress induced by raising the ambient temperature from 29 to 34 degrees C and then to 40 degrees C. With the heat exposure, MSNA was significantly increased with a significant increase in tympanic temperature. Skin blood flow and heart rate were also significantly increased, while mean blood pressure tended to decline and cardiac output tended to increase. The combination of the increased MSNA and skin blood flow may have caused the redistribution of the circulatory blood volume from the muscles to the skin, facilitating convection heat loss. The increases in MSNA counteracted the lowered blood pressure during heat exposure. Thus, the increased MSNA may play an important role both in thermoregulation and in the maintenance of blood pressure against heat stress.

Clinical and physiological characteristics of autonomic failure with Parkinson's disease

We analyzed the clinical and physiological features of autonomic failure with Parkinsons disease (AF-PD) in seven patients and compared them with those of autonomic failure with multiple system atrophy (AF-MSA). In AF-PD, parkinsonism was more gradually progressive than in AF-MSA, and symptoms were responsive to L-dopa. All seven patients with AF-PD had orthostatic hypotension, postprandial hypotension, and constipation, but no urinary retention. Of these, three had hypohidrosis and five had frequent urination; five patients had subnormal plasma norepinephrine (NE) concentrations. Supersensitivity to NE infusion was observed in all patients. Head-up tilting (HUT) test resulted in no increase of plasma NE concentrations in both groups, but a significant increase of the plasma arginine vasopressin (AVP) concentrations in the patients with AF-PD. Urodynamic studies revealed that urinary bladder function was relatively well preserved in AF-PD in contrast to AF-MSA. In conclusion, there exists some clinical and physiological differences in autonomic features between AF-PD and AF-MSA, and postganglionic involvement predominates in AF-PD.

Syncopal attack alters the burst properties of muscle sympathetic nerve activity in humans.

This study aimed at examining whether the properties of microneurographically recorded muscle sympathetic nerve activity (MSNA) were altered during hypotensive attacks. A retrospective study was performed on 74 subjects who participated in tilt studies when vasodepressive syncope was induced incidentally in six subjects. The specific features of MSNA that distinguish this activity from skin sympathetic nerve activity are (1) rhythmic pulse synchronous burst discharge, (2) a duration of approximately 150-300 ms, and (3) no response to arousal stimuli were abolished during the syncopal attack. The altered features observed during the syncopal attack in these six subjects were (1) scattered reflex latencies of MSNA peak from the ECG R-wave, (2) elongated burst duration twice to five times as long as that in conscious state, and (3) response to arousal stimuli. The reduced input from the baroreceptors due to suppression on the central sympathetic volley proximal to the nucleus tractus solitarius might be attributed to the lost features characteristic of MSNA.

Tissue distribution of pathological lesions and Hu antigen expression in paraneoplastic sensory neuronopathy

Abstract We investigated the distribution of lesions and Hu antigen expression in two autopsied cases of anti-Hu antibody-positive paraneoplastic sensory neuronopathy (carcinomatous subacute sensory neuropathy). Pathological changes in both patients were limited to the primary sensory neurons, some of the sympathetic ganglia and hippocampal regions. The lesions showed a multifocal distribution that differed among the spinal segmental levels and in the individual dorsal root ganglia as well as in the nerve fascicles. Western blot analysis of the patients’ serum revealed that Hu antigens were extensively and widely expressed throughout the central nervous system, sensory and sympathetic ganglia and cancer cells, but not in the non-neural visceral tissues. Reverse transcriptase-polymerase chain reaction also showed that the Hu D, Hu C, Hel-N1 and Hel-N2 mRNAs were extensively and widely expressed through the neural tissues and cancer cells, but not in the visceral tissues. Thus, the distribution of antigen expression was very different from that of the lesions. Taken together with the distribution of lesions and Hu antigen expression, it is suggested that factors other than anti-Hu antibodies are also involved in the pathogenesis of this neuronopathy.

Skin sympathetic outflow in Buerger's disease.

To clarify if sympathetic outflow is altered in Buergers disease (thromboangitis obliterans, TAO), we measured skin sympathetic nerve activity (SSNA) in TAO patients, and observed the sweating and vasoconstrictive responses during resting and with activating maneuvers. Multiunit postganglionic sympathetic activity was recorded in a skin fascicle of the tibial nerve innervating the skin of the sole (glabrous skin) and peroneal nerve innervating the skin of the dorsum pedis (hairy skin) from five TAO patients and five healthy subjects simultaneously with skin blood flow and sweat expulsion. TAO patients showed significantly less vasoconstrictor SSNA than healthy subjects (17.0+/-1.9 vs. 31.5+/-5.8 bursts/min, P<0.001). Moreover, we found no relationship between vasoconstrictor SSNA and skin blood flow in some patients, while they were well correlated in healthy subjects. There was no evidence for increased sympathetic activity in TAO patients, and no hypersensitive relationship was found between SSNA and skin blood flow. These observations suggested that these TAO patients exhibiting no relationship between skin blood flow reduction and vasoconstrictor activity might not respond to sympathectomy, which is generally expected to result in an increase in skin blood flow. The absence of increased sympathetic nerve activity provides further indirect evidence of a local vascular abnormality in TAO.

Skin sympathetic neuroeffector response is attenuated dose-dependently by systemic prostaglandin E1 injection in humans.

To clarify the effects of prostaglandin E1 (PGE1) on the vasoconstrictive responses, we compared the correlation between the amplitude of integrated skin sympathetic nerve activity (SSNA) and per cent reduction in skin blood flow (SBF) before and after the infusion of lipo PGE1 and placebo (bolus one-shot infusion, single blind study), and constant rate infusion of PGE1 (10 and 50 ng kg(-1) min(-1) by infusion pump, dose-dependency study) in ten healthy men. SSNA was recorded microneurographically from the median nerve simultaneously with SBF by laser Doppler flowmetry at the index fingertip. The measurement was conducted 30 min after injection of lipo PGE1 or placebo, and during the drip infusion of 10 and 50 ng kg(-1) min(-1) of PGE1 with maneuvers to enhance SSNA. The resting and activated skin blood flow were not significantly different between 10 ng lipo PGE1 and placebo administration, and between baseline and 10, 50 ng kg(-1) min(-1) of PGE1 injection. The vascular response, defined as the slope of regression line between logarithm of amplitude of integrated SSNA bursts and the reduction in SBF, was significantly suppressed by injection of lipo PGE1 as compared with that by placebo. It was also decreased dose-dependently by the constant rate infusion of PGE1 (10 and 50 ng kg(-1) min(-1)). We concluded that the intravenous injection of PGE1 attenuates vasoconstrictive responses to SSNA, and analysis of the relations between SSNA and vasoconstrictive response, i.e. the neuroeffector response, is suggested to be an important tool to assess the drug effect.

Chlorpromazine Increases the Expression of Polysialic Acid (PolySia) in Human Neuroblastoma Cells and Mouse Prefrontal Cortex

The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although the amount of NCAM remains unchanged. Impairments of the polySia-expression and several single nucleotide polymorphisms (SNPs) of the polysialyltransferase (polyST) ST8SIA2 gene are reported to be associated with schizophrenia and bipolar disorder. Chlorpromazine (CPZ) is well-known as an agent for treating schizophrenia, and our hypothesis is that CPZ may affect the polySia expression or the gene expression of polySTs or NCAM. To test this hypothesis, we analyzed the effects of CPZ on the expression of polySia-NCAM on human neuroblastoma cell line, IMR-32 cells, by immunochemical and chemical methods. Interestingly, the cell surface expression of polySia, especially those with lower chain lengths, was significantly increased on the CPZ-treated cells, while mRNAs for polySTs and NCAM, and the amounts of total polySia-NCAM remained unchanged. The addition of brefeldin A, an inhibitor of endocytosis, suppressed the CPZ-induced cell surface polySia expression. In addition, polySia-NCAM was also observed in the vesicle compartment inside the cell. All these data suggest that the level of cell surface expression of polySia in IMR-32 is highly regulated and that CPZ changes the rate of the recycling of polySia-NCAM, leading to the up-regulation of polySia-NCAM on the cell surface. We also analyzed the effect of CPZ on polySia-expression in various brain regions in adult mice and found that CPZ only influenced the total amounts of polySia-NCAM in prefrontal cortex. These results suggest a brain-region-specific effect of CPZ on the expression of total polySia in mouse brain. Collectively, anti-schizophrenia agent CPZ consistently up-regulates the expression polySia at both cellular and animal levels.

Different properties of polysialic acids synthesized by the polysialyltransferases ST8SIA2 and ST8SIA4

Polysialic acid (polySia) is mainly found as a modification of neural cell adhesion molecule (NCAM) in whole embryonic brains, as well as restricted areas of adult vertebrate brains, including the hippocampus. PolySia shows not only repulsive effects on NCAM-involved cell-cell interactions due to its bulky and hydrated properties, but also attractive effects on the interaction with neurologically active molecules, which exerts a reservoir function. Two different polysialyltransferases, ST8SIA2 and ST8SIA4, are involved in the synthesis of polySia chains; however, to date, the differences of the properties between polySia chains synthesized by these two enzymes remain unknown. In this study, to clarify this point, we first prepared polySia-NCAMs from HEK293 cells stably expressing ST8SIA4 and ST8SIA2, or ST8SIA2 (SNP-7), a mutant ST8SIA2 derived from a schizophrenia patient. The conventional sensitive chemical and immunological characterizations showed that the quantity and quality (structural features) of polySia are not so much different between ST8SIA4- and ST8SIA2-synthesized ones, apart from those of ST8SIA2 (SNP-7). Then, we assessed the homophilic and heterophilic interactions mediated by polySia-NCAM by adopting a surface plasmon resonance measurement as an in vitro analytical method. Our novel findings are as follows: (i) the ST8SIA2- and ST8SIA4-synthesized polySia-NCAMs exhibited different attractive and repulsive effects than each other; (ii) both polySia- and oligoSia-NCAMs synthesized by ST8SIA2 were able to bind polySia-NCAMs; (iii) the polySia-NCAM synthesized by a ST8SIA2 (SNP-7) showed markedly altered attractive and repulsive properties. Collectively, polySia-NCAM is suggested to simultaneously possess both attractive and repulsive properties that are highly regulated by the two polysialyltransferases.

Effects of bath water and bathroom temperatures on human thermoregulatory function and thermal perception during half-body bathing in winter

Abstract We clarified the effects of hot water and bathroom temperatures on human thermoregulatory function and thermal perception during half-body bathing in the winter season. Subjects were eight healthy male volunteers aged 27.4±6.0 yr. Subjects were requested to stand quietly for 1 min in either a 14 or 25°C bathroom, and then to bathe for 20 min in a bathtub filled up to the epigastrium with water at either 39 or 42°C. The following physiological parameters were measured continuously: tympanic temperature as core temperature, skin temperature at the chest, skin blood flow at the forearm and sweat rate on the back of the hand. At the same time we measured thermal sensation and comfort votes as physiological responses before, whilst, and after bathing several times. At the same bathroom temperature, bathing in the 42°C water elevated tympanic and skin temperatures, skin blood flow and sweat rate more than bathing at 39°C. Similarly, under the same water temperature, bathing in the 25°C bathroom increased those parameters more than in the 14°C bathroom. Subjects felt warm and comfortable during bathing in the 39°C water in the 25°C bathroom because of the reduced cold stress because of the bathroom temperature. They felt warm with a neutral sensation during bathing in the 42°C water in the 14°C bathroom because of the reduction in heat stress from the not water temperature. We suggest that during half-body bathing at a low water temperature but high bathroom temperature is better physiologically and psychologically, and that during half-body bathing at a hot water temperature, a low bathroom temperature is better psychologically.

Sympathetic Adjustment of Cardiovascular Control and Thermoregulation in Humans Exposed to Heat Stress

Muscle sympathetic nerve activity (MSNA) plays an essential role in adjusting cardiovascular control to maintain hemodynamic homeostasis. Recent studies have suggested that MSNA functions not only for cardiovascular control but also for thermoregulation, thus adjusting the interaction between cardiovascular and thermoregulatory systems. This chapter reviews the role of MSNA in homeostatic control of cardiovascular functions and body temperature in humans exposed to heat stress. Responses of microneurographically recorded MSNA to hot ambient temperature and a hot bath were analyzed in healthy human subjects. (1) MSNA increased when the subjects were exposed to hot ambient temperature. This MSNA increase was related to the rise in core temperature and counteracted the lowered blood pressure caused by heat-induced skin vasodilation and sweating. (2) MSNA decreased at the initial phase of the hot bath, possibly due to a fluid shift from the lower to the upper part of the body, which loads cardiopulmonary baro- or volume receptors, but recovered and even increased during and after exposure to the hot bath. This MSNA enhancement was related to an increase in core temperature, skin vasodilation, and sweating. These findings suggest that heat-induced MSNA responses may compensate skin vasodilation and sweating to maintain hemodynamic homeostasis, presumably through baroreflexes. On the other hand, MSNA may be also enhanced by central mechanisms to facilitate the blood shifting from the muscle to the skin surface to accelerate heat loss. Thus, MSNA plays a role to adjust both hemodynamic control and thermoregulation during exposure to heat stress.