Kazuyoshi Hirota

The relationship between salivary biomarkers and state-trait anxiety inventory score under mental arithmetic stress: a pilot study.

Measurement of stress hormones is a common objective method for assessment of mental stress. However, the stress of blood sampling alone may also increase stress hormone levels. In the present study, we sampled salivary biomarkers from healthy volunteers under noninvasive conditions and determined their efficacy to assess mental stress. Specifically, we examined the relationship between State Anxiety Inventory score (STAI-s) in subjects exposed to arithmetic stress and salivary chromogranin-A, &agr;-amylase, or cortisol. The STAI-s was significantly correlated to salivary &agr;-amylase (r = 0.589; P < 0.01) but not to salivary chromogranin-A or cortisol. Therefore, salivary &agr;-amylase is a useful indicator of psychosocial stress.

Orexinergic neurons and barbiturate anesthesia

Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates. OX A and B significantly decreased pentobarbital, thiopental and phenobarbital anesthesia times by 15-40%. SB-334867-A increased thiopental-induced anesthesia time by approximately by 40%, and reversed the decrease produced by OX A. In vitro, all anesthetic barbiturates inhibited OX-evoked norepinephrine release with clinically relevant IC50 values. A GABAA antagonist, bicuculline, did not modify the inhibitory effects of thiopental and the GABAA agonist, muscimol, did not inhibit norepinephrine release. In addition there was no interaction of barbiturates with either OX1 or OX2 receptors. Collectively our data suggest that orexinergic neurons may be an important target for barbiturates, and GABAA, OX1 and OX2 receptors may not be involved in this interaction.

Effects of central hypocretin-1 administration on hemodynamic responses in young-adult and middle-aged rats.

The prevalence of hypertension in middle age correlates with impaired autonomic regulation and as norepinephrinergic neurons decline with increasing age, and this reduction may contribute to this impairment. Central hypocretin-activated norepinephrinergic neurons contribute to sympathetic regulation. In the present study we compared sympathoadrenal effects of intracerebroventricular (i.c.v.) hypocretin-1(5 nmol) between young-adult (12-14 weeks) and middle-aged (12-14 months) rats. Arterial blood pressure, heart rate and plasma catecholamines were assessed under pentobarbital anesthesia. In addition, we compared hypocretin-1 and K(+)-evoked norepinephrine release from the cerebrocortical slices prepared from young-adult and middle-aged rats. We also examined whether the novel hypocretin receptor-1 antagonist (SB-334867) could reverse these hypocretin-1 effects both in vivo and in vitro. I.c.v. hypocretin-1 significantly increased blood pressure by some 7%, heart rate by 9% and plasma norepinephrine concentrations by 100% in young-adult rats. In middle-aged rats these parameters did not change. Plasma epinephrine did not increase in either group. There was a significant correlation between changes in mean arterial pressure and plasma norepinephrine. Similarly, hypocretin-1 evoked norepinephrine release from cerebrocortical slices prepared from young-adult rats was significantly higher than that of middle-aged rats whilst K(+)-evoked release did not differ between the groups. SB-334867 significantly attenuated hypocretin-1-increased blood pressure and both in vivo and in vitro norepinephrine release. The present data suggest that hypocretinergic neurons may contribute to the regulation of central but not adrenal sympathetic activity. Moreover, sympathetic regulation by hypocretinergic neurones may disappear in middle-age in rats.

Isoflurane increases norepinephrine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro: Relevance to thermoregulation during anesthesia

General anesthetics modulate autonomic nervous system function including thermoregulatory control, which resides in the preoptic area of the anterior hypothalamus. However, the mechanism by which anesthetics modulate hypothalamic function remains unknown. We hypothesized that isoflurane increases norepinephrine release in the preoptic area and in the posterior hypothalamus causing hypothermia during anesthesia. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo studies: 1) Norepinephrine release was measured by microdialysis in the preoptic area or the posterior hypothalamus (n=9 each) before, during (30 min), and after (50 min) rats were anesthetized with 2% isoflurane. 2) In five rats, blood gases and arterial pressure were measured. 3) Body temperature changes (n=6 each) were measured after prazosin (0, 0.05, 0.5 microg), norepinephrine (0, 0.1, 1.0 microg), or 0.5 microg prazosin with 1.0 microg norepinephrine injection into the preoptic area. In vitro study: Norepinephrine release was measured from anterior or posterior hypothalamic slices (n=10 each) incubated with 0, 1, 2, or 4% isoflurane in Ca2+-containing buffer or with 4% isoflurane (n=10) in Ca2+-free buffer. Data were analyzed with repeated measures or factorial ANOVA and Student-Newman-Keuls tests. P<0.05 was significant. During anesthesia, norepinephrine release in the preoptic area was increased approximately 270%, whereas the release in the posterior hypothalamus remained unchanged. During emergence, posterior hypothalamic norepinephrine release increased by approximately 250% (P<0.05). Rectal temperature changes correlated with norepinephrine release from the preoptic area. Norepinephrine in the preoptic area enhanced isoflurane-induced hypothermia, while prazosin reversed it. Norepinephrine release from anterior hypothalamic slices increased at all isoflurane concentrations, but only at the highest concentration in posterior hypothalamic slices. Under Ca2+-free conditions, 4% isoflurane increased norepinephrine from both regions. These results suggest that augmentation of norepinephrine release in the preoptic area is responsible for hypothermia during general anesthesia.

A marked decrease in bispectral index with elevation of suppression ratio by cervical haematoma reducing cerebral perfusion pressure

A 77-year-old man with a ruptured abdominal aortic aneurysm undergoing aneurysmectomy were anaesthetised with ketamine under bispectral index (BIS) monitoring, which is a clinical EEG monitor for measurement of depth of anaesthesia/sedation. First marked BIS reduction with elevation of suppression ratio (SR) was observed following severe hypotension by deflation of the aortic occlusion balloon. The re-inflation and rapid blood transfusion improved haemodyanamics and BIS and SR. At second marked BIS reduction with SR elevation, a heavy cervical swelling due to a massive subcutaneous haematoma around the previously mis-punctured right carotid artery extending throughout the whole neck was observed without hypotension. Cervical relief incision improved the BIS and SR. The present case suggests that BIS monitor may be a simple and convenient monitor for cerebral ischaemia detection.

The Effects of Local and Intravenous Anesthetics on Recombinant Rat VR1 Vanilloid Receptors

Capsaicin, acting at the vanilloid 1 receptor (VR1), may potentiate local anesthetic activity, and as a ligand-gated ion channel of the transient receptor potential family, may also be a target for IV general anesthetics. We have examined whether local (lidocaine, prilocaine, and procaine 0.1–10 mM; 10 mM represents 0.25%–0.27% wt/vol) or IV anesthetics (propofol 10 &mgr;M, thiopental 100 &mgr;M, and ketamine 100 &mgr;M) interact with recombinant rat VR1 expressed in human embryonic kidney (HEK293) cells (VR1-HEK293). We have assessed receptor interaction functionally by monitoring intracellular Ca2+ ([Ca2+]i) in Fura2-loaded cells at 37°C. The addition of capsaicin (60 nM) produced a time-dependent biphasic increase in [Ca2+]i amounting to 50–100 nM above than basal, which was inhibited by capsazepine 10 &mgr;M and was absent in wild type HEK293 cells. Lidocaine and prilocaine alone (e.g., at 10 mM) significantly increased [Ca2+]i by 67 ± 6 nM and 33 ± 7 nM, respectively, and concentration-dependently inhibited the capsaicin response. The effects of procaine were obscured by anesthetic-induced quenching of Fura2. In wild type HEK293 cells, lidocaine (10 mM) alone produced a small increase in [Ca2+]i. All IV anesthetics failed to modify capsaicin-increased [Ca2+]i. In conclusion, the present data suggest that local but not IV general anesthetics interact with recombinant rat VR1 receptors with the former anesthetics having antagonistic activity. IMPLICATIONS: Vanilloid receptors (VR1) are activated by capsaicin, the pain-producing component of hot chili peppers. We suggest that local (but not IV general) anesthetics may have inhibitory actions on this receptor.

Effects of propofol on bronchoconstriction and bradycardia induced by vagal nerve stimulation

Background:  Vagolysis has been considered as a mechanism by which propofol produces bronchodilation. However, it has also been suggested that propofol‐induced bradycardia may result from increased vagal tone. In this study, we have determined whether propofol has vagolytic effects on both the airway and cardiovascular system.

Initial distribution volume of glucose can be approximated using a conventional glucose analyzer in the intensive care unit

IntroductionWe previously reported that initial distribution volume of glucose (IDVG) reflects central extracellular fluid volume, and that IDVG may represent an indirect measure of cardiac preload that is independent of the plasma glucose values present before glucose injection or infusion of insulin and/or vasoactive drugs. The original IDVG measurement requires an accurate glucose analyzer and repeated arterial blood sampling over a period of 7 min after glucose injection. The purpose of the present study was to compare approximated IDVG, derived from just two blood samples, versus original IDVG, and to test whether approximated IDVG is an acceptable alternative measure of IDVG in the intensive care unit.MethodsA total of 50 consecutive intensive care unit patients were included, and the first IDVG determination in each patient was analyzed. Glucose (5 g) was injected through the central venous line to calculate IDVG. Original IDVG was calculated using a one-compartment model from serial incremental arterial plasma glucose concentrations above preinjection using a reference glucose analyzer. Approximated IDVG was calculated from glucose concentrations in both plasma and whole blood, using a combined blood gas and glucose analyzer, drawn at two time points: immediately before glucose injection and 3 min after injection. Subsequently, each approximated IDVG was calculated using a formula we proposed previously.ResultsThe difference (mean ± standard deviation) between approximated IDVG calculated from plasma samples and original IDVG was -0.05 ± 0.54 l, and the difference between approximated IDVG calculated from whole blood samples and original IDVG was -0.04 ± 0.61 l. There was a linear correlation between approximated and original IDVG (r2 = 0.92 for plasma samples, and r2 = 0.89 for whole blood samples).ConclusionOur findings demonstrate that there was good correlation between each approximated IDVG and original IDVG, although the two measures are not interchangeable. This suggests that approximated IDVG is clinically acceptable as an alternative calculation of IDVG, although approximated and original IDVGs are not equivalent; plasma rather than whole blood measurements are preferable.

Efficacy of landiolol in attenuating hemodynamic responses to local epinephrine infiltration in patients undergoing vaginal total hysterectomy

PurposeLocal epinephrine infiltration often causes β1-adrenoceptor-mediated tachycardia, hypertension, and arrhythmia. Landiolol, a short acting β1-adrenoceptor blocker, may represent the most ideal agent to attenuate these adverse effects. In this study, we examined the effects of landiolol on the hemodynamic changes resulting from local infiltration of epinephrine.MethodsThirty-six patients undergoing vaginal total hysterectomy under general anesthesia were randomly assigned to one of three groups: control group (n = 12), L5 group (n = 12), and L10 group (n = 12). In the control, L5, and L10 groups, the patients were given saline, landiolol 5 mg, and 10 mg, respectively, just before infiltration of epinephrine(1 : 300 000; total dose, about 100 µg) into the surgical field. Blood pressure and heart rate was assessed before and 5, 10, 15, 20, 25, 30 min after the initiation of epinephrine infiltration. If systolic blood pressure and heart rate exceeded 160 mmHg and 120 beats·min−1, respectively, Ca blockers of either diltiazem 5 mg or nicardipine 1 mg and/or 2% sevoflurane were given.ResultsEpinephrine infiltration significantly increased systolic blood pressure from 122 ± 15 to 170 ± 29 mmHg and heart rate from 63 ± 8 to 106 ± 10 beats·min−1. In both the L5 and L10 groups, the increase in heart rate (from 69 ± 16 to 87 ± 16 beats·min−1, P < 0.01, and from 70 ± 18 to 76 ± 9 beats·min−1, P < 0.01, respectively) was significantly smaller compared to the control group, but the increase in systolic blood pressure was significantly attenuated in the L10 group (from 116 ± 18 to 140 ± 27 mmHg, P < 0.01). The number of patients given either Ca blockers or sevoflurane in the control group was significantly higher than that in the landiolol groups (P < 0.01).ConclusionThe present study suggests that landiolol 10 mg may be a more suitable dose than landiolol 5 mg to antagonize hyperdynamic states induced by local administration of epinephrine.

The effects of benzodiazepines on orexinergic systems in rat cerebrocortical slices.

BACKGROUND: As orexinergic (OXergic) neurons have been reported to mediate emotional changes, benzodiazepines might interact with OXergic neurons. METHODS: We examined the interactions between OXergic neurons and benzodiazepine receptors in orexin-A (100 nM) and K+ (25 mM)-evoked norepinephrine release from rat cerebrocortical slices. RESULTS: Midazolam, diazepam, and flunitrazepam concentration-dependently inhibited both OX-A- and K+-evoked norepinephrine release. The IC50 of midazolam for orexin-A-evoked release (0.87 &mgr;M, P < 0.01), which was insensitive to flumazenil, was significantly lower than that of diazepam and flunitrazepam (around 60 &mgr;M), whereas the IC50s for K+-evoked release were not different among the benzodiazepines. CONCLUSION: There may be no interaction between OXergic neurons and central benzodiazepine receptors.