Tetsumi Sato

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.

Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia.

UNLABELLED BACKGROUND AND OBJECTIVES The goal of this study was to evaluate the analgesic effects of intrathecal versus epidural methylprednisolone acetate (MPA) in patients with intractable postherpetic neuralgia (PHN). METHODS We studied 25 patients with a duration of PHN of more than 1 year. The patients were randomly allocated to one of two groups: an intrathecal group (n = 13) and an epidural group (n = 12). Sixty milligrams of MPA was administered either into the intrathecal or the epidural space four times at 1-week intervals depending on the treatment group. Continuous and lancinating pain and allodynia were evaluated by a physician unaware of group assignment with a 10-cm visual analogue scale before treatment, at the end of treatment, and 1 and 24 weeks after treatment. In addition, cerebrospinal fluid (CSF) was obtained for measurement of interleukin (IL)-1beta, -6, and -8 and tumor necrosis factor-alpha before and 1 week after treatment. RESULTS We found marked alleviation of continuous and lancinating pain and allodynia in the intrathecal group (P < .001). The improvements were much greater in the intrathecal group than in the epidural group at all time points after the end of treatment (P < .005). IL-8 in the CSF decreased significantly in the intrathecal group as compared to the epidural group at the l-week time point (P < .01), whereas the other cytokines were undetectable. CONCLUSIONS Our results suggest the effectiveness of intrathecal as compared to epidural MPA for relieving the pain and allodynia associated with PHN. Also, our findings, together with the decrease in IL-8, may indicate that intrathecal MPA improves analgesia by decreasing an ongoing inflammatory reaction in the CSF.

Correlation Between Salivary α-Amylase Activity and Pain Scale in Patients With Chronic Pain

Background and Objectives: The visual analog scale (VAS) is commonly used to assess pain intensity. However, the VAS is of limited value if patients fail to reliably report. Objective assessments are therefore clearly preferable. Previous reports suggest that elevated salivary &agr;-amylase may reflect increased physical stress. There is a close association between salivary &agr;-amylase and plasma norepinephrine under stressful physical conditions. In this study, we have determined the usefulness of a portable salivary &agr;-amylase analyzer as an objective biomarker of stress. Methods: Thirty patients (male/female = 15/15, age: 60.5 ± 15.3 years) with chronic low back or leg pain (pain (+) group) and 20 pain-free control patients undergoing elective surgery under general anesthesia with epidural analgesia (pain (−) group) were recruited. Patients received epidural block with 5 to 10 mL 1% lidocaine. VAS, blood pressure, and heart rates were assessed before and 30 and 45 minutes after the epidural block. Salivary &agr;-amylase was simultaneously measured using a portable analyzer. The relationship between the VAS and salivary &agr;-amylase in chronic pain patients was assessed. Results: After the epidural block both heart rate and systolic blood pressure decreased by ˜8%. In the pain (+) group, the epidural block markedly decreased the VAS pain scale and salivary &agr;-amylase from 56 ± 22 to 19 ± 16 mm (P < .01) and from 82 ± 48 to 45 ± 28 U/mL (P < .01), respectively, with a significant correlation between the 2 measures (r = 0.561, P < .01). In contrast, salivary &agr;-amylase did not change significantly in the pain (−) group. Conclusions: Because there was a significant correlation between VAS pain scale and salivary &agr;-amylase, we suggest that this biomarker may be a good index for the objective assessment of pain intensity. In addition, a simple to use portable analyzer may be useful for such assessment.

Ketamine relaxes airway smooth muscle contracted by endothelin.

Endothelins (ETs) are synthesized not only in vascular endothelial cells but also in airway epithelial cells.Increased ET-1 has been demonstrated in bronchial epithelium of asthmatic patients, and, in severe asthma attacks, ET-1 increases in plasma and bronchoalveolar lavage fluid. In this study, we investigated whether ketamine (KET) relaxes ET-induced tracheal contractions. Female guinea pigs were killed with an overdose of pentobarbital. The trachea was removed and cut spirally into two strips that were mounted in an organ bath filled with Krebsbicarbonate buffer. The response of each strip to 10-7 M carbachol was taken as 100% contraction to which the response to ET was referred. The contribution of the epithelium to the relaxant effect of KET was studied in denuded tracheae or in the presence of 5 x 10-5 M indomethacin. ET-1 (3 x 10-8 M) induced contractions that were 76 +/- 3% of those induced by carbachol. KET reversed the response to ET-1 in a dose-dependent fashion. Similarly, ET-2 (3 x 10-8 M) induced contractions that were 74 +/- 5% of those induced by carbachol, and KET also reversed this response in a dose-dependent manner. In epithelium-denuded strips, ET-1 induced contractions that were 104 +/- 3% of those induced by carbachol, and KET still reversed this response. The tonic phase of the response to ET-1 was equal (100 +/- 6%) to the response to carbachol, and KET did not affect it significantly. In the presence of ryanodine, KET reduced the ET-1-induced contraction from 67 +/- 2% to 36 +/- 3.%, P < 0.01. In the presence of nicardipine, KET also inhibited the ET-1-induced contraction. We conclude that KET relaxes the tracheal smooth muscle contracted by ETs via a mechanism that is independent of the tracheal epithelium. The relaxant effect of KET on the ET-induced contraction of the trachealis muscle is not dependent upon blockade of 1) sarcolemma influx of Ca (2+) through the dihydropyridine Ca2+ channel or 2) the release of intracellular Ca2+ through the ryanodine-sensitive intracellular Ca2+ channel. It is likely that the action of KET relaxing ET-induced tracheal contractions is at some point of the inositol 1,4,5-trisphosphate signaling pathway. (Anesth Analg 1997;84:900-6)

Relaxant effect of magnesium and zinc on histamine-induced bronchoconstriction in dogs

OBJECTIVE Magnesium sulfate (MgSO4) has been reported to produce bronchodilation in asthmatic patients. In vitro studies have suggested that divalent cations inhibit L-type voltage-sensitive calcium ion (Ca2+) channels in cardiac and smooth muscles. In this study, we evaluated the in vitro and in vivo effects of magnesium ion (Mg2+) and zinc ion (Zn2+) on the airway contracted by histamine. SETTING A university research laboratory. SUBJECTS IN VITRO Tracheal smooth muscle from guinea pigs. IN VIVO Mongrel dogs. MEASUREMENTS AND MAIN RESULTS IN VITRO STUDY The tension of isolated guinea pig tracheal strips was measured isometrically with a force displacement transducer. The specimen was contracted with histamine (10 microM). Then, MgSO4 (n = 6), zinc sulfate (ZnSO4, n = 6), or sodium sulfate (Na2SO4, n = 6) was cumulatively added to the organ bath. IN VIVO STUDY The bronchial cross-sectional area of mongrel dogs was measured by a direct visualization method demonstrated previously. The dogs were randomly assigned to three groups: group Mg (n = 7), group Zn (n = 7), and group Na (n = 7). Bronchoconstriction was elicited with histamine (10 microg/kg plus 500 microg/kg/hr iv). Thirty minutes after the start of histamine infusion, 0 (saline), 1, 10, and 100 micromol/kg ZnSO4 or 1, 10, 100, and 1000 micromol/kg MgSO4 or Na2SO4 were administered intravenously in group Zn, Mg, or Na, respectively. The bronchial cross-sectional area was assessed before (basal) and 30 mins after the start of histamine infusion and 5 mins after each dose of ZnSO4, MgSO4, or Na2SO4. Arterial blood was also obtained to measure plasma levels of epinephrine and norepinephrine by gas chromatography-mass spectrometry. All data are expressed as mean +/- SEM. The doses of the divalent cations that reversed histamine-induced contraction by 50% were calculated by GraphPad Prism. MgSO4 and ZnSO4 (9.38+/-0.28 and 1.84+/-0.30 mM, respectively) relaxed histamine-contracted tracheal strip in a concentration-dependent manner, whereas Na2SO4 did not. Similarly, the in vivo study showed that MgSO4 and ZnSO4 dose-dependently reversed histamine-induced bronchoconstriction (potency, ZnSO4 > MgSO4), whereas Na2SO4 did not. In groups Mg and Zn, the plasma catecholamine levels also dose-dependently increased except when 1000 micromol/kg MgSO4 was administered. CONCLUSION Because the divalent cations tested produced a spasmolytic effect on the contracted airway, infusion of divalent cations might be effective against asthmatic attack. However, high concentrations of these cations produce significant toxicity, so dosage will be an important concern in development of these agents.

The role of the N-methyl-D-aspartic acid receptor in the relaxant effect of ketamine on tracheal smooth muscle.

Ketamine and magnesium (Mg2+), well known bronchodilators, have been used to treat patients with status asthmaticus.Both can block the N-methyl-D-aspartic acid (NMDA) receptor. NMDA receptors exist in the airway, and their activation seems to be linked to the release actions of sensory neuropeptides resulting in increased airway tone. We sought to determine whether ketamine relaxes the guinea pig trachea contracted by histamine by blocking the NMDA receptor. Female guinea pigs (250-400 g) were killed with an overdose of pentobarbital. The trachea was removed and cut spirally into strips 3 mm wide and 15 mm long. The strips were mounted in a 10-mL organ bath filled with Tyrodes solution bubbled through with 95% O2/5% CO2 at 37[degree sign]C. Strip contractions were measured isometrically with a force displacement transducer. We then studied the effect of NMDA receptor antagonists on histamine-induced tracheal contraction. In this protocol, we examined the effect of ketamine, Mg2+, zinc (Zn2+), or MK-801 (a noncompetitive NMDA receptor blocker) on strips contracted by 10-5 M histamine. After full contraction was attained, ketamine (0.5-1.5 mM), MgSO4 (2-8 mM), ZnCl2 (0.2-0.8 mM), or MK-801 (1.5-6 x 10-5 M) was added, and the strip tension was measured again. We also studied the effect of NMDA on the relaxation by ketamine. After full contraction by 10-5 M histamine, 0.5-1.5 mM KET was added alone or in combination with 0.1 mM NMDA, and the strip tension was measured again. Finally, we measured the effect of MK-801 on the relaxant effect of ketamine. After full contraction by 10-5 M histamine, 0.5-2 mM ketamine was added alone or in combination with 0.75 or 1.5 x 10-5 M MK-801, and the strip tension was measured again. All NMDA receptor antagonists tested reversed the tracheal contraction induced by histamine in a dose-dependent manner. However, neither the agonist NMDA nor the noncompetitive receptor blocker MK-801 affected tracheal relaxation induced by ketamine. We conclude that ketamine relaxes the tracheal smooth muscle contracted by histamine through a mechanism independent of NMDA receptors. The decreased bronchomotor tone induced by ketamine is probably due to interference with a Ca2+-requiring step necessary to maintain the contraction caused by histamine. Implications: Stimulation of the N-methyl-D-aspartic acid (NMDA) receptor in the airway results in airway constriction. The bronchodilator ketamine blocks the NMDA receptor. However, ketamine relaxes the guinea pig trachea contracted by histamine through a mechanism independent of the NMDA receptor. (Anesth Analg 1998;87:1383-8)

The Relaxant Effect of Ketamine on Guinea Pig Airway Smooth Muscle Is Epithelium-Independent

Airway epithelial cells and vascular endothelial cells modulate the tone of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO).In the present study, we investigated whether the relaxant effect of ketamine depends on any of the epithelium-derived relaxing factors. Tracheae of female guinea pigs were cut spirally into strips (15 x 3 mm) and mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with a mixture of 95% O (2) and 5% CO2 at 37 degrees C. Changes in the tension of the strips were measured isometrically with a force displacement transducer and recorded with a polygraph. In the first set of experiments, we examined the effect of ketamine on the concentration-response curves for histamine and carbachol in strips in which the epithelium was kept intact and in strips with denuded epithelium. In the second and third set of experiments, we studied the effect of indomethacin, a cyclooxygenase inhibitor, and N-omega-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, on the relaxant activity of ketamine on tracheal strips contracted by histamine or carbachol. The following results were obtained: 1.Mechanical denudation of the tracheal epithelium shifted the concentration-response curve for histamine to the left (the 50% effective concentration [EC50] value of histamine decreased from 3.5 +/- 0.02 x 10-6 M in the intact strips to 0.98 +/- 0.01 x 10-6 M in denuded strips, P < 0.001). However, removal of the tracheal epithelium did not change the response to carbachol (the EC50 for carbachol was 1.1 +/- 0.02 x 10-7 M in intact strips versus 0.88 +/- 0.01 x 10-7 M after epithelial removal, P > 0.05). 2.Ketamine shifted to the right the concentration-response curves for histamine and carbachol in both intact and denuded tracheae. 3.Indomethacin did not alter the relaxant effect of ketamine on the tracheae contracted by either histamine (the concentration that inhibits 50% [IC50] of ketamine = 1.5 +/- 0.01 x 10-3 M in control strips and 1.3 +/- 0.04 x 10-3 M in strips pretreated with indomethacin, P > 0.05) or carbachol (the IC50 of ketamine was 2.5 +/- 0.02 x 10-4 M in control strips and 2.4 +/- 0.01 x 10 (-4) M in strips pretreated with indomethacin, P > 0.05). 4.L-NAME did not influence the relaxant effect of ketamine on tracheae contracted by either histamine (the IC50 of ketamine = 1.6 +/- 0.05 x 10-3 M in control strips and 1.6 +/- 0.05 x 10-3 M in strips pretreated with L-NAME, P > 0.05) or carbachol (the IC50 of ketamine = 2.6 +/- 0.04 x 10-4 M in control strips and 2.3 +/- 0.01 x 10-4 M in trips pretreated with L-NAME, P > 0.05). These results indicate that neither the mechanical removal of the tracheal epithelium nor the blockade of the release of potent mediators from tracheal epithelial cells influence the relaxant effect of ketamine on guinea pig tracheal strips contracted by histamine or carbachol.We conclude that ketamine relaxes the airway smooth muscle by an epithelium-independent mechanism. (Anesth Analg 1997;84:641-7)

The relaxant effect of propofol on guinea pig tracheal muscle is independent of airway epithelial function and beta-adrenoceptor activity.

UNLABELLED Airway epithelium and vascular endothelium modulate the tension of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). We investigated whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. Tracheal spirals of female guinea pigs were mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with 95% O2 and 5% CO2 at 37 degrees C. Changes in isometric tension of the specimens were measured with a force-displacement transducer and recorded with a polygraph. Propofol (10(-4) to 10(-3) M) inhibited carbachol (CCh)-, histamine (HA)-, or endothelin-1-induced contractions of the muscles in a dose-dependent manner. Neither mechanical removal of the epithelial layer, chemical inhibition of epithelial synthesis of prostanoids, nor NO affected the relaxant effect of propofol on CCh- or HA-induced tracheal contraction. Furthermore, the blockade of beta-adrenoceptors did not change the relaxant effect of propofol. These results indicate that the relaxant effect of propofol on the airway smooth muscle is independent of the epithelial function or beta-adrenoceptor activity. Propofol is an excellent anesthetic for patients with hyperreactive airways in which the epithelial layer is damaged. IMPLICATIONS Airway epithelium, as well as vascular endothelium, plays an important role in modulating the baseline tone and reactivity of underlying smooth muscle. We investigated, in vitro, whether the relaxant effect of propofol on airway smooth muscle is dependent on airway epithelial function. We suggest that propofol relaxes airway smooth muscle independently of the epithelial function.

Milrinone attenuates serotonin-induced pulmonary hypertension and bronchoconstriction in dogs

We determined whether milrinone, a phosphodiesterase III inhibitor, attenuates serotonin-induced (5-hydroxytryptamine [5HT]) pulmonary hypertension (PH) and bronchoconstriction. Dogs were anesthetized with pentobarbital (30 mg/kg + 2 mg · kg−1 · h−1). Bronchoconstriction and PH were elicited by 5HT (10 &mgr;g/kg + 1.0 mg · kg−1 · h−1). Pulmonary vascular resistance was used to assess PH. Bronchoconstriction was also assessed by changes in bronchial cross-sectional area obtained from our bronchoscopic method. At 30 min after 5HT infusion started, seven dogs were given milrinone: 0 (saline), 5, 50, 500, and 5000 &mgr;g/kg at 10-min intervals. The other 12 dogs were given milrinone 5000 &mgr;g/kg 30 min after 5HT infusion, and 5 min later were given propranolol 0.2 mg/kg (n = 6) or saline (n = 6) IV. The 5HT significantly increased percentage of pulmonary vascular resistance to 208% ± 27% and decreased percentage of bronchial cross-sectional area to 52% ± 5% of the basal. Milrinone significantly attenuated both PH and bronchoconstriction in a dose-dependent manner. However, −log 50% effective concentration (mean ED50 in &mgr;g/kg) of milrinone for bronchoconstriction: 4.32 ± 0.13 (47.6) was significantly smaller than that for PH: 3.84 ± 0.29 (144.9) (P < 0.01). In addition, the spasmolytic effects of milrinone (5000 &mgr;g/kg) were not antagonized by propranolol, although this dose significantly increased plasma catecholamines. In conclusion, milrinone attenuates 5HT-induced PH and bronchoconstriction; however, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than in pulmonary vascular smooth muscle. In addition, the relaxant effects could not be caused by &bgr;-adrenoceptor activation because &bgr;-blocker did not antagonize. Implications: We studied the effects of milrinone on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Milrinone produces pulmonary vasodilation and bronchodilation, whose effects may not be caused by &bgr;-adrenoceptor activation. In addition, this drug may be more sensitive to phosphodiesterase III in the airway smooth muscle than that in pulmonary vascular smooth muscle.

Droperidol inhibits tracheal contraction induced by serotonin, histamine or carbachol in guinea pigs

PurposeDroperidol (D) is effective in the treatment of patients with status asthmaticus. It has been reported that D inhibits the bronchoconstriction induced by serotonin (5-HT) but not that by histamine (H) or acetylcholine. However, haloperidol, another butyrophenone, is known to interact with and inhibit calmodulin, an intracellular Ca++-binding protein which is important in the contraction of smooth muscles. The present study was designed to investigate the effects of D on tracheal contractions induced by 5-HT, H or carbachol (C) and to determine the contribution of α-adrenoceptors to the relaxant effect of D in vitro.MethodsTracheas of female guinea pigs were cut spirally into strips and mounted in water-jacketed organ baths in Tyrode’s solution, aerated with a mixture of 95% O2 and 5% CO2 at 37°C. The changes in isometric tension induced by each spasmogen in the strips were measured with a transducer and a polygraph.ResultsWe found that D inhibited the tracheal contractions induced by 5-HT, H or C in a concentration-dependent manner. At 1.25 × 10−6 M D blocked the effect of 10−4 M 5-HT by 44.1 ± 4.3% and at 2.5 × 10−6 M by 63.8 ± 3.8%. Similarly, at 5.0 × 10−6 M concentration, D blocked the effect of 10−5 M H by 27.7 ± 5.3% and at 10−5 M by 56.2 ± 2.6%. Furthermore, 5 ×10−6 M of D reduced the contractions produced by 10−7 M C by 37.1 ± 3.0% and 70−5 M of D by 76.1 ± 3.2%. The inhibiting effect of D was strongest on contractions induced by 5-HT. Prazosin (70−6 M) affected neither 5-HT-induced contractions nor the inhibition by D.ConclusionOur data indicate that D partially blocks the contractile responses not only to 5-HT, an effect which would be mediated through a blockade of the 5-HT receptors, but also to H or C, probably through inhibition of calmodulin. Our data support previous reports indicating that droperidol may be an important therapeutic agent in the treatment of patients with hyperreactive airways.RésuméObjectifLe dropéridol (D) constitue un traitement efficace du status asthmaticus. On a rapporté que D inhibait la bronchoconstriction induite par la sérotonine (5-HT) mais pas celle de l’histamine (H) ou de l’acétylcholine. Cependant on reconnaît que l’halopéridol, une autre butyrophénone, réagit avec la calmoduline et inhibe son action; la calmoduline, une protéine de liaison du Ca++ intracellulaire, est importante pour la contraction des muscles lisses. La présente étude vise à étudier les effets de D sur les contractions trachéales induites par 5-HT, H ou le Carbachol (C) et de déterminer la contribution des récepteurs α-adrénergiques sur l’effet relaxant de D in vitro.MéthodeDes trachées de cobayes femelles ont été découpées en spirales et montées au bain-marie dans une solution de tyrode, aérées avec un mélange de 95% d’O2 et de 5% de CO2 à 37°C. Les changements de tension isométrique induits par chacun des spasmogènes sur les spirales ont été mesurés à l’aide d’un transducteur et d’un polygraphe.RésultatsLes auteurs ont trouvé que D inhibait les contractions induites par 5-HT, H et C proportionnellement aux concentrations. A 1,25 × 10−6 M, D bloquait l’effet de 10−4 M de 5-HT par 44 ± 4,3 et à 2,5 × 10−6 par 63,8 ± 3,8%. De la même façon, à 5,0 × 10−6 M, D bloquait l’effet de 10−5 M H par 27,7 ± 5,3% et à 10−5 par 56,2 ± 2,6%. De plus, 5 × 10−6 M de D diminuait les contractions induites par 10−7 M de C par 37,1 ± 3,1% et 10−5 M de D par 76,1 ± 3,2%. L’effet inhibiteur de D était à son plus fort sur les contractions induites par 5-HT. La prazosine (10−6 M) n’avait d’effet ni sur tes contractions induites par 5-HT ni sur leur inhibition par D.ConclusionCes données montrent que D inhibe partiellement les réponses contractiles non seulement au 5-HT, effet d’une médiation probable du bloc des récepteurs 5-HT, mais aussi à H et à C, vraisemblablement par inhibition de la calmoduline. Ces données confirment les études antérieures qui rapportent que le dropéridol pourrait être un agent thérapeutique important contre l’hyperréactivité des voies aériennes.