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Biomedical subjects

K Shirato

Publications and source records attributed to K Shirato.

At least 91 records · Page 5Linked to original sources
PubMed1999

Diacylglycerol delays pH(i) overshoot after reperfusion and attenuates contracture in isolated, paced myocytes.

Although protein kinase C (PKC) plays a pivotal role in ischemic preconditioning, it is not clear what the end effector is that protects the myocardium. In isolated, paced (1.25 Hz, 36-37 degrees C) adult rat cardiomyocytes, the effects of PKC preactivation by diacylglycerol on cell motion, intracellular Ca(2+) concentration ([Ca(2+)](i); indo 1), and intracellular pH (pH(i); seminaphthorhodafluor-1) during simulated ischemia-reperfusion (I/R) were investigated. The degree of reperfusion-induced contracture was significantly attenuated in the myocytes pretreated with 10 microM 1, 2-dioctanoyl-sn-glycerol (DOG; n = 19) compared with the untreated myocytes (n = 23, P < 0.02). There were no differences in twitch amplitude, end-diastolic [Ca(2+)](i), or peak-systolic [Ca(2+)](i) during I/R between the DOG-pretreated and untreated myocytes. Although there were no differences in pH(i) during ischemia, the pH(i) overshoot during reperfusion was significantly delayed in the DOG-pretreated myocytes compared with the untreated myocytes (n = 17 for each, P < 0.01). Chelerythrine completely abolished the favorable effects of DOG on the reperfusion-induced contracture and the pH(i) overshoot. These data suggest that diacylglycerol attenuates I/R injury in isolated, paced cardiomyocytes, which may be related to the slower pH(i) overshoot during reperfusion.

Alkaloids↗
PubMed1999

Cholinomimetic action of macrolide antibiotics on airway gland electrolyte secretion.

We investigated the acute effects of erythromycin (EM) and its derivatives on ionic currents in airway glands from feline tracheae. Therapeutic concentrations of EM or clarithromycin (CAM) attenuated the whole cell currents evoked by ACh in a competitive manner. The maximally stimulated inward Cl- currents were reduced to 54 and 83% and the outward K+ currents to 55 and 84% of control values by EM and CAM, respectively, whereas the responses induced by phenylephrine, norepinephrine, caffeine, or ionomycin were unaffected by EM, CAM, or EM523, a synthetic derivative of EM. K+ channels in excised outside-out patches were not influenced by macrolides. Although therapeutic concentrations of macrolides showed no effect on the baseline currents, high concentrations of macrolides alone evoked currents mimicking the ACh response, which were abolished completely by atropine. We concluded that macrolides act as a partial agonist on cholinergic receptors, resulting in a reduction of Cl- secretion at pharmacological doses of the agents, which may exhibit a pronounced effectiveness on hypertrophied and/or cholinergically sensitized submucosal glands in pathological airways.

Acetylcholine↗
PubMed1999

Morphometric analysis of bronchial cartilage in chronic obstructive pulmonary disease and bronchial asthma.

To clarify the changes in bronchial cartilage in diseased airways, we performed morphometric analysis of airways in autopsied lungs of 16 patients with chronic bronchitis (Group CB), pulmonary emphysema (Group PE), and bronchial asthma (Group BA), and in control patients without respiratory diseases (Group CN). Although degeneration of bronchial cartilage was clearly observed in airways from all groups except Group CN, the most extreme change was seen in Group CB. Increased perichondrial fibrosis was observed in both Groups CB and BA, and the more extreme change was seen in Group BA. Both the area proportions of degenerated cartilage (Deg%) and perichondrial fibrosis (Fib%) to total cartilage in bronchi (3 to 8 mm in diameter), cut vertically in the cross-section profile, were measured with a digitizing tablet coupled to a computer. No significant differences in the area proportion of cartilage to bronchial wall were observed among the four study groups. The Deg% values of Groups CB (mean: 15.4%), BA (mean: 12.9%), and PE (mean: 9.6%) were significantly higher than those of Group CN (mean: 1.0%) (p < 0.01 in each case). The Deg% values correlated significantly with the number of neutrophils in the bronchial walls (r = 0.63, p < 0. 01). Both Group CB (mean: 28.5%) and Group BA (mean: 33.6%) showed significantly higher values of Fib% than did Group CN (mean: 18.5%) (p < 0.01, each), and the value for Group PE (mean: 21.8%) was slightly increased (p < 0.05). The values of Fib% correlated significantly with the number of eosinophils in the bronchial walls (r = 0.51, p < 0.05), thickness of basement membrane (r = 0.77, p < 0.0002), bronchial gland area (r = 0.56, p < 0.02), and goblet-cell area (r = 0.55, p < 0.02). Further, the values of Deg% correlated significantly with those of Fib% (r = 0.64, p < 0.01). These findings indicate that airways in chronic obstructive pulmonary disease and bronchial asthma have both degenerative changes in the cartilage (chondrocytes) and increased perichondrial fibrosis, and that these alterations in bronchial cartilage may differ in chronic bronchitis and bronchial asthma.

Aged↗
PubMed1999

Suplatast tosilate inhibits late response and airway inflammation in sensitized guinea pigs.

The effect of suplatast tosilate, which has been proven to inhibit T-cell synthesis of IL-4 and IL-5, on the response to antigen inhalation challenge was investigated in sensitized guinea pigs. The animals were given an oral dose of 30 or 100 mg/kg of suplatast or vehicle (distilled water) daily for 1 wk before antigen challenge. Measurement of pulmonary resistance for 6 h was followed by bronchoalveolar lavage and lung fixation. After antigen challenge, all guinea pigs in the vehicle group displayed dual-phase airway obstruction and accumulation of eosinophils and lymphocytes in the airways. After 1 wk of treatment with the high dose of suplatast, the late asthmatic response and the recruitment of eosinophils and lymphocytes into the airways were significantly inhibited, but the early asthmatic response was not affected. In situ hybridization revealed that challenge-induced increases in IL-5 mRNA-positive cells in lung tissue were significantly inhibited after treatment. Thus, suplatast inhibited airway obstruction in the late phase by specifically inhibiting the inflammatory process after mast cell degranulation.

Airway Resistance↗
PubMed1999

Role of peroxynitrite in airway microvascular hyperpermeability during late allergic phase in guinea pigs.

We investigated the role of peroxynitrite, which is formed by a rapid reaction between nitric oxide (NO) and superoxide anion (O(2)(-)), in the airway microvascular hyperpermeability during the late allergic response (LAR) in sensitized guinea pigs in vivo. The occurrence of LAR was assessed as a 100% increase in the transpulmonary pressure, which was monitored by the esophageal catheter technique. Airway microvascular permeability was assessed by Monastral blue dye trapping between the endothelium using an image analyzer. In the LAR phase (4 to 6 h after antigen inhalation), microvascular hyperpermeability and eosinophil infiltration within the airway wall were observed. NO production and xanthine oxidase (XO)/xanthine dehydrogenase activity, which are responsible for O(2)(-) production, were enhanced during the LAR. Peroxynitrite formation assessed by nitrotyrosine immunostaining was also exaggerated at that time. The microvascular hyperpermeability during the LAR was largely reduced by NO synthase inhibitor (L-NAME, 72.7% inhibition; p < 0.05), XO inhibitor (AHPP, 60.8% inhibition; p < 0. 05) and peroxynitrite scavenger (ebselen, 81.0% inhibition; p < 0. 05). L-NAME had a small but significant inhibitory effect on airway eosinophil accumulation, but AHPP and ebselen had no effect. These results suggest that excessive production of O(2)(-) and NO occurs in the LAR. These two molecules appear to cause airway microvascular hyperpermeability via peroxynitrite formation.

Animals↗
PubMed1999

Ovalbumin (OVA) and Mycobacterium tuberculosis bacilli cooperatively polarize anti-OVA T-helper (Th) cells toward a Th1-dominant phenotype and ameliorate murine tracheal eosinophilia.

A recent increase in allergic disorders has coincided with a decrease in infections, including tuberculosis. Although an inverse association between tuberculin responses and atopic disorders was reported, it was not known how T-helper (Th)1-biased immune responses to Mycobacterium tuberculosis influenced Th2-dominant responses to allergens. We examined whether M. tuberculosis could modulate ovalbumin (OVA)-induced eosinophilic inflammation in the murine trachea in a manner that transcended the barrier of antigen specificity. We found that CD4(+) T cells primed with OVA in complete Freund's adjuvant (CFA) inhibited OVA-induced tracheal eosinophilia through interferon (IFN)-gamma secretion. Immunization with an irrelevant antigen in CFA or with OVA in incomplete Freund's adjuvant failed to induce suppressor cells. In vitro experiments confirmed that both M. tuberculosis and OVA (as opposed to either one alone) were necessary to evoke polarized development toward a Th1-like phenotype through interleukin-12 secretion. These results indicate that exposure to an allergen along with M. tuberculosis switches development of allergen-specific T cells toward a Th1 phenotype, which, in turn, downregulates allergic manifestations in an antigen-specific manner. The possible implications of these results are discussed in the context of the causal relationship between a decrease in tuberculosis and an increase in allergic disorders.

Animals↗
PubMed1999

Transforming growth factor-beta secreted from CD4(+) T cells ameliorates antigen-induced eosinophilic inflammation. A novel high-dose tolerance in the trachea.

The induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Tolerance induction in the intestine has been studied extensively and therapeutic applications to autoimmunities are in progress, whereas tolerance in the respiratory tract is poorly investigated. We examined the immunoregulatory mechanisms for evading exaggerated inflammatory responses in the murine airway mucosa. Administration of an optimal dose of ovalbumin (OVA) to the trachea elicited eosinophilic inflammation in the trachea of OVA/aluminum hydroxide-sensitized BALB/c mice, whereas higher doses were unable to do so. This failure paralleled the downregulation of interleukin-4 production by mediastinal lymph node (LN) T cells. This high-dose tolerance was attributable to the mechanisms of antigen (Ag)-specific suppression, because the adoptive transfer of CD4(+) LN T cells from the OVA-tolerant mice inhibited the OVA-specific, but not irrelevant Ag KLH-specific, eosinophilic responses. The inhibitory effects were neutralized by the intratracheal administration of anti-transforming growth factor (TGF)-beta, but not that of anti-interferon (IFN)-gamma, monoclonal antibodies, indicating that the high-dose tolerance was mediated by secreted TGF-beta, but not by the dominance of transferred T helper (Th)1 cells over Th2 cells. The pivotal role of TGF-beta was reinforced by the finding that the LN cells from the OVA-tolerant mice produced TGF-beta in response to the in vitro Ag stimulation. These results demonstrate a novel regulatory mechanism in the airway: that TGF-beta secreted by T cells plays an important role in the downmodulation of the immune responses to high doses of Ag which might otherwise induce deleterious inflammation in the airway mucosal tissues.

Animals↗
PubMed1999

Nocturnal blood pressure during apnoeic and ventilatory periods in patients with obstructive sleep apnoea.

The exact nature of asleep blood pressure in relation to awake blood pressure is still unclear in patients with obstructive sleep apnoea. This study aimed: 1) to investigate the asleep blood pressure in both apnoeic and ventilatory periods; 2) to determine the diurnal and nocturnal factors correlated with the changes in blood pressure from apnoea to ventilatory periods during sleep. Thirty-two patients, newly diagnosed as moderate to severe obstructive sleep apnoea with a standard nocturnal polysomnography, were enrolled. The blood pressure was monitored by using the noninvasive continuous monitoring method during polysomnographic study. The mean blood pressures in ventilatory periods during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were 117.5+/-17.9 mm Hg and 128.8+/-21.9 mm Hg, and those in apnoea periods were 94.5+/-15.4 mm Hg and 102.7+/-19.0 mm Hg. The average blood pressure during NREM sleep (103.0+/-16.1 mm Hg) was higher than the awake blood pressure (97.0+/-15.7 mm Hg). The blood pressure during REM sleep was greater than that during NREM sleep. The changes in the nocturnal blood pressure from apnoea to ventilatory periods were inversely correlated with the age and nocturnal mean nadir saturation. In conclusion, patients with obstructive sleep apnoea have higher asleep blood pressure than awake blood pressure.

Adult↗
PubMed1999

Incidence of pulmonary thromboembolism in Japan.

Pulmonary thromboembolism (PTE) is considered an uncommon disease in Japan and there are not any reported prospective studies on the incidence of PTE in Japan. The objective of the present study was to determine the number of patients with PTE per year in a prospective study using a questionnaire. Letters were sent to clinical departments in university schools of medicine or medical colleges, and to hospitals with more than 100 beds. The diagnosis of PTE was to be confirmed by (1) pulmonary artery stenosis or occlusion on pulmonary angiography, (2) mismatch of pulmonary perfusion scintigraphy and pulmonary ventilation scintigraphy, (3) changes on pulmonary perfusion scintigraphy performed twice, or (4) autopsy. The questionnaire elicited 2,341 replies (the withdrawal rate was 40.7%). In 231 hospitals, 237 patients were diagnosed definitely during the study period of 2 months from 1 August to 30 September 1996. From this it was estimated that there are 3,492 (95% confidence interval: 3,280-3,703) patients with PTE per year, which implies that the incidence is 28 persons per 1,000,000 people per year, confirming that PTE is rare in Japan.

Adult↗
PubMed1999

Effects of low doses of endothelin-1 on basal vascular tone and autoregulatory vasodilation in canine coronary microcirculation in vivo.

The plasma level of endothelin-1 (ET-1) increases in several cardiovascular disorders. The present study examined whether threshold doses of ET-1 affect vascular tone and autoregulatory vasodilation during a reduction in perfusion pressure in the coronary microcirculation in vivo. In anesthetized open-chest dogs, arterial microvessels in the epimyocardium were observed through a microscope equipped with a floating objective. In 6 dogs, ET-1 (10(-13) to 10(-8)mol/L) was superfused onto the epimyocardium in a cumulative fashion. In another set of dogs (n= 16), the perfusion pressure of the observed vascular bed was reduced to 60 mmHg (mild stenosis) and to 40 mmHg (severe stenosis) by a hydraulic occluder, and the microvascular responses were observed in the presence (n=9) or absence (n=7) of ET-1 (10(-12) or 10(-11) mol/L). ET-1 > or =10(-11) mol/L constricted coronary arterioles (< or =100 microm in diameter) and small arteries (>100 microm in diameter) in a dose-dependent fashion. ET-1 of 10(-12) mol/L affected neither the basal diameters nor the dilation of vessels during the pressure reduction. ET-1 of 10(-11) mol/L decreased the diameters of arterioles and small arteries before and during the mild and severe stenosis. However, ET-1 did not attenuate the percentage dilation of arterioles from the baseline in response to the mild and severe stenosis. The data indicates the following: (1) ET-1 at doses > or =10(-11) mol/L similarly constricts coronary arterioles and small arteries; (2) ET-1 at 10(-11) mol/L, which is slightly higher than the pathophysiological plasma level, increases the basal vascular tone, but does not attenuate the autoregulatory vasodilation of the coronary microcirculation.

Animals↗
PubMed1999

The role of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes in alcohol-induced vasospastic angina.

Alcohol ingestion often provokes attacks in patients with vasospastic angina. Type 2 aldehyde dehydrogenase (ALDH2) deficiency, which is based on a single point mutation (Glu487Lys) of the ALDH2 gene, is common in the Japanese population, but rare among the Caucasian population. We investigated how the genotype of ALDH2 affects the characteristics of alcohol-induced vasospastic angina. Ninety-one patients with vasospastic angina who had ingested alcohol daily or occasionally were studied. Patients had been diagnosed as vasospastic angina by a provocation test with an intracoronary injection of ergonovine or acetylcholine during coronary angiography. The Glu487Lys mutation was detected by allele specific PCR. We interviewed the patients to obtain information concerning the relationship between alcohol ingestion and anginal attacks. Alcohol ingestion induced attacks in 16 of 66 patients without the Glu487Lys mutation, 8 of 22 in heterozygotes, and 1 of 3 in mutant homozygotes. The intervals between alcohol ingestion and the onset of anginal attacks were shorter in homozygotes (0.17 hours) and heterozygotes (1.5+/-0.6 hours) for ALDH2*2 than in normal homozygotes for ALDH2*1 (5.4+/-0.6 hours). The amount of ethanol which induced attacks was significantly greater in normal homozygotes than in homozygotes (11 ml) and heterozygotes (42.5+/-7.1 ml) for ALDH2*2 (96.1+/-13.4 ml in normal patients). The frequency of anginal attacks induced by alcohol ingestion did not differ between ALDH deficient and normal homozygotes. In ALDH deficient patients, however, anginal attacks were induced by a smaller amount of alcohol immediately after its ingestion. Thus, the ALDH2 genotype modifies the characteristics of the anginal attacks as a co-factor for the induction of vasospastic angina after alcohol ingestion.

Alcohol Dehydrogenase↗
PubMed1999

Adrenomedullin in monocytes and macrophages: possible involvement of macrophage-derived adrenomedullin in atherogenesis.

Macrophages secrete a variety of growth factors, cytokines and vasoactive peptides, which are related to the progression of atherosclerosis. Adrenomedullin (ADM) is a potent vasodilator peptide and inhibits proliferation and migration of vascular smooth muscle cells. In this study, we investigated the production and secretion of ADM by monocytes and macrophages by Northern blot analysis, RIA and immunocytochemistry. Northern blot analysis showed that ADM mRNA was expressed in human monocytes obtained from peripheral blood and monocyte-derived macrophages. The expression level of ADM mRNA in monocyte-derived macrophages was about five times higher than that in monocytes. Treatment with lipopolysaccharide (100 ng/ml) for 24 h increased ADM mRNA expression levels in both monocytes and monocyte-derived macrophages. The levels of immunoreactive ADM in the media of monocyte-derived macrophages were about three times higher than that of monocytes (0. 718+/-0.046 fmol/24 h/10(5) cells, n=8 compared with 0.259+/-0.018 fmol/24 h/10(5) cells, n=8; mean+/-S.E.M., P<0.01). The secretion was also increased by treatment with lipopolysaccharide. Immunocytochemistry showed positive ADM immunostaining in macrophages in atherosclerotic lesions of human aorta obtained at autopsy. ADM secreted from activated macrophages may play an inhibitory role in atherogenesis.

Adrenomedullin↗
PubMed1999

[Comparison of CRH test and ACTH test in patients with bronchial asthma].

Although glucocorticoid is the most effective agent for bronchial asthma, its systemic administration leads to suppression of adrenocortical function. Rapid ACTH test has been performed for assessing the function of the hypothalamic-pituitary-adrenocortical (HPA) system of asthmatics. Recently human corticotropin-releasing hormone (CRH) has been chemically synthesized. In order to evaluate clinical usefulness of CRH, we compared CRH test with ACTH test in 17 patients with bronchial asthma (3 patients out of them concurrently receiving prednisolone 5-10 mg/day). Both tests were carried out within 2 weeks after 6 month treatment with fluticasone propionate (800 micrograms/day) inhaled via pMDI. There is no significant difference between results obtained from the both tests. Thus, dividing subjects into high and low responders based on an extent of increases in plasma ACTH levels after the CRH injection, we found a significant difference in maximal plasma concentrations of cortisol between after CRH and ACTH injections in the low responders. Therefore, in some patients, CRH test provides more accurate assessment of the function of HPA system than ACTH test.

Adrenocorticotropic Hormone↗
PubMed1999

[Effects of an ATP-sensitive K+ channel activator, JTV-506, on antigen-induced early and late asthmatic responses in sensitized guinea pigs].

Effects of an ATP-sensitive K+ channel activator, JTV-506, on dual asthmatic responses and airway inflammation after antigen inhalation challenge were investigated in asthma model of guinea pigs. The animals were given an oral dose of 1 mg/kg of JTV-506 or vehicle (0.5% carboxymethyl cellulose sodium) 1 hour before and 3 hours after antigen inhalation challenge. Measurement of pulmonary resistance for 6 h was followed by bronchoalveolar lavage. After antigen challenge, all guinea pigs in the vehicle group displayed dual-phase airway obstruction and accumulation of eosinophils in the airways. After the treatment with JTV-506, the early asthmatic response was significantly inhibited, although the late asthmatic response or the recruitment of eosinophils into the airways were not inhibited. Therefore, we suggested that JTV-506 may inhibit airway smooth contraction induced by chemical mediators, but not function of CD4+ T lymphocytes.

Airway Resistance↗
PubMed1999

Safety and efficacy of the neuraminidase inhibitor zanamivir in treating influenza virus infection in adults: results from Japan. GG167 Group.

The study was carried out to evaluate the therapeutic effects of zanamivir, a highly selective, potent and specific inhibitor of influenza A and B virus neuraminidases, in adult patients with acute influenza-like illness. Patients who presented within 36 h of the onset of influenza-like symptoms were randomly assigned to receive one of three treatments, twice daily, for 5 days: 10 mg zanamivir powder for inhalation (zanamivir inhalation group), 10 mg zanamivir powder for inhalation plus 6.4 mg zanamivir nasal spray (zanamivir inhalation plus intranasal group) or placebo (placebo group). The primary end point was the time to alleviation of the three major symptoms (fever, headache and myalgia). The secondary end point was the time to alleviation of five influenza symptoms (fever, headache, myalgia, cough and sore throat). One hundred and sixteen patients with influenza-like illness were recruited to the study. No differences were observed between the two groups of patients who received zanamivir (inhalation group or inhalation plus intranasal group). Patients who received zanamivir recovered significantly faster (median 3 days to recovery) than the patients in the placebo group (median 4 days to recovery; P < 0.01). Topically administered zanamivir was well tolerated. This study confirms that in adults, topically administered zanamivir is well tolerated and is effective in reducing the time to alleviation of influenza symptoms.

Adult↗
PubMed1998

Nitric oxide modulates sympathetic control of left ventricular contraction in vivo in the dog.

Recently, evidence has been presented that nitric oxide (NO) modulates myocardial contraction induced by beta-adrenergic stimulation in vitro and in vivo. In this study, we investigated whether inhibition of the L-arginine NO system augments the positive inotropic response of the left ventricle to direct stimulation of the sympathetic nerves in vivo in the dog. Electrical stimulation was applied to the left stellate ganglion (LSG) for 1 min at submaximal (5 V, 2.5, 5 and 10 Hz) and supramaximal intensities (10 V, 10 Hz) in twelve anesthetized and vagotomized dogs. Next, in the same dogs, N(omega)-nitro L-arginine methylester (L-NAME) was infused into the left anterior descending (LAD) coronary artery, and LSG stimulation repeated using the same protocol. Finally, L-arginine was infused into the LAD artery, and LSG stimulation repeated. We used the maximum of the first derivative of left ventricular pressure (LV max d P/dt) as an index of the myocardial contractility. Plasma epinephrine and norepinephrine concentrations were measured in the coronary sinus at 5 V, 2.5 Hz before and after L-NAME treatment in five of twelve dogs. L-NAME treatment significantly augmented the inotropic response of the left ventricle (percent change in the LV max dP/dt) to LSG submaximal stimulation trains from 164 +/- 13 to.212 +/- 21 (P < 0.03), from 187 +/- 15 to 234 +/- 25 (P < 0.05) and from 220 +/- 19 to 280 +/- 33% (P < 0.05), respectively. This response was reversed by L-arginine treatment. However, the inotropic response to the supramaximal stimulation train did not change after L-NAME and L-arginine treatment. L-NAME significantly increased plasma norepinephrine concentration from 0.69 +/- 0.41 to 1.00 +/- 0.52 ng/ml without changing plasma epinephrine concentration in the coronary sinus. It is concluded that the inhibition of the L-arginine NO system augmented the positive inotropic effect on the left ventricle during sympathetic nerve stimulation in normal dogs in vivo.

Animals↗
PubMed1998

Induction of adrenomedullin by hypoxia and cobalt chloride in human colorectal carcinoma cells.

Adrenomedullin (ADM) is a vasodilator peptide, first isolated from human pheochromocytoma. To explore the pathophysiological role of ADM in ischemic conditions, we investigated the effects of hypoxia on ADM production and ADM mRNA expression in a cultured human colorectal carcinoma cell line, DLD-1. Northern blot analysis and radioimmunoassay showed that hypoxia stimulated the accumulation of ADM mRNA in the DLD-1 cells and immunoreactive ADM (ir-ADM) in the cultured media. Exposure to hypoxia for 12 hours increased ADM mRNA levels about 6-fold and ir-ADM levels about 4-fold. Moreover, treatment of DLD-1 cells with cobalt chloride, which mimics hypoxic states, significantly increased ADM mRNA levels about 18-fold and ir-ADM levels about 4-fold. These results suggest that ADM plays an important role in the pathophysiology of ischemic states.

Adrenomedullin↗