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Biomedical subjects

H Kosaka

Publications and source records attributed to H Kosaka.

At least 73 records · Page 4Linked to original sources
PubMed1998

Increased release of nitric oxide in ischemic hearts after exercise in patients with effort angina.

OBJECTIVES: The aim of this study was to determine whether the release of nitric oxide (NO) from the ischemic heart increases during exercise in patients with effort angina. BACKGROUND: Myocardial ischemia increases NO production in the canine heart, but no such increase has been demonstrated in the ischemic human heart. METHODS: Fifteen patients with effort angina underwent supine ergometer exercise tests. All patients had severe proximal stenosis (>90%) in the left anterior descending coronary artery. The control group consisted of 17 subjects without coronary artery disease or systemic hemodynamic abnormalities. RESULTS: Neither the lactate extraction ratio (LER) nor the difference in NO concentration between coronary venous and arterial blood (deltaVA[NO]) was affected by exercise in the control subjects. In patients with effort angina, neither variable differed from that in the control group at rest; however, exercise markedly decreased LER and significantly increased deltaVA(NO) (from 4.7 +/- 0.3 to 16.5 +/- 1.6 micromol/liter, p < 0.001) in the patient group. The extent of decrease in LER was significantly correlated with the extent of increase in deltaVA(NO) in the patients with effort angina (r2 = -0.837, p < 0.001). CONCLUSIONS: Provocation of myocardial ischemia by exercise stress increases NO production in the hearts of patients with effort angina.

Aged↗
PubMed1998

Role of nitric oxide in vascular hyper-responsiveness to norepinephrine in hypertensive Dahl rats.

OBJECTIVE: To determine whether the abnormal vascular responses observed in salt-sensitive hypertension are caused by an impairment in vascular nitric oxide function. DESIGN: Isometric tension was measured in aortic rings isolated from Dahl salt-sensitive and salt-resistant rats fed a regular-salt (0.4% NaCl) or a high-salt (8% NaCl) diet, with and without inhibition of endogenous nitric oxide synthesis. METHODS AND RESULTS: Systolic arterial pressure, measured weekly by the tail-cuff method, increased markedly in DS rats with a high-salt diet but did not increase in the other groups. In aortic rings, norepinephrine evoked dose-dependent contractions which were significantly increased in rings from DS rats with a high-salt diet Pretreatment with Nomega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, increased the norepinephrine-induced contraction in all groups and abolished differences in contractile responses between high-salt DS rats and the other groups. Acetylcholine induced endothelium-dependent relaxation, which was significantly depressed in high-salt DS rats. L-NAME attenuated the acetylcholine-induced relaxation in all groups and abolished the difference in relaxation response between high-salt DS rats and the other groups. Sodium nitroprusside-induced relaxation was significantly depressed in high-salt DS rats. CONCLUSIONS: Vascular hypercontractile responses to norepinephrine in DS hypertensive rats can, in part, be explained by an impairment in endothelial nitric oxide production.

Acetylcholine↗
PubMed1998

Is a hypertensinogenic factor present in the kidney of hypertensive dahl rats?

1. Early studies suggest that hypertension in Dahl salt-sensitive (S) rats is related to an uncommon humoral factor that may be released from the kidney. 2. To investigate whether the kidney releases a hypertensinogenic factor for developing salt-induced hypertension in S rats, we examined a pressor effect, or vascular contractive activity of a kidney extract from S rats using a conscious recipient rat or an isolated aortic ring. 3. Donor S and Dahl salt-resistant (R) rats were fed a 0.4 or 8% NaCl diet for 4 weeks and were then used to provide four kinds of kidney extracts (S-0.4%, S-8%, R-0.4%, R-8%). The systolic arterial pressure (SAP) was significantly increased in donor S rats fed an 8% NaCl diet compared with other donor rat groups. 4. All four types of kidney extract increased mean arterial pressure (MAP) in a recipient rat fed a 0.4% NaCl diet. However, the increase in MAP observed following infusion of the S-8% extract was the least of all groups. An angiotensin AT1 receptor antagonist, CV-11974, abolished any pressor effect of all kidney extracts. In an in vitro experiment, all four types of kidney extract evoked contractile responses in aortic rings, but elicited no significant difference in aortic ring contractile force. 5. These results suggest that the kidney of S rats may not release an active hypertensinogenic factor that would cause salt-induced hypertension.

Angiotensin Receptor Antagonists↗
PubMed1998

Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens.

There is now convincing evidence that CD8+ T cells can be activated by professional antigen-presenting cells which present antigens derived from non-lymphoid tissues in association with MHC class I molecules in the draining lymph nodes. This mechanism, referred to as cross-presentation, enables the immune system to respond to those microorganisms that infect only non-lymphoid tissues. Consistent with this view, cross-presentation was found to focus on antigens expressed in high concentrations and those released from dying cells, which can be expected to result from viral infections. Recent evidence, however, demonstrates that high dose self antigens can be cross-presented constitutively, resulting in the activation of autoreactive CD8+ T cells. This does not lead to auto immunity under physiologic conditions, but to CD95-mediated deletion of the T cells. Cross-presentation can thus engage a well-defined pathway of antigen-induced T-cell death and purge the immune system of autoreactive CD8+ T cells. Low dose self antigens are not cross-presented and are consequently ignored. The immune system therefore uses two strategies to avoid CD8+ T-cell-mediated autoimmunity in the periphery: deletion of autoreactive CD8+ T cells responding to high dose self antigens and ignorance of self antigens expressed at low concentrations.

Animals↗
PubMed1998

Inducible nitric oxide synthase augments injury elicited by oxidative stress in rat cardiac myocytes.

The effects of nitric oxide (NO) produced by cardiac inducible NO synthase (iNOS) on myocardial injury after oxidative stress were examined: Interleukin-1 beta induced cultured rat neonatal cardiac myocytes to express iNOS. After induction of iNOS, L-arginine enhanced NO production in a concentration-dependent manner. Glutathione peroxidase (GPX) activity in myocytes was attenuated by elevated iNOS activity and by an NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). Although NO production by iNOS did not induce myocardial injury, NO augmented release of lactate dehydrogenase from myocyte cultures after addition of H2O2 (0.1 mM, 1 h). Inhibition of iNOS with N omega-nitro-L-arginine methyl ester ameliorated the effects of NO-enhancing treatments on myocardial injury and GPX activity. SNAP augmented the myocardial injury induced by H2O2. Inhibition of GPX activity with antisense oligodeoxyribonucleotide for GPX mRNA increased myocardial injury by H2O2. Results suggest that the induction of cardiac iNOS promotes myocardial injury due to oxidative stress via inactivation of the intrinsic antioxidant enzyme, GPX.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit.

In previous studies we used NG-nitro-L-arginine (L-NNA) to investigate the role of nitric oxide (NO) in baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA). L-NNA increased resting mean arterial pressure (MAP), decreased HR, and did not change or slightly decreased RSNA. These changes complicated the assessment of the central effects of NO on the baroreflex control of HR and RSNA. Therefore, in the present study the effects of the relatively selective neuronal NO synthase inhibitor 7-nitroindazole (7-NI) on the baroreflex control of HR and RSNA were investigated in rabbits. Intraperitoneal injection of 7-NI (50 mg/kg) had no effect on resting HR, MAP, or RSNA. 7-NI significantly reduced the lower plateau of the HR-MAP baroreflex curve from 140 +/- 4 to 125 +/- 4 and from 177 +/- 10 to 120 +/- 9 beats/min in conscious and anesthetized preparations, respectively (P < 0.05). In contrast, there was no significant difference in the RSNA-MAP curves before and after 7-NI administration in conscious or anesthetized preparations. These data suggest that blockade of neuronal NO synthase influences baroreflex control of HR but not of RSNA in rabbits.

Animals↗
PubMed1998

Role of Ca2+-activated K+ channels in the protective effect of ACE inhibition against ischemic myocardial injury.

Angiotensin-converting enzyme (ACE) inhibitors increase the production of nitric oxide (NO) and prostacyclin and open Ca2+-activated K+ channels. The effects of these actions of ACE inhibitors on infarct size were investigated in open-chest dogs subjected to myocardial ischemia and reperfusion. Infarct size was assessed 6 hours after the onset of reperfusion, subsequent to 90 minutes of occlusion of the left anterior descending coronary artery. The ACE inhibitor cilazaprilat was administered into the coronary artery 10 minutes before coronary occlusion, and infusion was continued until 1 hour after reperfusion. The bradykinin and NO concentrations in coronary venous blood 10 minutes after the onset of reperfusion were significantly higher in dogs treated with cilazaprilat (3 microg x kg(-1) x min(-1)) than in control animals. Although there were no significant differences in collateral flow during ischemia, infarct size in the cilazaprilat group was smaller than that in the control group (15.1+/-3.0% versus 46.7+/-4.2% of the area at risk, P<0.0001). The infarct size-limiting effect of cilazaprilat was partially reduced by either N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or iberiotoxin (a blocker of Ca2+-activated K+ channels) and was abolished by N(G)-nitro-L-arginine methyl ester plus iberiotoxin. Indomethacin (an inhibitor of cyclooxygenase) had no effect on the beneficial action of cilazaprilat. Inhibition of ACE thus reduced myocardial infarct size, an effect that was mediated by NO and the opening of Ca2+-activated K+ channels in canine hearts.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

[Load on the low back of teachers in kindergartens].

In order to evaluate the load on the low back of teachers in kindergartens, basic activity and working posture were analyzed for four teachers by means of video recording. The trunk inclination angle (TIA) was also measured continuously during full workshifts for 12 kindergarten teachers by means of an inclination monitor. The kindergarten teachers spent 67% of the workshift on activities in contact with children, "indoor group childcare", "indoor free playing", "outdoor childcare", "preparation and clearing away" and "help and care", and did not take a recess during the workshift. They spent 36% of the workshift in three working postures with the load on the low back, "standing bent forward", "squatting" and "kneeling". Cumulative time at a TIA of 20 degrees or more represented 43% of the workshift. The frequency of trunk-lifting from severe bending forward (TIA > 45 degrees) was 95 times/hr on average. A comparison of the kindergarten teachers and nursery teachers in 4-5 year age classes showed that the time distributions of basic activities were generally similar to each other. Although the time distributions of working postures were also similar, time spent "standing bent forward", "squatting" and "kneeling" was longer in the kindergarten teachers than in the nursery teachers. Cumulative time at a TIA of 45 degrees or more was significantly longer in the kindergarten teachers. Although the frequency of trunklifting was not significantly different, the kindergarten teachers tended to lift their trunk more frequently. The present study found that the load on the low back was considerably great in the kindergarten teachers.

Adult↗
PubMed1997

Stability of mutant superoxide dismutase-1 associated with familial amyotrophic lateral sclerosis determines the manner of copper release and induction of thioredoxin in erythrocytes.

We analyzed mutant superoxide dismutase-1 (SOD-1) in erythrocytes from patients with familial amyotrophic lateral sclerosis (FALS) by using ion exchange chromatography and HPLC/electrospray ionization mass spectrometry and were able to divide mutant SOD-1 proteins into a stable form including G37R and H46R, and an unstable form including I149T and a two base pair deletion mutant. Each mutant sample showed abnormal copper peaks in different chromatographic fractions without relation to SOD-1 activities. In addition, thioredoxin, known as an antioxidant molecule, was markedly increased in the stable form but not in the unstable form. These results suggest the presence of different pathways leading to motor neuron death between stable and unstable mutants.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels.

BACKGROUND: 17Beta-estradiol increases the production of nitric oxide (NO) and prostacyclin and opens Ca2+-activated K+ (K(Ca)) channels. Whether these effects of 17beta-estradiol reduce infarct size and the incidence of ventricular arrhythmia was investigated in dogs subjected to myocardial ischemia and reperfusion. METHODS AND RESULTS: Infarct size was measured in open-chest dogs after 90 minutes' occlusion of the left anterior descending coronary artery and a subsequent 6 hours of reperfusion. Infusion of 17beta-estradiol into the coronary artery was initiated 10 minutes before coronary occlusion and continued until after 1 hour of reperfusion, with the exception of the occlusion period. The difference in NO concentration between coronary venous and arterial blood 10 minutes after the onset of reperfusion was significantly greater in dogs treated with 17beta-estradiol (10 ng x kg(-1) x min(-1)) than in control animals. Infarct size (13.1+/-3.0% versus 43.7+/-5.4% of the area at risk) and the incidence of ventricular arrhythmia during ischemia and reperfusion periods were significantly reduced in the 17beta-estradiol group. Both N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) and iberiotoxin (a blocker of K(Ca) channels) reduced both the infarct size-limiting effect (infarct size, 29.3+/-3.0% and 31.7+/-2.1%, respectively) and the antiarrhythmic effect of 17beta-estradiol; indomethacin (an inhibitor of cyclooxygenase) did not attenuate the beneficial effects of 17beta-estradiol. CONCLUSIONS: 17Beta-estradiol reduced both myocardial infarct size and the occurrence of ischemia- and reperfusion-induced ventricular arrhythmias, which appear to be mediated by NO and the opening of K(Ca) channels in canine hearts.

Animals↗
PubMed1997

Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells.

In this report, we show that cross-presentation of self-antigens can lead to the peripheral deletion of autoreactive CD8(+) T cells. We had previously shown that transfer of ovalbumin (OVA)-specific CD8(+) T cells (OT-I cells) into rat insulin promoter-membrane-bound form of OVA transgenic mice, which express the model autoantigen OVA in the proximal tubular cells of the kidneys, the beta cells of the pancreas, the thymus, and the testis of male mice, led to the activation of OT-I cells in the draining lymph nodes. This was due to class I-restricted cross-presentation of exogenous OVA on a bone marrow-derived antigen presenting cell (APC) population. Here, we show that adoptively transferred or thymically derived OT-I cells activated by cross-presentation are deleted from the peripheral pool of recirculating lymphocytes. Such deletion only required antigen recognition on a bone marrow-derived population, suggesting that cells of the professional APC class may be tolerogenic under these circumstances. Our results provide a mechanism by which the immune system can induce CD8(+) T cell tolerance to autoantigens that are expressed outside the recirculation pathway of naive T cells.

Adoptive Transfer↗
PubMed1997

Bradykinin mediation of Ca(2+)-activated K+ channels regulates coronary blood flow in ischemic myocardium.

BACKGROUND: Endothelium-dependent hyperpolarizing factor relaxes vascular smooth muscles by opening the Ca(2+)-activated K+ (KCa) channels. The role of the opening of KCa channels in coronary vasodilation during myocardial ischemia was investigated. METHODS AND RESULTS: The left anterior descending coronary arteries of open-chest dogs were perfused with blood through an extracorporeal bypass tube from the carotid artery. Intracoronary administration of bradykinin increased coronary blood flow (CBF) in dogs treated with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase; this effect was completely inhibited by the KCa channel blocker iberiotoxin. In dogs treated with L-NAME, the bypass tube was occluded to reduce CBF to one third of the baseline value, after which coronary perfusion pressure was maintained constant. Intracoronary administration of iberiotoxin for 20 minutes further decreased CBF (from 33 +/- 2 to 19 +/- 2 mL.100 g-1.min-1, P < .01), fractional shortening, and lactate extraction ratio during coronary hypoperfusion. Bradykinin was released, and the bradykinin receptor antagonist HOE-140 blocked the effects of iberiotoxin on coronary hemodynamic and metabolic parameters during myocardial ischemia. Although the combination of L-NAME and the adenosine receptor antagonist 8-sulfophenyltheophylline reduced reactive hyperemic flow after 20 seconds of coronary occlusion, the additional presence of iberiotoxin resulted in a further decrease in this parameter. CONCLUSIONS: The opening of KCa channels in response to endogenous bradykinin contributed to coronary vasodilation and reduced contractile and metabolic dysfunction during myocardial ischemia in open-chest dogs.

Animals↗
PubMed1997

T cell tolerance and autoimmunity.

Many T cells with auto-aggressive potential are deleted in the thymus. Although some of these escape to the general circulation, they do not usually damage organs such as the pancreas. To investigate the mechanisms preventing autoimmunity, we generated transgenic mice expressing known genes under the control of various promoters. We found that the occurrence of autoaggression depended on factors such as the precursor frequency of responding T cells, their state of activation, their accessibility to the autoantigen, the physicochemical properties of the autoantigen, the possibility of priming by environmental antigens which mimic the target antigen, and some inflammatory reaction in the target site.

Animals↗
PubMed1997

Role of nitric oxide in oxygen transport in rat liver sinusoids during endotoxemia.

To evaluate the role of nitric oxide (NO) in hepatic microcirculation and liver injury during endotoxemia, we studied O2 transport in the hepatic microcirculation of endotoxin-infused rats. Rats were continuously infused with Escherichia coli lipopolysaccharide (LPS) (0.8 mg/kg/h) for 7 hours. LPS increased the plasma levels of NO2- + NO3- and aspartate transaminase (AST), and decreased the bile flow rate and hepatic adenosine triphosphate (ATP) level. Hepatic microcirculation was evaluated by two methods: reflectance spectrophotometry showed a decrease in the oxygenation of hemoglobin (Hb) in the liver, and dual-spot microspectroscopy indicated that LPS administration decreased blood velocity, the oxygenation of Hb, and O2 release from sinusoids to hepatocytes. The observed decreases in the O2 transport parameters were prominent in pericentral sinusoids. All of these phenomena were further aggravated by the administration of N(w)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg/h) plus LPS, and by aminoguanidine (AMG) (5 mg/kg/h) plus LPS, and these could be reversed by the concomitant administration of L-arginine (L-Arg) (100 mg/kg/h). These results suggest that deterioration of hepatic oxygen transport and liver function induced by endotoxin can be ameliorated by NO.

Adenosine Triphosphate↗
PubMed1997

Increased nitric oxide levels in exhaled air of rat lung allografts.

In organ transplantation nitric oxide has been reported to be involved in allograft rejection. We examined in a rat lung transplantation model whether nitric oxide is overproduced in acute rejection and can be detected in exhaled air. Thirteen rat right lung transplants were separated into three groups: group 1 (n = 5), untreated allografts (Brown-Norway [RT1n] to Lewis [RT1l]); group 2 (n = 4), cyclosporine-treated allografts; and group 3 (n = 4), isografts (Lewis to Lewis). We examined exhaled nitric oxide levels with a chemiluminescence analyzer and chest roentgenograms on days 2 through 5. Histologic samples were obtained on days 3 and 5. On day 5, the recipients were killed and we measured exhaled nitric oxide from the right and left lungs separately. Blood samples were also obtained for measurement of serum nitrite/nitrate. The exhaled nitric oxide level in untreated allografts increased significantly from day 5 (63.9 +/- 39.2 ppb, p = 0.0095) and was significantly higher than that in treated allografts (9.1 +/- 1.6 ppb) (p = 0.0085) and isografts (6.9 +/- 0.5 ppb) (p = 0.0068). The nitric oxide level in untreated allografts (826.5 +/- 416.1 ppb) was 75 times as high as that from the contralateral normal left lungs (11.2 +/- 2.6 ppb) (p = 0.0118). The level of exhaled nitric oxide correlated significantly with the histologic rejection grade (p = 0.0001). There was no significant difference in the serum nitrite/nitrate levels between allografts and isografts. These data suggest that increased exhaled nitric oxide levels might reflect acute rejection in lung transplants.

Animals↗