Biomedical subjects

H Ishihara

Publications and source records attributed to H Ishihara.

At least 199 records · Page 11Linked to original sources

PubMed1997

Functional importance of Shc tyrosine 317 on insulin signaling in Rat1 fibroblasts expressing insulin receptors.

Shc is phosphorylated on Tyr-317, which serves as a docking site for Grb2. To investigate the specific role of Shc phosphorylation and Shc.Grb2 coupling on insulin signaling, we generated expression vectors for wild-type (WT-Shc) and a mutant Shc with a Tyr-317 --> Phe substitution (317Y/F-Shc) and stably transfected them into Rat1 fibroblasts expressing insulin receptors (HIRc). From different clonal cell lines, cells expressing 10 times greater amounts of WT-Shc or 317Y/F-Shc compared with endogenous Shc were chosen for analysis of insulin signaling. Insulin-induced Shc phosphorylation and subsequent association with Grb2 was enhanced in WT-Shc cells. Because of competition between Shc and IRS-1 for interaction with the insulin receptor, insulin-stimulated tyrosine phosphorylation of IRS-1 was decreased in WT-Shc cells compared with that in HIRc cells. Likewise, reduction of endogenous Shc expression by antisense Shc mRNA resulted in increased insulin stimulation of IRS-1 phosphorylation. Although 317Y/F-Shc was also able to interact with insulin receptor, decreased amounts of Shc phosphorylation and Shc association with Grb2 were observed in 317Y/F-Shc cells, indicating that 317Y/F-Shc functions as a dominant-negative mutant. The kinetics of mitogen-activated protein (MAP) kinase activation closely paralleled the kinetics of Shc phosphorylation. Thus, insulin stimulation of MAP kinase activation occurred more rapidly and was prolonged in WT-Shc cells, while the activation was delayed and transient in 317Y/F-Shc cells compared with that in HIRc cells. Importantly, WT-Shc cells displayed enhanced sensitivity to insulin stimulation of thymidine and bromodeoxyuridine incorporation, whereas the sensitivity was decreased in 317Y/F-Shc cells. These results indicate that Shc Tyr-317 phosphorylation plays an important role, via coupling with Grb2 and competition with IRS-1, in signal transduction to MAP kinase by insulin, ultimately leading to mitogenesis in Rat1 fibroblasts.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Protease-activated receptor 3 is a second thrombin receptor in humans.

Thrombin is a coagulation protease that activates platelets, leukocytes, endothelial and mesenchymal cells at sites of vascular injury, acting partly through an unusual proteolytically activated G-protein-coupled receptor. Knockout of the gene encoding this receptor provided definitive evidence for a second thrombin receptor in mouse platelets and for tissue-specific roles for different thrombin receptors. We now report the cloning and characterization of a new human thrombin receptor, designated protease-activated receptor 3 (PAR3). PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, including human bone marrow and mouse megakaryocytes, making it a candidate for the sought-after second platelet thrombin receptor. PAR3 provides a new tool for understanding thrombin signalling and a possible target for therapeutics designed selectively to block thrombotic, inflammatory and proliferative responses to thrombin.

Amino Acid Sequence↗

PubMed1997

Massive actin polymerization induced by phosphatidylinositol-4-phosphate 5-kinase in vivo.

The Rho family GTP-binding proteins have been known to mediate extracellular signals to the actin cytoskeleton. Although several Rho interacting proteins have been found, downstream signals have yet to be determined. Many actin-binding proteins are known to be regulated by phosphatidylinositol 4,5-bisphosphate in vitro. Rho has been shown to enhance the activity of phosphatidylinositol-4-phosphate 5-kinase (PI4P5K), the phosphatidylinositol 4,5-bisphosphate synthesizing enzyme. Recently we isolated several isoforms of type I PI4P5K. Here we report that PI4P5K Ialpha induces massive actin polymerization resembling "pine needles" in COS-7 cells in vivo. When truncated from the C terminus to amino acid 308 of PI4P5K Ialpha, both kinase activity and actin polymerizing activity were lost. Although the dominant negative form of Rho, RhoN19, alone decreased actin fibers, those induced by PI4P5K were not affected by the coexpression of RhoN19. These results suggest that PI4P5K is located downstream from Rho and mediates signals for actin polymerization through its phosphatidylinositol-4-phosphate 5-kinase activity.

Actins↗

PubMed1997

Expansive lumbar laminoplasty for degenerative spinal stenosis in patients below 70 years of age.

We reviewed the clinical and radiological results of patients with lumbar degenerative spinal stenosis who underwent expansive laminoplasty with a mean follow-up term of 5.6 years. Twenty-seven patients underwent open-door-type expansive lumbar laminoplasty, which has both decompression and stabilization effects. Clinical results were assessed based on the score system devised by the Japanese Orthopaedic Association (JOA score). The number and causes of repeat surgery were also evaluated. Radiological changes, such as degenerative scoliosis and spondylolisthesis, were evaluated at the operated levels and at levels L1-L5. There was marked recovery of clinical symptoms assessed by pre- and postoperative JOA score. Nearly 80% of patients obtained good or excellent results. Only one patient (4%) required additional surgery, which involved discectomy at the caudal level of the laminoplasty. Radiographic evaluation revealed that postoperative changes of spondylolisthesis and scoliosis were slight both in the expanded area and the L1-L5 levels. Range of motion of the disc space angle in the expanded area showed a significant decrease postoperatively. However, pre- and postoperative radiological changes showed no significant correlation with JOA score changes and repeat surgery. In conclusion, lumbar fusion after posterior decompression in active patients with spinal stenosis offers satisfactory clinical results concomitantly with a relatively small risk of repeat surgery.

Age Factors↗

PubMed1997

Midazolam reverses histamine-induced bronchoconstriction in dogs.

PURPOSE: Midazolam has been used clinically as a sedative and as an anaesthetic induction agent. However, the bronchodilating effects of midazolam have not been comprehensively evaluated. We sought to determine relaxant effects of midazolam on the airway. METHODS: After our Animal Care Committee approved the study, eight mongrel dogs were anaesthetized with 30 mg.kg-1 pentobarbitone iv, and were paralysed with 200 micrograms.kg-1.hr-1 pancuronium. The trachea was intubated with an endotracheal tube (ID 7 mm) that had a second lumen for insertion of a superfine fibreoptic bronchoscope (OD 2.2 mm) to measure the bronchial cross-sectional area (BCA) continuously. The tip of the bronchoscope was placed at the level of the second or third bronchial bifurcation of the right bronchus. A videoprinter printed the BCA which was then measured with a NIH image program. Bronchoconstriction was produced with histamine (H) 10 micrograms.kg-1 followed by 500 micrograms.kg-1.hr-1. Thirty minutes later, 0 [saline], 0.01, 0.1 and 1.0 mg.kg-1 midazolam and 25 micrograms.kg-1 flumazenil were given. The BCA was assessed before (basal area) and 30 min after the start of H infusion, and was also measured five minutes after each midazolam and flumazenil iv. At the same time, arterial blood was sampled for plasma catecholamine measurement. RESULTS: Histamine infusion decreased BCA to 49.7 +/- 17.3% of basal BCA. More than 0.1 mg.kg-1 midazolam increased BCA up to 71.7 +/- 15.3% of the basal (1.0 mg.kg-1) (P < 0.01). Plasma adrenaline concentration was decreased from 6.9 +/- 3.8 to 3.7 +/- 1.9 ng.ml-1 by 1.0 mg.kg-1 midazolam (P < 0.05). Flumazenil did not antagonize the relaxant effect of midazolam but reversed the inhibitory effect of midazolam on histamine-induced adrenaline release. CONCLUSION: Midazolam has a spasmolytic effect on constricted airways but this bronchodilatation was not reversed by flumazenil.

Anesthetics, Intravenous↗

PubMed1997

Fatty acid induced insulin resistance in rat-1 fibroblasts overexpressing human insulin receptors: impaired insulin-stimulated mitogen-activated protein kinase activity.

Saturated fatty acids cause insulin resistance but the underlying molecular mechanism is still unknown. We examined the effect of saturated nonesterified fatty acids on insulin binding and action in transfected Rat-1 fibroblasts, which over-expressed human insulin receptors. Incubation with 1.0 mmol/l palmitate for 1-4 h did not affect insulin binding, insulin receptor autophosphorylation, insulin-stimulated tyrosine kinase activity toward poly(Glu4:Tyr1), pp185 and Shc phosphorylation and PI3-kinase activity in these cells. However, the dose response curve of insulin-stimulated glucose transport was right-shifted. Palmitate inhibited the maximally insulin-stimulated mitogen activated protein (MAP) kinase activity toward synthetic peptide to 7% that of control. The palmitate treatment influenced neither cytosolic protein kinase A activity nor cAMP levels. These results suggested that 1) palmitate did not inhibit the early steps of insulin action from insulin binding to pp185 or Shc phosphorylation but inhibited insulin-stimulated MAP kinase, and that 2) palmitate decreased insulin sensitivity as manifested by inhibited insulin-stimulated glucose uptake. In conclusion, the mechanism of saturated non-esterified fatty acid induced insulin resistance in glucose uptake may reside at post PI3-kinase or Shc steps, including the level of MAP kinase activation.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Prediction of the surgical outcome for the treatment of cervical myelopathy by using hyperbaric oxygen therapy.

The effectiveness of hyperbaric oxygen therapy (HBO) in predicting the recovery after surgery in patients with cervical compression myelopathy was evaluated. HBO has been used to treat brain and spinal cord diseases, but the effect is generally temporary. This is the first paper to utilize HBO as a diagnostic tool to evaluate the functional integrity of the spinal cord. The study group consisted of 41 cervical myelopathy patients aged 32-78 years. Before surgery, the effect of HBO was evaluated and was categorized as four grades. The severity of the myelopathy and the recovery after surgery were evaluated by the score proposed by the Japanese Orthopaedic Association (JOA score). The correlation between many clinical parameters including the HBO effect and the recovery rate of JOA score was evaluated. The recovery rate of JOA score was found to be 75.2 +/- 20.8% in the excellent group, 78.1 +/- 17.0% in the good group, 66.7 +/- 21.9% in the fair group and 31.7 +/- 16.4% in the poor group. There was a statistically significant correlation between the HBO effect and the recovery rate of the JOA score after surgery (r = 0.641, P < 0.0001). The effect of HBO showed a high correlation with the recovery rate after surgery as compared to the other investigated parameters. HBO can be employed to assess the chance of recovery of spinal cord function after surgical decompression.

Adult↗

PubMed1997

Uneventful total intravenous anaesthesia with ketamine for schizophrenic surgical patients.

Ketamine has been considered to be contraindicated for schizophrenic patients because it may induce psychological emergence reactions and psychiatric deterioration. Total intravenous anaesthesia (TIVA) with ketamine combined with droperidol and fentanyl (DFK) has been used in 14 schizophrenic patients undergoing various surgical procedures. Two patients died post-operatively of concomitant severe disease rather than from schizophrenia related pathophysiology or anaesthetic complication. One patient showed transient mild anxiety in the early post-operative period soon relieved by the patient's routine medication. However, no patient developed exacerbations of psychosis or psychological emergence reactions during the first post-operative month. The cardiovascular state during and after DFK remained stable in all cases. It is concluded that ketamine when combined with droperidol and fentanyl is a satisfactory anaesthetic for patients with schizophrenia.

Adjuvants, Anesthesia↗

PubMed1997

Increase in serum creatine phosphokinase concentrations after suxamethonium during sevoflurane or isoflurane anaesthesia in children.

We have studied whether sevoflurane or isoflurane anaesthesia modulates the effect of suxamethonium on serum concentrations of enzyme markers of skeletal muscle function in paediatric patients. Eighty patients undergoing bilateral tonsillectomy, aged 5-12 yr, were allocated randomly to receive anaesthesia with either sevoflurane and nitrous oxide or isoflurane and nitrous oxide. Serum creatine phosphokinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) concentrations were measured before, and at 30 min and 20 h after induction of anaesthesia. Mean CK concentrations increased from 97.0 (SD 17.3) to 478 (170) iu litre-1 in the sevoflurane group and from 86.9 (22.4) to 628 (223) iu litre-1 in the isoflurane group, 20 h after induction of anaesthesia. Mean peak serum CK concentration in the sevoflurane group (478 (170) iu litre-1) was significantly less (P < 0.05) than that in the isoflurane group (628 (223) iu litre-1). Mean serum AST concentration increased from 17.5 (4.9) to 31.7 (3.5) iu litre-1 in the sevoflurane group and from 17.3 (2.4) to 34.8 (5.7) iu litre-1 in the isoflurane group, 20 h after induction of anaesthesia. Mean peak serum AST concentrations in the sevoflurane group were significantly lower (P < 0.05) than those in the isoflurane group. There were no significant differences in serum ALT or LDH concentrations between the groups either before or after anaesthesia. We conclude that administration of suxamethonium during either sevoflurane or isoflurane anaesthesia caused a marked increase in serum CK concentrations in paediatric patients. The clinical significance of this finding is uncertain.

Anesthetics, Inhalation↗

PubMed1997

In vivo assessment of droperidol-induced bronchial relaxation in dogs using a superfine fibreoptic bronchoscope.

Droperidol has been reported to cause bronchodilatation but its mechanism(s) of action is unknown. We have evaluated the spasmolytic effect of droperidol on histamine- and serotonin (5-HT)-induced bronchoconstriction in dogs. Bronchial cross-sectional area was assessed with a superfine fibreoptic bronchoscope. Twenty-eight mongrel dogs were allocated randomly to one of two groups (histamine and 5-HT) to receive either histamine or 5-HT to induce bronchoconstriction. Changes in bronchial cross-sectional area were presented as percentage of basal bronchial cross-sectional area. Continuous i.v. infusion of histamine 500 micrograms kg-1 h-1 or 5-HT 500 micrograms kg-1 h-1 decreased percentage bronchial cross-sectional area by 46.4 (14.3)% or 68.9 (13.7)%, respectively. In both groups, droperidol reversed bronchoconstriction in a dose-dependent manner. In the histamine but not in the 5-HT group, plasma adrenaline and noradrenaline concentrations increased significantly after i.v. droperidol. In addition, propranolol antagonized droperidol-induced relaxation in the histamine but not in the 5-HT group. Our data indicate that the spasmolytic effect of droperidol on canine airway was caused, at least in part, by both catecholamine releases and 5-HT receptor antagonism.

Animals↗

PubMed1997

Measurement of bronchodilatation using a superfine fibreoptic bronchoscope.

In this study, we report the development and accuracy of a direct technique to measure airway calibre using a superfine fibreoptic bronchoscope. Ten mongrel dogs were anaesthetized with pentobarbitone and the trachea intubated with a tracheal tube; the small lumen of the tube allowed passage of a superfine fibreoptic bronchoscope (od 2.2 mm). Bronchial cross-sectional area and airway pressure were recorded continuously and dynamic pulmonary compliance and airway resistance calculated. The dogs were allocated to one of two groups. In the first group (six dogs), bronchoconstriction was induced with histamine 10 micrograms kg-1 i.v. and 500 micrograms kg-1 h-1 c.i.v. Thirty minutes later, adrenaline 0-0.4 mg kg-1 was given i.v. Bronchial cross-sectional area, dynamic pulmonary compliance and airway resistance were assessed simultaneously. In the second group, 0.9% saline was given 30 min after placement of the superfine fibreoptic bronchoscope and 10 min later atropine 0.1 microgram kg-1 was administered. In the first group, histamine decreased mean percentage bronchial cross-sectional area by 49.2 (SD 11.5) %, reduced dynamic pulmonary compliance from 32.1 (12.6) to 22.3 (5.2) ml cm H2O-1 and increased airway resistance from 39.1 (11.6) to 57.2 (10.2) cm H2O litre-1 s-1. Adrenaline produced a dose-dependent increase in percentage bronchial cross-sectional area and dynamic pulmonary compliance to 119.4 (31.3)% and 27.4 (5.5) ml cm H2O-1, respectively, and a decrease in airway resistance to 43.9 (7.2) cm H2O litre-1 s-1. There were significant correlations between percentage bronchial cross-sectional area and dynamic pulmonary compliance (r = 0.720, P < 0.0001) and airway resistance (r = 0.727, P < 0.0001). Atropine 0.1 mg kg-1 increased basal bronchial cross-sectional area to 137.5 (16.9) %. These data indicate that adrenaline reversed histamine- and pentobarbitone-induced bronchoconstriction.

Airway Resistance↗

PubMed1997

A rapid increase in foot tissue temperature predicts cardiovascular collapse during anaphylactic and anaphylactoid reactions.

BACKGROUND: Cardiovascular collapse during anaphylactic and anaphylactoid reactions results from release of histamine and other vasoactive substances. Intense arteriolar vasodilation associated with severe allergic reactions is likely to increase convective transfer of heat and peripheral tissue temperature, and finally to provoke cardiovascular collapse. Therefore the authors tested the hypothesis that during anaphylactic and anaphylactoid reactions, an acute increase in peripheral tissue temperature precedes cardiovascular collapse and that the magnitude of the increase correlates with the severity of the reaction. METHODS: During a 13-yr period, approximately 120,000 patients were screened for clinical evidence of intraoperative anaphylactic and anaphylactoid reactions. Core temperature was measured in the distal esophagus, and "deep" foot tissue temperature was measured on the sole of one foot in all these patients. Otherwise unexplained cardiovascular collapse accompanied by bronchospasm and/or cutaneous signs such as urticaria, flushing, or angioedema occurred in 32 patients who were entered into a prospective diagnostic protocol. Among these, 15 met laboratory criteria for anaphylactic or anaphylactoid reactions. Anaphylaxis was confirmed in nine of them by a positive skin test to the suspected agent, the in vitro leukocyte histamine-release test, or the Praunitz-Küstner test. Reactions were considered anaphylactoid in six others when laboratory evidence did not support anaphylaxis, but plasma histamine or tryptase concentrations were much greater during episodes than 6 weeks later. RESULTS: Development of anaphylactic and anaphylactoid reactions followed a characteristic pattern: (1) Foot temperature, which was initially 3.3 +/- 1.7 degrees C less than core temperature, increased to within 0.3 degrees C of core temperature 3.2 +/- 1.4 min after drug administration; (2) onset of cardiovascular collapse ensued 1.8 +/- 0.8 min later; and (3) core temperature increased from 34.7 +/- 1.0 degrees C to peak values 37.1 +/- 0.6 degrees C 13 +/- 5 min after drug administration. The most severe reactions were associated with shorter times to comparable core and foot temperatures, faster onset of cardiovascular collapse, and higher maximum core temperatures. CONCLUSIONS: The normal core-to-peripheral tissue temperature gradient was obliterated several minutes before hemodynamic consequences associated with anaphylactic and anaphylactoid reactions. Further, a rapid increase in deep foot temperature and maximum core temperature correlated with clinical severity.

Adolescent↗

PubMed1997

Effect of dobutamine and OPC-18790 on diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy.

We investigated the acute effects of the positive inotropic agents (dobutamine and a novel phosphodiesterase inhibitor OPC-18790) on left ventricular diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy (DCM). We obtained pressure-volume (PV) data before and after drug administration in 17 patients with DCM by using a conductance catheter with a micromanometer tip. Patients were randomly assigned to receive intravenous infusions of dobutamine (2.5-7.5 micrograms/kg body weight per min, n = 8) or OPC-18790 (5-10 micrograms/kg body weight per min, n = 9). The dynamic diastolic chamber stiffness constant was calculated from a steady-state beat. The passive diastolic chamber stiffness constant was determined from the end-diastolic PV relation determined during transient inferior vena caval occlusion. Dobutamine and OPC-18790 similarly improved left ventricular end-systolic elastance (Ees) and left ventricular isovolumic relaxation time constants. The dynamic diastolic chamber stiffness constant decreased significantly in both the dobutamine (0.0934 +/- 0.0271 to 0.0685 +/- 0.0248; p < 0.01) and OPC-18790 (0.0843 +/- 0.0477 to 0.0569 +/- 0.0246; p < 0.05) groups. The passive diastolic chamber stiffness constant decreased significantly in the OPC-18790-treated group (0.0211 +/- 0.0114 to 0.0144 +/- 0.0117; p < 0.005) but not in the dobutamine-treated group (0.0197 +/- 0.0130 to 0.010186 +/- 0.0102; p > 0.05). Thus both dobutamine and OPC-18790 reduced the dynamic diastolic chamber stiffness constant, but only OPC-18790 reduced the passive diastolic chamber stiffness constant. OPC-18790 had a favorable effect on diastolic function in patients with DCM, compared with that of dobutamine. The passive diastolic chamber stiffness obtained from the end-diastolic PV relations represents more likely passive chamber properties than the dynamic diastolic chamber stiffness obtained from traditional single-beat analysis.

Adult↗

PubMed1997

Proteoglycan synthesis in the intervertebral disk nucleus: the role of extracellular osmolality.

Proteoglycans, through their polyelectrolyte properties, regulate the ionic composition and hence the osmotic pressure of the extracellular matrix. We measured the change in [35S]sulfate incorporation, a marker of proteoglycan synthesis, in explants of bovine nucleus pulposus. During incubation, nucleus slices swelled 200% and proteoglycans leached from the matrix, so that extracellular osmolality fell from 420-450 to approximately 300 mosmol/kg H2O. When in vivo extracellular osmolality was maintained either by adding 80 mM NaCl or 150 mM sucrose to the swollen tissue or by preventing swelling, synthesis rates were 260-280% greater than in swollen tissue. Synthesis rates also increased 200% in cells isolated from the nucleus pulposus by enzyme digestion when medium osmolality was raised from 280 to 430 mosmol/ kgH2O by sucrose addition. The cells, either in the tissue or isolated from it, swelled by more than 20% as osmolality fell from 430 to 280 mosmol/kgH2O and showed little regulatory volume decrease over 150 min. Synthesis rates thus appear to be regulated by extracellular osmolality rather than by the macromolecular composition of the matrix and correlated well with measured changes in cell volume.

Animals↗

PubMed1997

Block by MOPS reveals a conformation change in the CFTR pore produced by ATP hydrolysis.

ATP hydrolysis by the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel predicts that energy from hydrolysis might cause asymmetric transitions in the gating cycle. We found that 3-(N-morpholino)propanesulfonic acid (MOPS) blocked the open channel by binding to a site 50% of the way through the electrical field. Block by MOPS revealed two distinct states, O1 and O2, which showed a strong asymmetry during bursts of activity; the first opening in a burst was in the O1 state and the last was in the O2 state. Addition of a nonhydrolyzable nucleoside triphosphate prevented the transition to the O2 state and prolonged the O1 state. These data indicate that ATP hydrolysis by the nucleotide-binding domains drives a series of asymmetric transitions in the gating cycle. They also indicate that ATP hydrolysis changes the conformation of the pore, thereby altering MOPS binding.

Adenosine Triphosphate↗

PubMed1997

Roles of PI 3-kinase and Ras on insulin-stimulated glucose transport in 3T3-L1 adipocytes.

The dominant negative p85alpha regulatory subunit (delta p85alpha) of phosphatidylinositol (PI) 3-kinase or dominant negative Ras (N17Ras) was overexpressed in 3T3-L1 adipocytes using an adenovirus-mediated gene transduction system. Functional expression of delta p85alpha and N17Ras was confirmed by marked inhibition of insulin-stimulated PI 3-kinase activity and mitogen-activated protein kinase activity, respectively. N17Ras expression did not affect glucose transport activity, whereas delta p85alpha expression inhibited insulin-stimulated glucose transport with impairment of GLUT-4 translocation, although inhibition of glucose transport activity was less remarkable than that of PI 3-kinase activity in delta p85alpha-expressing cells. Thus the Ras signaling pathway does not play a major part in either translocation or intrinsic activity of glucose transporters, but PI 3-kinase activation, via phosphotyrosyl proteins and heterodimeric PI 3-kinase, plays a pivotal role in insulin-stimulated glucose transport. However, a discrepancy was observed between PI 3-kinase activity and glucose transport activity, suggesting a possibility that a different pathway(s) is involved in insulin-stimulated intrinsic activity of glucose transporters.

3T3 Cells↗

PubMed1997

Depressed pituitary-adrenal response to surgical stress in chronic schizophrenic patients.

We evaluated whether pituitary-adrenal response to surgical stress is modified in chronic schizophrenic patients. Twenty-two schizophrenic patients on chronic antipsychotic therapy of phenothiazine derivatives over 10 years underwent orthopedic surgery of the extremities under general anesthesia by isoflurane and nitrous oxide. In chronic schizophrenic patients, responses of plasma epinephrine, norepinephrine, ACTH and cortisol levels during surgical stress were significantly lower than those of control patients. The attenuated response to surgical stress in these patients may be associated with their autonomic dysfunction and decreased pituitary-adrenal activity due to chronic administration of antipsychotic agents.

Adrenocorticotropic Hormone↗

PubMed1997

Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic beta cells.

We examined a possible mechanism underlying the link between obesity and hyperinsulinemia, focusing on leptin, a peptide released from adipocytes which affects the satiety center in the brain. The leptin receptor isoforms, Ob-Ra and Ob-Rb, are present in the pancreatic beta cell line MIN6 and in rat pancreatic islets, based on RT-PCR. A 2 hr, but not a 30 min, incubation with 1 nM recombinant mouse leptin, the concentration observed in obese subjects, stimulated basal (at 5 mM glucose) insulin secretion by approximately 40% in both MIN6 and rat islets. Stimulatory effects were not observed without glucose or when the incubation medium containing 1 nM leptin had been preincubated with the immobilized leptin antibody. In contrast to the stimulatory effects on basal insulin secretion at 1 nM, the maximally stimulated insulin secretion at 25 mM glucose was not significantly changed by 1 nM leptin in isolated rat islets. In addition, 10 and 100 nM leptin exerted small but significant inhibitory effects on 16.7 mM glucose-stimulated insulin secretion. Thus, leptin acts directly on pancreatic beta cells, and stimulation of basal insulin secretion by physiological concentrations of leptin may account in part for the fasting hyperinsulinemia observed in obese subjects.

Animals↗