Lack of acute insulin effect on plasma endothelin-1 levels in humans.
Acute hyperinsulinemia does not increase circulating ET-1 levels in subjects with normal and deranged glucose metabolism.
Adolescent↗
Biomedical subjects
A Saeki
Publications and source records attributed to A Saeki.
Effects of milrinone and sulmazole on left ventricular mechanoenergetics in canine hearts.
BACKGROUND: The effect of cardiotonic drugs with calcium-sensitizing effect (Ca2+ sensitizers) on cardiac mechanoenergetics is not fully understood. Accordingly, the effects of milrinone (a phosphodiesterase inhibitor) and sulmazole (a calcium sensitizer with a phosphodiesterase-inhibiting effect) on left ventricular mechanics and energetics were studied. METHODS AND RESULTS: In excised, cross-circulated canine hearts, myocardial oxygen consumption (Vo2), left ventricular contractility index (Emax), and systolic pressure-volume area (a measure of ventricular total mechanical energy) were measured before and during administration of either drug. Milrinone significantly increased Emax by 108.7 +/- 45.9% (mean +/- SD), from 6.3 +/- 3.5 to 13.1 +/- 6.8 mmHg.mL-1.100 g (P < .05), and sulmazole, by 73.6 +/- 54.2%, from 6.3 +/- 2.6 to 10.3 +/- 2.9 mmHg.mL-1.100 g (P < .05). Milrinone significantly abbreviated the contraction duration (Tmax) from 171 +/- 19 ms to 153 +/- 20 ms (P < .05), whereas sulmazole did not (164 +/- 36 ms to 161 +/- 31 ms, not significant), suggesting that the inotropic mechanisms of these two drugs differed. However, both drugs significantly increased the Vo2 intercept of the Vo2/pressure-volume area relation (milrinone: 0.027 +/- 0.004 to 0.036 +/- 0.003 mL O2/beat/100 g, P < .05; sulmazole: 0.025 +/- 0.005 to 0.032 +/- 0.006 mL O2/beat/100 g, P < .05) without significantly changing the slope (reciprocal of contractile efficiency). This parallel upward shift of the Vo2/pressure-volume area relation was similar to that observed with epinephrine and ouabain in our previous studies. CONCLUSIONS: These results suggest that the two positive inotropic drugs exhibit similar mechanoenergetic effects in the normal canine heart despite the different mechanisms of action.
Animals↗
Mechanoenergetics of negative inotropism of ventricular wall vibration in dog heart.
Mechanical vibration depresses cardiac contractility. We studied the mechanoenergetic effects of this negative inotropism in the left ventricle (LV) of an isolated, cross-circulated dog heart preparation. We took full advantage of the mechanoenergetic relationship among the LV end-systolic elastance (Emax, contractility index), systolic pressure-volume area (PVA), and myocardial oxygen consumption (VO2). PVA is a measure of the total mechanical energy that cardiac contraction generates. PVA correlates closely with VO2. The VO2 intercept of the VO2-PVA relation reflects the VO2 component for excitation-contraction (E-C) coupling plus basal metabolism (PVA-independent VO2). VO2 above the PVA-independent VO2 reflects the VO2 component for mechanical contraction (PVA-dependent VO2). When we applied 70-Hz vibration of 2-mm amplitude to a LV wall region, it instantly decreased Emax and PVA by 20%, followed by a 10% decrease in VO2 at a fixed volume. However, the vibration neither lowered the VO2-PVA relation obtained at different LV volumes, unlike ordinary negative inotropism, nor changed its slope (1.88 +/- 0.23 vs. 1.86 +/- 0.23 x 10(-5) ml O2.mmHg-1.ml-1). The virtually zero delta PVA-independent VO2/delta Emax with vibration indicates a much smaller O2 cost of Emax than that seen with calcium and propranolol inotropism. These mechanoenergetics support the hypothesis that mechanical vibration primarily suppresses cardiac contractility without suppressing E-C coupling.
Animals↗
Pulse pressure-related changes in coronary flow in vivo are modulated by nitric oxide and adenosine.
Acute increases in arterial pulsatile load imposed on the left ventricle can increase coronary flow without commensurate changes in myocardial oxygen consumption. One explanation is that augmenting pulsatile perfusion at the same mean pressure itself stimulates flow by releasing endothelium-mediated vasorelaxant factors such as NO. The present study tested this hypothesis and determined whether NO and adenosine modulate this response. In open-chest anesthetized dogs, the distal left anterior descending coronary artery (LAD) was whole-blood-perfused by a novel servopump system to control mean and pulsatile perfusion pressure within the isolated vascular bed. Central aortic pressure was measured, stored to computer memory, and then digitally modified (varying the pulse pressure [PP]) to generate a real-time servocommand that was still synchronous with ventricular contraction. Left heart workload was unchanged. LAD flow was measured before and after increasing the PP (to 60 to 100 mm Hg) from baselines of either 0 or 40 mm Hg. With normal basal coronary vascular tone, raising the PP increased flow (+9 +/- 2% at a PP of 100 mm Hg). This response was markedly amplified (+39 +/- 8%) when basal tone was first partially reduced by adenosine. Competitive inhibition of NO synthase by N omega-monomethyl-L-arginine reduced acetylcholine and PP-dependent flow responses by 50%. Thus, enhanced pulsatile perfusion increases in vivo coronary flow in part by triggering NO release. The marked augmentation of the PP response with reduced basal coronary tone from adenosine suggests that this mechanism may play a role in improving myocardial perfusion during exercise.
Adenosine↗
Lack of C-peptide suppression by exogenous hyperinsulinemia in subjects with symptoms suggesting reactive hypoglycemia.
The C-peptide suppression test employing the euglycemic hyperinsulinemic clamp technique has been proposed as a useful diagnostic measure for insulinoma. To examine the specificity of the C-peptide suppression, we applied this test to subjects with symptoms suggesting reactive hypoglycemia. Five subjects studied had never experienced fasting hypoglycemia, and were negative in ultrasound, CT and MRI of the pancreas. Plasma C-peptide was not suppressed by physiological (50-100 microU/ml) and supraphysiological (200-500 microU/ml) hyperinsulinemia (% of baseline: 97.3 +/- 8.6% and 90.6 +/- 10.4%, +/- SEM, respectively, both NS). Three subjects were re-examined one year later, when their hypoglycemic episodes were noticeably attenuated. No significant suppression was found. Significant suppression was observed when plasma glucose was clamped at 50-60 mg/dl in four of five subjects (61.7 +/- 11.5%, P < 0.05), but one subject responded to neither higher plasma insulin nor low-normal glucose. In contrast, normal glucose tolerance (n = 13), IGT (n = 12) and obese NIDDM (n = 31) subjects showed highly significant suppression during euglycemic and physiological hyperinsulinemia (37.1 +/- 3.8%, 46.3 +/- 5.6%, 39.9 +/- 2.6%, respectively, all P < 0.001). In conclusion, the results of the present study indicate that a failure of hyperinsulinemic suppression of C-peptide in euglycemia is not specific for insulinoma, and that suppression of C-peptide by insulin at lower plasma glucose levels (50-60 mg/dl) would be a better diagnostic test.
Adolescent↗
[Diagnosis of pulmonary aspergillosis in cases with cavity as sequela of tuberculosis].
Non-invasive pulmonary aspergillosis is frequently seen in cases with cavity as sequela of tuberculosis. Diagnosis of non-invasive pulmonary aspergillosis is not easy except for cases whose chest X-ray findings show a typical fungus ball. How to diagnose pulmonary aspergillosis was studied in 21 patients who showed changes in the radiological findings of cavity as sequela of tuberculosis. We made sputum culture of Aspergillus, measurement of precipitin antibody titer to Aspergillus fumigatus and measurement of PASTOREX ASPERGILLUS in serum and sputum on the 21 patients (group A). PASTOREX ASPERGILLUS in sputum was evaluated in three grades: 1+ approximately 3+. We diagnosed 14 patients as pulmonary aspergillosis (PA group) among the 21 patients taking into account the chest X-ray findings and the results of the above-stated investigations. The types of chest X-ray findings of these 14 patients were fungus ball type (FB) in 2 patients, productive aspergilloma on the inner wall of a cavity (PAIC) in 8, mixed type with FB and PAIC in 2 and non-specific change in 2. However, there were 3 patients with the chest X-ray findings suggestive of PAIC in 7 patients (non-PA group) who were not diagnosed as pulmonary aspergillosis. Sputum culture were positive in 11 patients of PA group (79%) and negative in all patients of non-PA group. Precipitin antibody were positive in 8 patients of PA group (67%) and negative in all patients of non-PA group. PASTOREX ASPERGILLUS in serum were negative in all 21 patients. PASTOREX ASPERGILLUS in sputum were 3+ (+3) in all 14 patients of PA group and in 2 patients of non-PA group and 2+ (+2) in 2 patients of non-PA group. 12 patients of PA group were treated by antifungal agents and 11 patients responded well to the treatment. We also made sputum culture of Aspergillus and measurement of PASTOREX ASPERGILLUS in sputum on 14 patients (group B) who had respiratory diseases with stable cavities and 17 patients (group C) who had respiratory diseases without a cavity. In group B, sputum culture were positive in 1 patient and PASTOREX ASPERGILLUS in sputum were 3+ (+3) in 2 patients, 2+ (+2) in 1 and 1+ (+) in 2. In group C, sputum culture were negative in all patients and PASTOREX ASPERGILLUS in sputum were 3+ (+3) in 1 patient, 2+ (+2) in 3 and 1+ (+) in 2. Measurement of PASTOREX in sputum was a useful tool to diagnose non-invasive aspergillosis in addition to sputum culture and measurement of precipitin antibody titer. The sensitivity of PASTOREX in sputum was high but its specificity was low, however, its specificity could be raised by applying semi-quantitative analysis of PASTOREX in sputum.
Adult↗
[Hyperuricemia and insulin resistance].
Hyperuricemia is often associated with obesity, hypertension and dyslipidemia, and is thought to be a risk factor for cardiovascular disease, thereby making resemblance to the insulin resistance syndrome. Our data showed a low, but significant correlation between serum uric acid concentration and the degree of insulin resistance (GIR) estimated by euglycemic hyperinsulinemic clamp method in 67 subjects with combined normal glucose tolerance and IGT(r = -0.278, p < 0.05). Plasma HDL-C and TG levels were also correlated with uric acid levels. One hundred sixty NIDDM patients who had undergone the clamp study were stratified into 5 groups according to the serum uric acid level. In the top quintile (UA : 7.8 +/- 0.8 mg/dl), BMI, male prevalence, plasma TG, HDL-C, fasting IRI, and total IRI response(0 + 60 + 120 min) during meal tolerance test were significantly higher, while age and GIR value tended to be lower without significance compared with those in the bottom quintile (UA : 3.4 +/- 0.5 mg/dl). These results, which are in agreement with the previous studies, support the notion that elevated serum uric acid is a feature of insulin resistance syndrome.
Cardiovascular Diseases↗
[Erythropoietin improved anemia in a case of multicentric Castleman's disease].
Severe anemia A 37 year-old male with therapy resistant multicentric Castleman's disease (MCD) anemia was treated by subcutaneous injection of erythropoietin. Although immunoglobulin and CRP concentration increased, anemia obviously improved with hemoglobin levels increasing from 4.8 g/dl to 8.5 g/dl without any side effects. Colony assay revealed that the bone marrow mononuclear cells responded to erythropoietin in a dose dependent manner. The mechanism of anemia of MCD is not clearly understood, and treatment is sometimes very difficult. There is no other previous report concerning erythropoietin as a treatment for anemia in MCD.
Adult↗
[Impaired neutrophil function in chronic renal failure--dysregulation of surface adhesion molecule expression and phagocytosis].
To elucidate the impaired neutrophil function in patients with chronic renal failure, we analyzed the expression of the adhesion molecules, LAM-1, LFA-1, Mac-1, gp150/95 and phagocytosis activity of neutrophils in predialysis and hemodialysis patients by flow cytometry. Further, the response to granulocyte colony-stimulating factor (G-CSF), N-formyl-methionyl-leucyl-phenylalanine (fMLP) and tumor necrosis factor alpha (TNF alpha) were investigated. In hemodialysis patients, the expression of LAM-1 was decreased and that of MAC-1 was increased, indicating the activation of neutrophils. Also in predialysis patients, the same condition of "low LAM-1, high MAC-1" was observed, but to a lesser degree. Phagocytosis activity was significantly decreased in hemodialysis patients, whereas the neutrophils of predialysis patients showed almost the same phagocytosis activity compared to the controls. The responses to G-CSF, fMLP, TNF alpha were significantly reduced both in hemodialysis and predialysis patients. The inadequate activation of neutrophils and impaired response to stimulation may play an important role in uremic patients with regard to increased susceptibility to infections.
Adult↗
Prevalence of macro- and microvascular diseases in non-insulin-dependent diabetic and borderline glucose-intolerant subjects with insulin resistance syndrome.
This study was undertaken to ascertain whether patients with insulin resistance syndrome, a cluster of risk factors for coronary artery disease (CAD), are really a high risk population for macro- and microvascular diseases in Japanese NIDDM and borderline glucose-intolerant subjects. A diagnosis of insulin resistance syndrome was made if four of the six following criteria are satisfied: glucose disposal rate < 2.2 mg/kg/min, fasting plasma IRI > 15 microU/ml or peak plasma IRI > 100 microU/ml during meal tolerance test, plasma triglyceride > 150 mg/dl at fasting or > 200 mg/dl after meal, serum HDL-cholesterol < 40 mg/dl, blood pressure > 140 mm Hg systolic and > 90 mm Hg diastolic or treatment with antihypertensive agents, and body mass index (BMI) > 27 for men or > 25 for women. We compared the prevalence of CAD, cerebral vascular disease (CVD), peripheral vascular disease (PVD), retinopathy and nephropathy between the insulin resistance syndrome group (group A, n = 57) and the remaining group (group B, n = 164). Both groups did not differ with respect to age, duration of diabetes, BMI, fasting plasma glucose, HbA1c, composition of NIDDM and borderline glucose-intolerance (BGI) or treatment modality. The prevalence of CAD was significantly higher in group A compared with that in group B (31.6% vs. 14.0%, P < 0.002), but not for CVD (8.8% vs. 3.7%, respectively, P = 0.12) or PVD (1.8% vs. 2.4%, respectively, P = 0.76). The prevalence of late-stage retinopathy in group A was significantly higher than that in group B (12.3% vs. 2.4%, respectively, P < 0.005). Macroalbuminuria, but not microalbuminuria, was significantly higher in group A than that in group B (12.3% vs. 3.6%, P < 0.02). We conclude that the insulin resistance syndrome preferentially increases the development of CAD, and is also involved in the progression of microvascular diseases.
Adult↗
The relationship between insulin resistance and insulin secretion in Japanese subjects with borderline glucose intolerance.
Insulin resistance and impaired insulin secretion can be involved in the development of non-insulin-dependent diabetes mellitus (NIDDM), but their relative importance or temporal relationship are poorly understood. To elucidate this issue, we studied 51 subjects with borderline glucose intolerance (BGI) and 18 normal glucose tolerant subjects (NGT) according to the Japan Diabetes Society criteria. The glucose infusion rate (GIR, mg/kg/min), an index of whole body insulin resistance (IR), was measured by the euglycemic (80 mg/dl) hyperinsulinemic clamp technique (insulin infusion rate 1.12 mU/kg/min). Insulinogenic index (delta IRI/delta BS at 30 min) and the insulin area under the curve during a 75-g oral glucose tolerance test (OGTT) were estimated. In the BGI subjects, the GIR values showed marked variation ranging from 2.24 to 10.44 mg/kg/min (5.54 +/- 0.31, mean +/- S.E.M.). The GIR values were lower in obese BGI subjects compared with non-obese BGI and NGT subjects, and the insulin area was markedly higher in BGI subjects with increased insulin resistance. There was a significant negative correlation between the GIR values and the insulin area or delta IRI/delta BS (30') ratio in the subjects with BGI either in the whole group or solely in the non-obese group. We conclude that the increased insulin secretion compensates for the peripheral insulin resistance of subjects with slightly deteriorated glucose tolerance, implying that insulin resistance plays an important role in the pathogenesis of NIDDM in some fraction of Japanese population.
Adolescent↗
Metabolic regulation and microangiopathy in a cohort of Japanese IDDM-patients.
In Caucasian patients with insulin-dependent diabetes mellitus (IDDM) proliferative diabetic retinopathy (PDR) and persistent proteinuria (PP) are associated, and major risk factors for development of microangiopathy have been identified. The aim of the present study was to evaluate whether these risk factors are also relevant and whether an association exists between the microangiopathic complications in Japanese IDDM-patients. A clinic-based cohort of 324 Japanese IDDM-patients was followed (a mean follow-up of 7 years). Annual examination for development of PDR and PP was performed. Fifty-eight patients developed PDR and 24 developed PP. Development of PDR was associated to high HbA1c-levels, i.e., the 4th quartile (RR 7.9, P < 0.0001), background retinopathy at admission (RR 9.9, P < 0.0001), high age at diabetes onset (RR 2.9, P < 0.0001) and female gender (RR 1.7, P < 0.05). Development of PP was associated to high HbA1c-levels (RR 2.8, P < 0.001) and background background retinopathy at admission (RR 7.9, P < 0.0001). The risk of developing PP was 9 times higher in patients developing PDR than in patients not developing PDR (P < 0.0001). The effect of metabolic control in our cohort was similar to that found in the DCCT and SDIS studies. In conclusion, development of PP is closely associated with PDR, also in Japanese IDDM-patients. The effect of metabolic control is the same as in Caucasian patients. Development of malignant angiopathy in IDDM-patients is not confined to Caucasian IDDM-patients, and the incidence rates are comparable to those found in Caucasian IDDM.
Adolescent↗
Cardiac quick-release contraction mechanoenergetics analysis using a cardiac muscle cross-bridge model.
Huxley's sliding filament cross-bridge muscle model coupled with parallel and series elastic components was simulated to examine the conflicting reports on the amount of energy saved by quick release at the peak contraction time. Cross-bridge energy utilization was determined by considering the ATP hydrolysis for the cross-bridge cycling. The quick-release cases were simulated by letting the muscle fiber suddenly shorten to the resting fiber length at peak systole, and then the contraction was allowed to continue at the resting length. Simulation results demonstrated that, using realistic parameter values, typically approximately 15% of the muscle fiber energy is used after peak systole (and approximately 30% of the cross-bridge energy), but this is also a function of the muscle fiber properties characterized by cross-bridge association and dissociation rate constants. Increasing the kinetic rate constants, the series elasticity, the initial fiber length, or the time of peak intracellular calcium will increase the amount of energy left, which may explain some of the discrepancies in the literature. Cardiac muscle hypertrophy will increase the fraction of muscle fiber energy left after peak systole to approximately 30%. The strongest indicator of the percent energy left at peak systole was the time the fiber reached peak systole, and as the fiber reached peak systole faster, the amount of energy saved by quick release increased.
Animals↗
Newly discovered familial juvenile gouty nephropathy in a Japanese family.
Our attention was initially called to 2 young Japanese sisters with gout and renal insufficiency, which led to an investigation of members of their family with similar conditions. One sister, a 26-year-old woman who had suffered from polyuria since infancy, suffered from gout and renal insufficiency. Her younger sister also had a history of polyuria, hyperuricemia, and moderately reduced renal function. Their urinary uric acid levels were reduced but purine enzyme activities in the erythrocytes were normal. A renal biopsy specimen from the younger sister showed severe interstitial fibrosis with tubular atrophy. An investigation of the family revealed an autosomal dominant transmission pattern. We believe these are new familial cases of juvenile gouty nephropathy found in a Japanese family.
Adult↗
systolic flow augmentation in hearts ejecting into a model of stiff aging vasculature. Influence on myocardial perfusion-demand balance.
Age-related arterial stiffening and widening of the pulse pressure elevates ventricular systolic wall stress while it lowers diastolic coronary perfusion pressure. These changes are thought to adversely alter the balance between myocardial work load and blood supply. To test this hypothesis, the native compliant thoracic aorta was surgically bypassed by a stiff tube in reflex-blocked anesthetized dogs. Ventricular outflow was directed into either native aorta or the bypass; the latter resulting in an increase in arterial pulse pressure from 37.8 to 107.5 mm Hg (P < .001), with minimal change in mean pressure and flow. Cardiac work load was assessed by pressure-volume area (PVA), which combines external and internal left ventricular work and is linearly related to myocardial oxygen consumption (MVO2), and by MVO2 itself. Regional phasic and mean coronary flow were measured in the left anterior descending coronary artery, and global flow was assessed by radiolabeled microspheres. Myocardial supply-demand balance was assessed by comparing flow at matched PVA or MVO2, flow-PVA relations, and endocardial-to-epicardial flow ratios. When blood flow was directed into the stiff bypass tube, peak systolic pressure, wall stress, and PVA all rose nearly 50%, yet diastolic perfusion pressure fell by 20 mm Hg (all P < .01). Rather than being compromised, however, mean coronary flow rose by 34%, maintaining the same endocardial-to-epicardial flow ratio (approximately 1.1). Flow augmentation persisted when data were compared at matched work load (PVA or MVO2), and mean arterial pressure, as well as over a range of work loads (P < .001 from ANCOVA of flow-PVA relations). The increased flow resulted from enhanced systolic perfusion, which nearly equaled diastolic flow when ejection passed into the stiff bypass. These data counter the notion that cardiac coupling with a stiff arterial system (as with aging) necessarily compromises myocardial flow versus metabolic demand. However, the data highlight a greater role of systolic flow under such conditions and also raise the novel suggestion that enhanced pulsatility of the arterial pressure waveform may itself augment coronary perfusion.
Aging↗
Insulin sensitivity and negative insulin feedback after pancreas transplantation in insulin-dependent diabetic patients.
The aims of this study were to determine the change in the rate of insulin-stimulated glucose disposal (insulin sensitivity) and the ability of insulin to inhibit its own secretion in four pancreas-kidney transplant recipients with insulin-dependent diabetes mellitus. Insulin sensitivity (glucose infusion rate, GIR) was measured by a euglycemic hyperinsulinemic clamp technique before and 2, 6 and 12 months after transplantation. The GIR values in the four recipients were normalized within 2 months and remained normal for 12 months after transplantation, despite long-term steroid therapy for immunosuppression. Physiological hyperinsulinemia (50-70 microU/ml) suppressed plasma C-peptide, but its nadirs were still higher than the basal levels in normal controls. Taking into account evidence of a minimal increase in the concentration of circulating insulin that inhibits insulin secretion in healthy subjects and evidence of increased insulin secretion in pancreas recipients, the authors speculate that defective feedback inhibition of insulin secretion could contribute, at least in part, to the disproportionate basal hyperinsulinemia in patients with a denervated, transplanted pancreas in the absence of insulin resistance.
Adult↗
Association of sick sinus syndrome with hyperinsulinemia and insulin resistance in patients with non-insulin-dependent diabetes mellitus: report of four cases.
We report four non-insulin-dependent diabetic (NIDDM) patients accompanied by a unique combination of sick sinus syndrome (SSS) and hyperinsulinemia of unknown etiology. SSS of all four cases was due to sinus arrest in association with paroxysmal atrial fibrillation (Rubenstein-III). Of special interest is that one patient showed a high prevalence of SSS and NIDDM among her close relatives. Hyperinsulinemia of moderate degree was seen at fasting state or after carbohydrate ingestion in the absence of obesity. The resistance to the action of insulin on glucose metabolism which was evaluated in three patients by the euglycemic hyperinsulinemic clamp study was found to be comparable to the lowest quartile level for common NIDDM patients. Because insulin is a physiological regulator of cell-membrane Na+/K+-ATPase, we speculate that malfunction of the sinus node automaticity may be caused by chronic exposure to hyperinsulinemia secondary to insulin resistance in these NIDDM patients.
Aged↗
[RAEB in T with monosomy 7 after treatment of severe aplastic anemia with long term G-CSF].
A 19-year-old male who suffered from severe aplastic anemia had been treated with granulocyte colony stimulating factor (G-CSF) from September 1991. Marked increase of hematopoietic cells in his bone marrow was observed, and maintenance administration of G-CSF was continued. 15 months later, myeloblasts with nuclear abnormality increased, and 22 months later, myeloblasts with chromosomal abnormality presenting 46, XY, -7, +21 exceeded 20%, and aplastic anemia seemed to be transformed into refractory anemia with excess of blasts in transformation (RAEB in T). The usefulness of G-CSF in the treatment of aplastic anemia is now established, but there are some reports questioning the effect of long-term administration, especially transformation to MDS with monosomy 7. Leukemic transformation from aplastic anemia is very complex, but in some cases, long term administration of G-CSF may affect the natural course and may lead to the earlier development of leukemia.
Adult↗