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Adrenal Gland Neoplasms↗
Biomedical subjects
H Mikami
Publications and source records attributed to H Mikami.
A new model to study repair of gastric mucosa using primary cultured rabbit gastric epithelial cells.
The process of wound repair was investigated using primary cultured rabbit gastric mucosal cells. A confluent monolayer gastric mucosal cell sheet consisting mainly of mucous cells was wounded to make a cell-free area of constant size. The changes in the cell-free area were analyzed quantitatively by image analysis. The wound recovered in 36-48 h in controls; wound repair was accelerated by the addition of fetal calf serum (FCS) and hepatocyte growth factor (HGF) to the medium and was retarded by inhibitors of cytoskeletal proteins. In the process of normal wound repair, 5-bromodeoxyuridine (BrdU)-positive cells appeared around the wound in 24-36 h but disappeared after complete repair. In the FCS- and HGF-treated group, BrdU-positive cells were mainly detected 12-24 h after wounding. In this model the wound was repaired in two steps: an initial cell migration stage and a later proliferation stage. In conclusion, FCS and some growth factors accelerate wound repair with the induction of both epithelial cell migration and proliferation. The cytoskeletal system plays an important role in normal gastric restoration.
Animals↗
The effect of central amino acid neurotransmitters on the antihypertensive response to angiotensin blockade in spontaneous hypertension.
OBJECTIVE: To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974. MATERIALS AND METHODS: We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and gamma-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 mu g/kg per min) or vehicle. RESULTS: In SHR, CV 11974 decreased mean arterial pressure (-40 +/- 6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 +/- 83%) and gamma-aminobutyric acid (363 +/- 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35 +/- 4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, -18 +/- 5 mmHg; nitroglycerin, -20 +/- 7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or gamma-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the gamma-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR. CONCLUSION: The present results suggest that the release of the inhibitory amino acids glycine and gamma-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.
Angiotensin Receptor Antagonists↗
Augmentation by converting enzyme inhibition of accelerated endothelin release from rat mesenteric arteries following nephrectomy.
We investigated the release of endothelin-1 (ET) from rat mesenteric arteries to clarify its pathophysiological role in the sustained hypertension of spontaneously hypertensive rats (SHR) following nephrectomy and the regulatory mechanism of the ET release which might be modified by vascular angiotensins and bradykinins. Nephrectomy increased the plasma level of ET and enhanced the ET release in both SHR and Wistar-Kyoto rats (WKY). CV-11974, an angiotensin II receptor antagonist, did not affect the ET release from arteries of nephrectomized rats. On the contrary, infusion of captopril, a converting enzyme inhibitor, further enhanced the ET release in both intact and nephrectomized rats. These findings suggest that the release of ET from mesenteric arteries may be regulated by bradykinins, but not by angiotensins. This pressor substance does not contribute to the sustained hypertension because the enhanced production of ET observed in both SHR and WKY. However, there is a possibility that the exaggerated responsiveness of vascular ET may in part account for local vascular tone and vascular remodeling in renal dysfunction.
Analysis of Variance↗
Role of extracellular matrix in wound repair by cultured gastric mucosal cells.
Effects of extracellular matrix on wound repair of cultured gastric epithelial cells were assessed. Artificial wounds were made by mechanical cell denudation in confluent rabbit gastric epithelial cell sheets which were formed on different types of extracellular matrix (e.g., collagen type I and type IV, laminin, fibronectin and Matrigel). Changes in wound size were analyzed quantitatively. Cell migration and proliferation were observed in stages of the wound repair process. The speed of wound repair was different with each extracellular matrix studied and was fastest on Matrigel. The type of extracellular matrix used in this study modulated both cell migration and proliferation. Therefore, it is concluded that extracellular matrix plays an important role in rates of gastric mucosal wound healing.
Animals↗
Estimation of time of death by quantification of melatonin in corpses.
A method for the estimation of time of death (TOD), was evaluated by measuring the melatonin (MT) content of pineal bodies (PBs), sera and urine samples from 85 cadavers. A total of 44 cadavers were investigated in Sapporo (geographical coordinates N 43 degrees 4', E 141 degrees 21') and 41 in Tokyo (N 35 degrees 39', E 139 degrees 44'). MT contents were measured by radioimmunoassay (RIA) in 75 PBs, 27 sera and 14 urine samples. Exponential differences of pineal MT content were recognized between peaks in nighttime and nadirs in daytime, ranging from 0.099 to 63.2 ng/PB. Circadian rhythms were also observed for the concentrations of MT in serum (11-205 pg/ml), and in urine (7.5-137.5 pg/ml). Consequently, criteria for the TOD estimation are proposed as follows. 1) Pineal MT contents--(1) 0-0.2 ng/PB: TOD 1100-1700 hours, (2) 0.2-0.3 ng/PB: TOD 0700-2000 hours, (3) 0.3-1 ng/PB: inconclusive, (4) 1-4 ng/PB: TOD 1600-1000 hours, (5) 4-8 ng/PB: TOD 2000-0800 hours, (6) over 8 ng/PB: TOD 2000-0500 hours, 2) Serum MT concentration--(1) 0-100 pg/ml: inconclusive, (2) over 100 pg/ml: TOD 2200-0100 hours, and 3) Urinary MT concentration--(1) 0-35 pg/ml: inconclusive, (2) over 35 pg/ml: TOD 1800-0600 hours. The range of the estimation can be limited by a combination of these 3 criteria. The present method can be combined with other methods for estimating the TOD to decrease the range.
Adolescent↗
Antihypertensive effects of the neutral endopeptidase inhibitor SCH 42495 in essential hypertension.
The antihypertensive effects and safety of a novel neutral endopeptidase inhibitor, SCH 42495, were investigated in hypertensive patients. A multicenter, open clinical trial was conducted in 27 patients with essential hypertension, WHO Stage I or II. Mean age was 64 +/- 1 years. After 2 to 4 weeks of a placebo run-in, 50 mg twice daily, was started, with the dose increased to 100 mg twice daily, and 200 mg twice daily, every 2 weeks, if necessary, to achieve a predetermined response. Blood pressure and pulse rate were monitored every 2 weeks. Blood chemistry, plasma atrial natriuretic peptide (ANP), and plasma cGMP levels were determined before and after the 8-week treatment period. Blood pressure was significantly reduced, from 171 +/- 1/100 +/- 1 mm Hg to 146 +/- 3/84 +/- 2 mmHg (P < .001) at the end of the 8-week treatment period. No change in pulse rate was noted. Efficacy rate was evaluated in 25 patients treated for 4 weeks or more. Efficacy rate was 44% with 50 mg twice daily, 60% with 100 mg twice daily, and 80% with 200 mg twice daily. Adverse reactions such as headaches and palpitation were observed in six patients (22.2%), with treatment discontinued in five. Significant correlation was observed between increment in plasma ANP levels and blood pressure reductions (r = -0.53, P < .05). Increase in plasma cGMP was positively correlated with increments in plasma hANP (r = 0.80, P < .001). SCH 42495 has potent antihypertensive effect associated with an enhancement of endogenous hANP and may be clinically useful as a new class of antihypertensive drug.
Aged↗
Identification of two novel mutations in the methylmalonyl-CoA mutase gene with decreased levels of mutant mRNA in methylmalonic acidemia.
Genetic defects in the methylmalonyl-CoA mutase (MCM) gene result in methylmalonic acidemia which is inherited as an autosomal recessive disease. We investigated fibroblast cultures obtained from two Japanese patients with MCM deficiency. MCM mRNA was not detected by Northern blot analysis, suggesting that MCM mRNA was markedly decreased. Reverse transcription/polymerase chain reaction (RT-PCR) of MCM mRNA followed by analysis on a fluorescent fragment analyzer indicated that the level of MCM mRNA in these fibroblasts was less than 1% of normal controls. This minute amount of MCM mRNA was successfully amplified by nested RT-PCR and subjected to primary structure analysis. Sequence analysis revealed two novel mutations: a G-to-T substitution at nucleotide position 425 and a 2 bp deletion at nucleotide positions 769 and 770. The first mutation (G425T) resulted in the substitution of a termination codon for glutamic acid at amino acid position 117. The second mutation (769 delta CA) resulted in a frame shift which created a premature termination codon 508 amino acid upstream of the C-terminus of the protein. Patient 1 was homozygous for G425T and patient 2 was a compound heterozygote for G425T and 769 delta CA. Our report is the first to identify MCM mutations that affect the stability of MCM mRNA. An analysis of 16 Japanese patients revealed the presence of G425T in six patients, suggesting a relatively high incidence of the mutation among Japanese patients. This is in sharp contrast to a previous report describing diverse heterogeneity of MCM mutations among Caucasians.
Amino Acid Metabolism, Inborn Errors↗
Augmentation of angiotensin II release from isolated mesenteric arteries of Wistar-Kyoto and spontaneously hypertensive rats following nephrectomy.
1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.
Angiotensin II↗
The effects of central administration of angiotensin II type-1 receptor antagonist, CV-11974, in nephrectomized spontaneously hypertensive rats.
1. The role of the brain renin-angiotensin system in the pathogenesis of genetic hypertension was evaluated using a specific non-peptide angiotensin II type-1 receptor antagonist, TCV-116. 2. CV-11974 (active metabolite of TCV-116) was acutely injected either intravenously (i.v.) or intracerebroventricularly (i.c.v) in male spontaneously hypertensive rats (SHR; 12 week old). In separate groups of nephrectomized and sham-operated SHR, graded doses of CV-11974 were administered either i.v. or i.c.v. for 2 days using an osmotic minipump. In another group, the effects of nephrectomy on the depressor effect of chronic treatment with CV-11974 were investigated. Haemodynamics at three points: before infusion, before nephrectomy and 48 h after nephrectomy, were monitored. 3. Acute i.c.v. injection of CV-11974 decreased blood pressure in the presence of the kidney. Prolonged i.c.v. administration of the drug for 2 days decreased blood pressure even at the lowest dosage, which had no hypotensive effects when given i.v. The hypotensive effect of centrally administered CV-11974 was noted even 48 h after bilateral nephrectomy. 4. These results suggest that the brain renin-angiotensin system has a primary role in the maintenance of hypertension after eliminating the circulating renin-angiotensin system in SHR.
Angiotensin Receptor Antagonists↗
Differential control of vascular tone and heart rate by different amino acid neurotransmitters in the rostral ventrolateral medulla of the rat.
1. To test the hypothesis that a central mechanism may play a role in the minimal reflex tachycardia noted in response to peripheral converting enzyme inhibition, we compared the effects of intravenous (i.v.) ceronapril (CER) with nitroglycerin (NTG) on neurotransmitter release in the rostral ventrolateral medulla (RVLM), using an in vivo microdialysis method in pentobarbital anaesthetized rats. 2. CER (0.1 mg/kg, i.v.) caused a progressive decrease in glutamate (GLU) release (CER 65 +/- 7% vs NTG 83 +/- 3% of each baseline at 140 min, P < 0.05) and attenuated the increase in glycine (GLY) release (CER 100 +/- 8% vs NTG 122 +/- 9%, P < 0.05). 3. Prevention of blood pressure reduction due to i.v. CER by concomitant infusion of a subpressor dose of angiotensin II (AII) attenuated the progressive reduction of GLU release (87 +/- 4%, P < 0.05 compared with NTG group), whereas GLY release was not affected (106 +/- 5%, NS compared with NTG group). 4. Perfusion of GLU into this area at approximately physiological concentrations resulted in a sustained tachycardia with an attenuation of the depressor effect of i.v. CER and perfusion of GLY solely lowered blood pressure. 5. These results demonstrate that i.v. converting enzyme inhibitor reduces the release of GLU in the RVLM, which was specifically caused by reducing circulating AII, without any effect on GLY release, thus resulting in the reduction of blood pressure with minimal effect on the heart rate.
Anesthesia↗
Chronic administration of angiotensin II receptor antagonist, TCV-116, in cardiomyopathic hamsters.
We examined whether specific blockade of the renin-angiotensin system is beneficial for the treatment of cardiac dysfunction in heart failure. The angiotensin II type-1 (AT1) receptor antagonist TCV-116 (10 mg.kg-1.day-1) or its vehicle was given orally to UM-X 7.1 cardiomyopathic (CM) and normal Golden Syrian (GS) hamsters for 8 wk. Plasma and cardiac angiotensin II levels were significantly higher in CM than in GS hamsters. The CM heart showed a smaller response of left ventricular (LV) pressure and first derivative of maximal LV pressure (+dP/dtmax) to the elevation of perfusion pressure (from 60 to 120 cmH2O) in Langendorff-perfused than in GS heart. Treatment with TCV-116 did not affect LV function in GS but significantly improved cardiac contractility in CM hamsters. These results suggest that the renin-angiotensin system plays an important role in the development of cardiac dysfunction due to cardiomyopathy. Blockade of this system by the AT1 antagonist TCV-116 appears to be useful in the prevention of heart failure.
Angiotensin II↗
Effects of age and hypertension on autonomic nervous regulation during passive head-up tilt.
To study the effects of age and hypertension on autonomic nervous function with passive postural change, we examined 31 normotensive subjects (25 to 85 years old) and 31 hypertensive patients (21 to 71 years old) without any cardiac disease, diabetes mellitus, or neurological disorders. Subjects were passively placed in a 60 degrees head-up tilting position after 15 minutes in the supine position. Autonomic nervous function was evaluated by frequency domain analysis of heart rate with the autoregressive method. Using low-frequency (0.1 Hz) and high-frequency (0.25 Hz) peaks, the ratio of low- to high-frequency power (L/H) was calculated as an index of sympathetic activity and the ratio of high to total power (%HF) as that of parasympathetic activity. With the patient in the supine position, total power spectral density declined logarithmically with age in normotensive subjects and hypertensive patients, but %HF and L/H showed no changes. In response to passive tilting, L/H was increased and %HF was decreased in the normotensive subjects, and these responses declined with age logarithmically. In contrast, hypertensive patients exhibited less autonomic response to postural change regardless of age. These results suggest that autonomic neural response to tilt is decreased with age; however, attenuation of the response by hypertension is not associated with an increase in age.
Adult↗
Role of glucose intolerance in cardiac diastolic function in essential hypertension.
Insulin resistance and glucose intolerance have been suggested to be involved in the pathogenesis of various cardiovascular diseases. We examined the role of glucose intolerance in cardiac performance and cardiac hypertrophy in 33 patients with essential hypertension (28 to 71 years of age, mean +/- SD: 53 +/- 13 years) who had never been treated. Patients with obesity (body mass index > 30 kg/m2) or overt diabetes were excluded. Plasma glucose and insulin were measured after oral administration of 75 g glucose. The incremental areas of glucose and insulin were used as indices of glucose intolerance and insulin resistance, respectively. Patients with impaired glucose tolerance according to World Health Organization criteria (n = 12) showed a significantly higher ratio of peak velocity during atrial contraction to early left ventricular filling phase (A/E ratio) than those with normal glucose tolerance (n = 21) despite similar age, blood pressure, and left ventricular mass index. By regression analysis, left ventricular mass index positively correlated with systolic blood pressure (r = .392, P < .05) but not with any parameters of glucose and insulin metabolism. A/E ratio determined by a Doppler system significantly correlated with age ( r = .776) and fasting and peak levels and incremental area of plasma glucose (r = .529, r = .468, and r = .634) but not with those parameters of insulin. In contrast, ejection fraction was not related to blood pressure, glucose tolerance, or insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Prognosis of patients with severe congestive heart failure referred to the cardiac transplant program. Osaka University Cardiac Transplant Program.
In any program for cardiac transplantation, appropriate recipient selection is critically important. The purpose of this study is to evaluate the prognosis of 42 patients with severe cardiac dysfunction who were referred to the Patient Referral Committee of the Osaka University Cardiac Transplant Program from August 1990 to July 1993. All of the patient profiles and clinical data were presented and discussed in the Committee Conference. The Committee classified the patients into three groups according to the following criteria: Class A; 14 patients judged to have a medical indication for heart transplantation, Class B; 7 patients with possible indications which required reevaluation for a definite indication after further intensive medical treatments, and Class C; 21 patients who did not have indications for heart transplantation or who required further clinical examinations and/or medical treatments before a final judgment. Twelve of the 14 Class A patients had a history of NYHA functional class IV and ejection fractions were 25% or less in all of the patients but one (18.5 +/- 1.7%). Six patients in Class A had a history of ventricular tachycardia. The one-year survival rate of Class A patients was 60%, and only 28% survived for 28 months. One patient underwent successful heart transplantation in the United States. If we assume that this patient would have died within a year without heart transplantation, the estimated one-year survival rate would fall to 48%, which is comparable to the survival rate of patients who have been accepted for transplant, but are being treated medically, in Western countries.(ABSTRACT TRUNCATED AT 250 WORDS)
Actuarial Analysis↗
Immunohistochemical findings on androgen receptor in mouse androgen-dependent tumor (Shionogi Carcinoma 115) and its independent sublines.
To examine the androgen receptor in androgen-dependent and -independent tumor immunohistochemically, an indirect immunofluorescence study with an antibody to human androgen receptor was performed. Shionogi Carcinoma 115 (SC 115) cells are an androgen-dependent mouse tumor, but the growth is sustained without androgen when fetal bovine serum is added to serum-free medium. Cells obtained from successive culture (A (-)X cells; X is generations after removal of androgen) were androgen-independent but showed binding to androgen. SC 115 cells, A (-) cells and CS 2 cells which are the other androgen-independent cells derived from SC 115, were used in the study. The androgen receptor (AR) in SC115 cells was stained as small-sized oval granules localized in the nucleus, and the number of the granules was 10-20 per cell. Removal of testosterone for one day as well as one week did not change the size of the AR, but some of the AR in A (-) 10 cells and in generations thereafter appeared to be large. Other small ones were similar to that in SC 115 cells. The nuclear location of the AR did not change in A (-) cells. The ratio of cells containing large AR to the total number of cells increased with each generation after the removal of testosterone from the culture. The addition of testosterone to the culture changed the AR in A (-) 40 cells to small ones, but did not influence the form of the AR in A (-) 60 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Androgens↗
Differential regulation of brain angiotensin II in genetically hypertensive and normotensive rats after nephrectomy.
To investigate the role of tissue angiotensin II (Ang II) in the maintenance of hypertension after nephrectomy in spontaneously hypertensive rats (SHR), Ang II levels were measured in various tissues of both 12-week-old SHR and normotensive control, Wistar-Kyoto rats (WKY), 48 h after nephrectomy or sham operation. Ang II was determined by radioimmunoassay coupled with high performance liquid chromatography. Nephrectomy caused a decrease of plasma renin activity and plasma Ang II concentration in both SHR and WKY. Aortic Ang II levels were significantly lowered by nephrectomy only in WKY, and not in SHR. Ang II levels in hypothalamic block, brainstem and cerebellum of SHR increased after nephrectomy, whereas those of WKY were unchanged. Intracerebroventricular administration of ceronapril, an angiotensin converting enzyme inhibitor, significantly decreased sustained high blood pressure in SHR 48 h after nephrectomy compared with vehicle administration, whereas intravenous administration had no effect. These results suggest that in spite of the important role of the renal renin-angiotensin system in maintenance of high blood pressure in SHR, control mechanisms may switch to other systems after nephrectomy, and that the increased brain Ang II levels after nephrectomy may be related to these mechanisms.
Angiotensin II↗
[Risk factors related to the wall thickness of carotid artery assessed by ultrasonography].
Progression of atherosclerotic lesion of the carotid artery is suggested to induce the development of cerebrovascular events. We evaluate the risk factors related to carotid artery, wall thickness by ultrasonography. A total of 159 patients, who had received no medication for hypertension or hyperlipidemia were enrolled in this study. The wall thickness of carotid artery was evaluated as an intima-media (IM) complex measured by B-mode ultrasonography with a 7.5 MHz probe. Simple regression analysis demonstrated significant correlation between the IM complex and both age and systolic blood pressure, but not with fasting levels of plasma glucose, hemoglobin A1c, total and HDL cholesterol, triglyceride or gender. Stepwise regression analysis showed age and systolic blood pressure contribute to IM thickness (r = 0.623). However, in patients aged 60 or over, blood pressure did not contribute to the IM wall thickness. Smoking was not a risk factor for IM thickness, but the Brinkman Index (daily consumption of cigarettes x years smoking) was significantly higher in patients with plaques in the carotid artery than those without it. These results suggest that high blood pressure is a risk factor for mild atherosclerotic lesions of the carotid artery for those aged under 60. Smoking may contribute to the formation of plaque, which may consequently lead to the ischemic cerebrovascular disease.
Aged↗