[Hypothalamo-pituitary diseases].
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Biomedical subjects
Publications and source records attributed to R Takeda.
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The effect of acetaldehyde on the contractile responses induced by potassium-rich solution was studied in the guinea-pig taenia caeci. Acetaldehyde at a concentration between 1 and 50 mM reduced the tonic contraction induced by a high potassium solution containing a normal concentration of CaCl2 without affecting the phasic one. The phasic contraction was depressed only slightly at a very high concentration of acetaldehyde (100 mM). The tonic component increased with increasing external Ca concentration, and the reduction of this tonic contraction by acetaldehyde was greater at high Ca concentrations. In Ca-free, K-rich solution, carbachol induced a transient contraction. This carbachol-induced contraction in the absence of external Ca was markedly depressed at the second application of carbachol, but it reappeared after exposure to a Ca-containing solution. In this condition acetaldehyde did not affect these carbachol-responses, while it decreased a slow rise of tension during exposure of Ca. These results suggest that acetaldehyde inhibits the entry of external calcium without having an appreciable effect on the release of Ca and on the filling of the internal stores with Ca.
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A rare case of acromegaly developing gross hyperlipidemia not associated with overt diabetes was presented. Gross hyperlipidemia revealed type V hyperlipoproteininemia, according to agarose gel electrophoretic pattern of serum lipoprotein. Before pituitary surgery, the serum levels of cholesterol and triglyceride were 320 mg/dl and 1830 mg/dl respectively, and the basal level of growth hormone was markedly elevated, ranging from 129 to 231 ng/ml with the mean +/- SD of 168 +/- 39 ng/ml. The enzymatic activities of hepatic triglyceride lipase (H-TGL) and lipoprotein lipase (LPL) were 14.2 and 1.50 mumoles/ml/hour, respectively. H-TGL activity was normal, while LPL activity was extremely low compared to those of normal subjects. After combined therapy with pituitary surgery and 60Co radiation, the serum level of growth hormone was decreased to 35.9 +/- 8.6 ng/ml in the mean +/- SD, but not normalized. However, the serum level of triglyceride was decreased and both H-TGL and LPL activities were increased to 19.3 and 2.7 mumoles/ml/hour, respectively. LPL activity was increased 79% compared to the level of pretreatment. Agarose gel electrophoretic pattern of lipoprotein changed from type V to type IV and ultracentrifugal analysis showed that very low density lipoprotein (VLDL)-cholesterol was decreased and intermediate density lipoprotein (IDL)-cholesterol, low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol were increased.
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The purpose of the present study was to investigate the effects of niceritrol on HDL metabolism. In study (A), niceritrol, 750 mg/day was given for initial period of 12 weeks and 1,500 mg/day was prescribed for an additional 12 weeks to 12 subjects. In six of them, the HDL cholesterol (Ch) levels were less than 45 mg/100 ml with normal plasma cholesterol levels and with plasma triglyceride levels of less than 250 mg/100 ml. In the remaining six subjects, HDL-Ch, plasma cholesterol and triglyceride levels were all within normal limits except in one subject having a higher triglyceride level, 213 mg/100 ml. Plasma lipoproteins were fractionated by sequential ultracentrifugation and analyzed for cholesterol, triglyceride (TG), phospholipid(PL), apolipoprotein(Apo) B and Apo A-I, every 4 weeks. Niceritrol decreased plasma-Ch, VLDL-Ch, LDL-Ch, plasma-TG, VLDL-TG, plasma-PL, VLDL-PL and LDL-PL. Niceritrol increased HDL-Ch and the HDL-Ch/LDL-Ch ratio. These effects were more significant for the dose of 1,500 mg/day than 750 mg/day and were more marked in the patients with lower pretreatment HDL-Ch levels. Apo B level at 20 weeks was significantly lower than that before treatment. Initial plasma Apo A-I levels of the patients were approximately one-half of the control plasma. After treatment with niceritrol, Apo A-I concentration tended to increase. In study (B), changes of lipids concentration in HDL2 and HDL3 fraction were investigated in 5 patients during treatment with niceritrol, 1,500 mg/day for 8 weeks. Lipoproteins were analyzed every 2 weeks. HDL2-Ch levels tended to increase without significant changes of HDL3-Ch levels and HDL2-Ch/HDL3-Ch ratio showed a tendency to increase. A significantly but weakly inverse correlation between changes of VLDL-TG and HDL-Ch was observed, suggesting that the increment of HDL might be due partly to promoted lipolysis of TG-rich lipoproteins. However, it was suggested that the effects of niceritrol on lipoprotein synthesis in the liver and HDL catabolism should be considered.
We studied the effects of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on serum levels of lipoproteins and ubiquinone-10-in seven heterozygous patients with familial hypercholesterolemia. ML-236B was given at doses of 30 to 60 mg per day for 24 weeks. Serum cholesterol decreased from 390 +/- 9 to 303 +/- 8 mg per deciliter (101 +/- 0.2 to 7.88 +/- 0.2 mmol per liter, mean +/- S.E.M.; p less than 0.001) and serum triglyceride decreased from 137 +/- 18 to 87 +/- 9 mg per deciliter (1.55 +/- 0.20 to 0.98 +/- 0.01 mmol per liter; p less than 0.05). Intermediate-density-lipoprotein (DL) cholesterol, IDL triglyceride, low-density-lipoprotein (LDL) cholesterol, and LDL triglyceride decreased significantly (p less than 0.01, P less than 0.001, and P less than 0.001, respectively). However, there were no significant changes in very-low-density-lipoprotein (VLDL) cholesterol and triglyceride or high-density-lipoprotein (HDL) cholesterol. Serum ubiquinone-10 levels did not change, and LDL levels of ubiquinone-10 decreased by 50 per cent, from 0.39 +/- 0.07 to 0.20 +/- 0.01 microgram per milliliter (P less than 0.05). No adverse effects were observed. We conclude that ML-236B is effective in lowering serum cholesterol without lowering serum ubiquinone-10 in heterozygous patients with familial hypercholesterolemia.
The first successful treatment by plasma exchange of acute renal failure and disseminated intravascular coagulation, as well as liver and central nervous system damage, was achieved in two patients with severe multiorgan damage associated with extensive muscle tissue damage caused by heatstroke and/or electrical injury. Substances derived from damaged muscle tissue, such as myoglobin and enzymes, were efficiently removed by a cellulose acetate membrane filter. Improvement of consciousness, disturbance, coagulation disorder, and renal failure were observed. The disorders associated with extensive rhabdomyolysis seem to be a promising indication for this therapy. Plasma exchange with a membrane filter is useful for treatment of patients with renal failure, being readily connected on-line with conventional dialysis.
The plasma aldosterone (PA) response to sodium restriction (25 mEq daily for 4 days) and to graded infusions of angiotensin II (AII, 2, 4 and 8 ng/kg/min each for 30 min) during a low-sodium intake were studied in 15 elderly subjects with mild essential hypertension versus 10 elderly normotensive subjects. The PA response to sodium restriction relative to changes in plasma renin activity (PRA) was estimated by the ratio of PA increment to PRA increment after sodium restriction (delta PA/delta PRA). THe PA response to graded AII infusions was determined by the increment of PA above the basal level after each dose of AII. In 10 of the 15 elderly hypertensive subjects whose PRAs responded normally to sodium restriction, the delta PA/delta PRA ratios and PA increments during the graded AII infusions were similar to those in the elderly normotensive subjects. However, in the remaining 5 elderly hypertensive subjects whose PRAs responded subnormally to sodium restriction, the delta PA/delta PRA ratios were high and the PA increments greater during the graded AII infusions. THe increments of mean blood pressure during the graded AII infusions were similar in the foregoing 10 of 15 hypertensive subjects, and significantly greater during the AII infusion rates of 4 and 8 ng/kg/min in the remaining 5 hypertensive subjects when compared with those in the normotensive subjects. Apparently some subjects with essential hypertension, whose PRAs response subnormally to sodium restriction, have an abnormally enhanced adrenal responsiveness to AII under the conditions of low-sodium intake.
Hemodynamic effects of [Sar1, Ile8] AII, an angiotensin II analog, were studied in 30 patients with essential hypertension, who were subdivided into 11 low renin, 10 normal renin and 9 high renin groups according to low, normal and high PRA values both before and after furosemide administration (80 mg, orally) plus 4 h of ambulation, respectively. [Sar1, Ile8] AII infusion (600 ng/kg/min) produced significant increases in mean blood pressure (MBP) and total peripheral resistance index (TPRI) in normal renin and low renin groups and significant decreases in MBP and TPRI in high renin group, while the cardiac index and heart rate remained unchanged during the infusion in these three groups. Change in MBP at 30 min of [Sar1, Ile8] AII infusion correlated significantly with alteration in TPRI in 23 patients with essential hypertension, who completed the 30-min infusion. The response of both MBP and TPRI to [SAR1, Ile8] AII also correlated significantly with basal PRA. These results suggest that blood pressure response to [SAR1, Ile8] AII in essential hypertension is primarily due to alteration in total peripheral resistance and that direction and amplitude of the response of both MBP and TPRI are practically dependent on basal PRA levels.
The relationship between the concentrations of intermediate-density lipoprotein (IDL) and other lipoproteins and the extent of coronary artery disease (CAD) was studied in 182 consecutive patients evaluated by selective coronary cineangiography. On univariate analysis, the extent of CAD correlated significantly and positively with very low density lipoprotein (VLDL) cholesterol, IDL cholesterol and low-density lipoprotein (LDL) cholesterol, and negatively with high-density lipoprotein (HDL) cholesterol. Analysis of four subgroups divided by IDL cholesterol and LDL cholesterol levels indicated that moderately increased levels of IDL cholesterol were closely associated with a high frequency of CAD. Moreover, multi-variate regression analysis demonstrated that IDL cholesterol for men, LDL cholesterol for men and women and HDL cholesterol for men were significant variables of use in the final weighting procedure. IDL cholesterol was closely associated with cholesterol-rich VLDL. This study shows that IDL and cholesterol-rich VLDL combine to contribute to the development of CAD.
We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of (125)I-LDL were 0.5+/-0.3 ng/mg protein (mean+/-SEM), 14+/-8 and 8+/-6 ng/mg protein per 6 h (four normal cells; 44+/-3, 386+/-32, and 1,335+/-214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of (125)I-LDL were 6+/-2, 29+/-8, and 90+/-32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed approximately 46% of the normal activities of receptor.ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [(14)C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 mug/ml. However, at 0.05 mug/ml of ML-236B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 mug/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and a heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes.