Biomedical subjects
E Murakami
Publications and source records attributed to E Murakami.
Effect of oral potassium on urinary kallikrein excretion in essential hypertension.
Urinary kallikrein and potassium were excreted in parallel in not only static but also dynamic sodium states. Oral potassium load stimulated the release of urinary kallikrein in normotensive subjects and WHO stage I essential hypertensive patients. Stage II essential hypertensive patients had the lowest value of basal level of urinary kallikrein and showed no increase in urinary kallikrein by oral potassium load. These results suggest that the functional activity of renal kallikrein-kinin system decreases with the development of essential hypertension.
Myocardial tissue characterization by magnetic resonance imaging in Fabry's disease.
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Blood pressure elevation caused by inhibition of brain glutathione reductase.
The effect of brain glutathione reductase activity on blood pressure regulation was investigated. The intravenous administration of the glutathione reductase inhibitor, nitrofurantoin (0.1-0.3 mg/rat), to seven normotensive Wistar rats caused dose-dependent rises in blood pressure and the heart rate (delta mean blood pressure 17 +/- 1 mmHg; delta heart rate 89 +/- 7 beats/min for 0.3 mg). Rats treated with 0.3 mg nitrofurantoin showed a 50% decrease in glutathione reductase activity with a twofold increase in the ratio of glutathione disulphide to reduced glutathione in the hypothalamus and brainstem, and a 1.5-fold increase in plasma noradrenaline and plasma renin activity compared with controls. These nitrofurantoin-induced effects were totally abolished by pretreatment with a sympathetic ganglion blocker (4 mg pentolinium tartrate, administered subcutaneously) except for the increased ratio of glutathione disulphide to reduced glutathione and the decreased glutathione reductase activity in the brain. These results suggest that the blood pressure elevation caused by inhibition of brain glutathione reductase activity occurs through activation of the sympathetic nervous system and the renin-angiotensin system.
Effects of renin inhibitors on the expression of kidney renin gene and tissue renin-like activity.
The effect of renin inhibitor ES-1005 on renin gene expression was investigated in sodium-depleted marmosets. The kidneys were removed after continuous infusion of ES-1005 (12 mg/kg per h) for 2 h. The relative amount of kidney renin messenger (m)RNA was measured by densitometric Northern blot analysis using an alpha-32P-labelled human renin complementary (c)DNA fragment as a hybridization probe. Plasma renin activity was completely inhibited by ES-1005. The level of kidney renin mRNA decreased significantly to about one-third of the normal control value. We also investigated the inhibitory potency of the renin inhibitor ES-6864 on the renin-like activity in dog tissues (adrenal glands, aorta and brainstem). ES-6864 inhibited the tissue renin-like activity with an IC50 of 10(-7) to 10(-8) mol/l in vitro. Renin inhibitors not only inhibit the activity of plasma and tissue renin, but also suppress the synthesis of renin in the kidney.
Body surface potential mapping in anterior myocardial infarction--a longitudinal study in acute, convalescent and chronic phases.
Body surface potential mapping (BSPM) was performed to evaluate the infarct size and the viability of myocardium in the infarct area in 20 patients with anterior myocardial infarction (MI). BSPM was performed at the early acute phase, 1 week, 1 month and 2 months after onset of the symptoms. The departure areas were obtained according to the potential distribution below the mean normal range and were compared with the value for creatine phosphokinase (CPK), hemodynamic parameters, ejection fraction measured by radionuclide ventriculography, extent score (ES) and severity score (SS) of thallium-201 single photon emission computed tomogram. Two months after the infarction, the ergometer exercise was performed and departure areas before and after exercise were compared. With the departure map technique, the departure areas in all cases were found in the anterior region of the thorax; From 1 week to 2 months after MI, the departure areas were significantly reduced. One week after MI, the departure areas had a positive significant relation with peak CPK and sigma CPK. One month after MI the departure areas also had a positive relation with ES or SS. One week and 1 month after MI, the departure areas had a negative relation with the left ventricular stroke work index or the left ventricular ejection fraction. After exercise test in the chronic phase, the departure areas were significantly enlarged. In conclusion, the departure map is useful in evaluating the location, sequential changes of size of anterior MI including the ischemic area around the infarct site and the left ventricular function. It is suggested that the enlarged departure areas after exercise might be the ischemic areas provoked by exercise.
Blood pressure distribution and determinants of higher levels of blood pressure in Japanese rural adolescents.
The blood pressures (BP) and anthropometric values of 1,014 Japanese rural school children aged 12-17 years old were measured at one-year interval. The strongest correlation for systolic BP (SBP) was weight and for diastolic BP (DBP) it was age. Larger values of weight, body mass index, triceps skinfold thickness and smaller increment of height showed significant discriminative powers in differentiating the subjects who had been above the age-sex specific 80th percentile value (H-H group) from those who had been below the 20th percentile value (L-L group) for both SBP and DBP. Subjects with a family history of hypertension (FHH) had higher SBP than those without a FHH, and were more prevalent in H-H group for SBP. These results indicate that larger body size and more mature stature are determinants of higher levels of BP during adolescence, and that FHH affects SBP only in this period.
[A case of chemical hyperthyroidism induced by antiarrhythmic agent amiodarone].
Amiodarone, an antiarrhythmic agent, is known to occasionally induce alterations in thyroid function because of its iodine content and ability to inhibit T4 5'-monodeiodination. We herein describe the drug-induced chemical hyperthyroidism in a diabetic patient with ventricular premature beats. A 46-year-old man with well controlled diabetes mellitus revealed neck swelling during a 4 months' treatment with amiodarone for his frequent occurrence of ventricular premature beats. Physical findings were unremarkable other than grade III diffuse struma. Routine laboratory studies were almost normal. The results of thyroid function studies showed hyperthyroidism, including increases in T4 and free T4, slight increases in T3 and free T3, a marked increase in reverse T3 and a decrease in 123I 24-h uptake. TSH was low and did not respond to TRH. Antithyroid antibodies and TSH receptor antibodies were negative. The findings of the thyroid biopsy were unremarkable except for a mild follicular hyperplasia. After cessation of the drug, T3 and free T3 were returned to normal within 2 weeks, T4 and free T4 within 2 months and reverse T3 after 6 months. These data suggest that the struma and chemical hyperthyroidism observed in our patient were induced by amiodarone treatment.
A highly potent and long-acting oral inhibitor of human renin.
An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
The role of brain glutathione in blood pressure regulation.
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Dose-effect relationship of carvedilol in essential hypertension. An open study.
This study was performed to find the optimal dose of carvedilol, in terms of efficacy and safety, in Japanese patients with mild to moderate essential hypertension. 134 patients with blood pressure greater than 160/95 mm Hg after a 4-week placebo run-in period were initially given carvedilol 5mg once daily. The dose was increased to 10 and 20mg at 4-weekly intervals if the target blood pressure was not achieved. The duration of treatment was 12 weeks. After 12 weeks' administration, the average blood pressure was significantly (p less than 0.001) reduced from 170/101 to 150/91 mm Hg. The hypotensive activity of carvedilol 5mg was mild, but sufficient hypotensive effect was observed in 65% of patients receiving up to 20 mg/day. No significant postural changes in blood pressure were observed. Although heart rate was significantly decreased (77 to 66 beats/min, p less than 0.001), no patient was judged to have bradycardia. Side effects occurred in 5.2% of patients. Carvedilol 10 to 20mg once daily is considered to be an effective and safe treatment for essential hypertension.
The role of hypothalamic glutathione in hypertensive animals.
The role of brain glutathione metabolism in hypertensive animals was studied. In spontaneously hypertensive rats (SHR) from prehypertension to established hypertension, the content of oxidized glutathione (GSSG) and the ratio of GSSG to GSH in the hypothalamus were significantly (p less than 0.05) higher than those in age-matched normotensive Wistar Kyoto rats (WKY). Hypothalamic glutathione reductase (GR) activities in prehypertensive and established hypertensive SHR were significantly (p less than 0.05) lower than those in WKY. DOCA-salt hypertensive rats (DSR) also had a significantly (p less than 0.05) higher content of GSSG and GSSG/GSH ratio and a significantly (p less than 0.05) lower GR activity in the hypothalamus than the normotensive control. There were no significant differences in these values in the brain stem between hypertensive and normotensive rats. These results suggest that the increased GSSG/GSH ratio due to reduced activity of GR in the hypothalamus may have an important role in the development of hypertension in SHR and DSR.
[Differentiation of hypertrophic cardiomyopathy from left ventricular hypertrophy induced by essential hypertension using magnetic resonance imaging].
To examine the efficacy of magnetic resonance imaging (MRI) in diagnosing hypertrophic cardiomyopathy (HCM), 16 patients with HCM and 14 hypertensives with left ventricular hypertrophy (LDH) were studied using a 0.5 Tesla Siemens MRI apparatus equipped with cardiac gating. In HCM, left ventricular hypertrophy was localized to the septal wall in four, to the apical wall in two, to both the septal and apical walls in two, and to the apical and inferior walls in one, and it was diffuse in seven patients. In hypertensives, LVH was localized to the septal wall in three, to both the septal and anterior walls in two, to the free wall in one, and it was diffuse in eight patients. The distribution of the hypertrophic portion was nearly equal in both groups. The thickest portion of the left ventricular wall was 24.6 +- 4.8 mm in HCM and 21.6 +- 5.4 mm in hypertension, and there was no significant difference between them. The T2 relaxation time of the hypertrophic portion was 52.2 +- 4.8 msec in HCM and 45.3 +- 6.1 msec in hypertension, and there was a significant difference between them (p less than 0.01). However, there were no significant differences between the T2 relaxation times of the hypertrophic and non-hypertrophic portions in both groups. In conclusion, it may be difficult to differentiate HCM from hypertension based on the distribution of hypertrophic portions, but measurements of the T2 relaxation times may be useful for making the differential diagnosis.
First-degree atrioventricular block induced by oral cimetidine.
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In vitro inhibition of human renin by statine-containing tripeptide renin inhibitor (ES-1005).
Dipeptide and tripeptide derivatives containing a statine residue were synthesized as human renin inhibitors. ES-305, bis[(1-naphthyl)methyl]acetyl-histidyl-statine-2(S)-methylbutylami de, was found to be a highly potent human renin inhibitor that is species-specific and enzyme-specific. The replacement of the methylbutylamide of ES-305 with the leucyl-lysinol (ES-1005) showed similar high potency against human renin (Ki value of 2.4 x 10(-9) M) and monkey renin (Ki value of 7.9 x 10(-9) M) as ES-305. ES-1005 competitively inhibited human renin. The compound was about one order of magnitude less potent against pig, dog, and rabbit renins. It had moderate inhibitory potencies against cathepsin D and pepsin (IC50 of cathepsin D and pepsin of 1.6 x 10(-5) and 8.0 x 10(-6) M, respectively). ES-1005, a newly synthesized tripeptide derivative containing statine, is a highly potent inhibitor of not only primate renin but also a wide variety of nonprimate renins.
The effect of low dose carvedilol on circadian variation of blood pressure in patients with essential hypertension.
The effect of once daily low-dose carvedilol on circadian variations of blood pressure (BP) was studied in Japanese patients with mild or moderate essential hypertension. Thirty-one patients were admitted to hospital whose BP was 150/90 mm Hg/day or greater and they participated in the study. After a placebo period of 1 week, 5 or 10 mg carvedilol was given once daily in the morning for 3 to 7 days, and if BP reduction was not sufficient, the dose was increased to 20 mg daily. The blood pressure variation was monitored before and 1, 2, 4, 6, 8, 10, 12, and 24 h after administration of the drug on the last day of placebo and final dose of carvedilol. Of the 31 cases receiving carvedilol once daily, cumulative effectiveness (13 mm Hg reduction in mean BP) was 48.4% at 10 mg/day and 54.8% at 20 mg/day. Both systolic and diastolic pressures decreased significantly and heart rate decreased slightly. There was no significant difference between the standard deviations of BP on the last days of the control period and the carvedilol treatment. The difference between maximum and minimum BP during the day was not significant between the two periods. Circadian variations of heart rate were also not significantly different for the two periods. This indicates that carvedilol did not have any effect on circadian variations of BP and heart rate. The present study also suggests that low-dose carvedilol once daily may be effective in the treatment of hypertension.
Brain glutathione and blood pressure control.
The role of glutathione in the central nervous system in regulating blood pressure (BP) and sympathetic nerve activity (SNA) was investigated in rats. Intracerebroventricular (ICV) injection of glutathione disulfide (GSSG: 1.7-33 nmol) resulted in a dose-dependent increase in BP [delta mean BP: 17 +/- 1 mm Hg (n = 7) for 33-nmol dose] together with a marked increase in SNA [163 +/- 13 to 672 +/- 70 spikes/10 s (n = 7), p less than 0.001]. Intracerebroventricular administration of its reduced form (GSH, 33 nmol) produced a vasodepressor response (delta mean BP: -9 +/- 2 mm Hg) accompanied by a corresponding decrease in SNA [192 +/- 15 to 54 +/- 22 spikes/10 s (n = 6), p less than 0.01]. These responses were not due to a leakage into the systemic circulation, since intravenous injection of GSSG or GSH (33 nmol) did not show any cardiovascular effects. Electrical stimulation of the posterior hypothalamus induced hypertension with a significant decrease of GSSG in the brain stem. The results indicate that GSSG has a stimulatory control over the sympathetic nervous system while GSH has an inhibitory effect on SNA. Glutathione disulfide and GSH may act within the central nervous system to modulate the tone of the sympathetic nervous system.
Efficacy of dibutyryl cyclic AMP in heart failure unresponsive to catecholamines.
The efficacy of dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) was evaluated in eight patients with heart failure unresponsive to catecholamine therapy. Seven patients who were hemodynamically at Forrester's hemodynamic subset stage H-IV and had a left ventricular stroke work index (LVSWI) of less than 20 g-m/m2 despite administration of unloading drugs and catecholamines were studied both hemodynamically and clinically. Another patient with dilated cardiomyopathy, in whom invasive hemodynamic monitoring could not be carried out, was studied clinically. The DBcAMP was administered intravenously at a mean (+/- SD) of 0.05 +/- 0.036 mg/kg/min, and hemodynamic measurements were made 63 +/- 37 min after administration. The cardiac index (CI) increased from 1.92 +/- 0.22 to 2.49 +/- 0.59 L/min/m2, and LVSWI from 14 +/- 4.0 to 18 +/- 5.1 g-m/m2, both significantly (CI, P less than 0.01; LVSWI, P less than 0.025). The total systemic vascular resistance index (TSVRI) decreased significantly from 2,746 +/- 427.2 to 2,218 +/- 582.6 dan.sec.cm-5.m2 ( P less than 0.01). The increase in CI was accompanied by a proportional decrease in TSVRI in all patients. Left ventricular function, which was estimated by the relation between pulmonary arterial end-diastolic pressure and LVSWI, was improved in five of seven patients after administration of DBcAMP. Two patients in whom DBcAMP was given intermittently improved clinically and survived. The authors conclude that DBcAMP has powerful vasodilating and mild positive inotropic effects and hence can be useful for treating heart failure unresponsive to catecholamines.