Biomedical subjects
Publications and source records attributed to E Murakami.
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Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.
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From 1970 to 1983, eight patients who had severe right ventricular dilatation with little or no left ventricular abnormality were referred to our hospital. There were two men and six women, whose ages ranged from 16 to 38 years and averaged 27. Five patients were members of two families, which had definite hereditary histories of this disease. ECGs of seven patients suggested right ventricular abnormalities. Ventricular arrhythmias were documented in seven, whose ECGs suggested that the origins of the arrhythmias were in the right or both ventricles. Cardiothoracic ratios ranged from 0.50 to 0.66 and averaged 0.59. Five patients had wide respiratory splitting of the second heart sound. Echocardiography showed a marked increase in the right ventricular dimension. Right ventricular diastolic pressure was increased in three; left ventricular diastolic pressure was increased in two. Right ventricular angiography revealed marked dilatation and low ejection fractions of the right ventricle in all, but left ventricular function was nearly normal in them, except two patients who had minimal abnormality. The average follow-up period was 6.3 years and ranged from 3 months to 11 years. During the follow-up period, only two patients had ventricular tachycardia and three developed overt heart failure. Three patients died, two suddenly, and one from an attack of ventricular tachycardia. Autopsies of these two showed extreme dilatation of the right ventricle and one of them showed concentric hypertrophy of the left ventricle. Histological abnormalities were found in both ventricles. In summary, it is suggested that idiopathic dilated right ventricular cardiomyopathy can be classified in the spectrum of dilated cardiomyopathy.
Renin substrate was characterized in incubation medium of isolated hepatocytes, plasma, and brain extracts of the rat by isoelectric focusing and polyacrylamide gel electrophoresis. The isoelectric focusing (IEF) profile of renin substrate released into incubation medium of rat hepatocytes demonstrated two peaks with isoelectric points (pI) of 4.1 (minor peak) and 4.6 (major peak). Extracts of normal rat brain also showed two forms (pI 4.6 major form, and pI 5.1 minor form). In contrast, normal rat plasma contained a single broad peak of substrate with pI 4.5. On polyacrylamide gel electrophoresis (PAGE), the hepatocytes medium and brain extracts contained forms of substrate with reduced mobility as compared to the plasma form. Intraperitoneal injection of 17 beta estradiol (1 mg) or bilateral nephrectomy significantly elevated renin substrate levels in plasma and increased its release from hepatocytes, however, no change in the IEF or PAGE profiles was evident. There was no remarkable change of substrate concentration in the brain following these treatments. Molecular weights of renin substrate were 60,000-65,000 from all preparations. It remains to be established whether the different forms of renin substrate from hepatocytes represent precursor forms of circulating plasma substrate. The presence of distinct forms of brain renin substrate and the lack of an increase in brain renin substrate following nephrectomy or estrogen treatment suggest local synthesis and support the postulate of an independent renin-angiotensin system in the central nervous system.
We investigated the coronary angiography (CAG) of 1,022 patients to clarify the clinical significance of myocardial squeezing and obtained the following results. Of 1,022 patients undergoing CAG, 164 patients (16.0%) had myocardial squeezing of the left anterior descending artery (LAD) and 16 patients (1.6%) had only the first septal perforating branches producing a squeezing of the artery during systole. The association of myocardial squeezing of the LAD with different diagnosis was anterior chest pain syndrome (26.6%), arrhythmia (23.6%), cardiomyopathy (21.7%), angina pectoris (15.8%) and myocardial infarction (6.9%). The degree of narrowing of the LAD was classified into 4 grades; 25-49%: 36 patients (22.0%), 50-74%: 82 patients (50.0%), 75-89%: 35 patients (21.3%) and greater than 90%: 11 patients (6.7%). The morphology of the vessel subjected to myocardial squeezing was classified into 4 patterns on CAG. Type A is localized narrowing. Type B is bead-like narrowing. Type C is diffuse narrowing. Type D is tapering and obstructive narrowing. All type D patients had the septal perforating branches. We investigated whether only myocardial squeezing has ischemic ST-T segment changes in the ECG. Fifty-five of 87 patients (63.2%) with myocardial squeezing of greater than 75% and organic stenosis of less than 50% of the LAD had ischemic changes in the ECG during exercise or pacing-induced tachycardia. There was no special feature between myocardial squeezing and subjective symptoms.
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The use of nifedipine in patients with hypertension, heart failure, and acute myocardial infarction is discussed. Data from over a ten-year period are presented. Results indicate that nifedipine, although frequently prescribed as an antianginal agent, is also useful as an antihypertensive agent, especially when used concomitantly with other drugs. Its ability to cause fluctuations in blood pressure remains a shortcoming, however.
To evaluate the hemodynamic effects of dibutyryl cyclic AMP (DBcAMP) in congestive heart failure (CHF), right-sided cardiac catheterization was performed in 11 patients with CHF, and hemodynamic variables were investigated before and after infusion of various doses of DBcAMP at a rate of 0.025 to 0.2 mg/kg/min (mean 0.14 +/- 0.077 [standard deviation]). DBcAMP reduced total systemic vascular resistance index from 3,171 +/- 1,158 to 1,880 +/- 554 dynes s cm-5 X m2 (mean +/- standard deviation) and pulmonary arterial end-diastolic pressure from 23 +/- 13 to 20 +/- 11 mm Hg, and increased cardiac index from 2.24 +/- 0.60 to 3.41 +/- 1.02 liters/min/m2. Mean arterial blood pressure decreased from 91 +/- 14 to 84 +/- 13 mm Hg, and heart rate increased from 91 +/- 16 to 99 +/- 13 beats/min. The increase in cardiac index was accompanied by a proportional decrease in total systemic vascular resistance index in all patients except 1. In 8 patients the decrease in pulmonary arterial end-diastolic pressure was accompanied by an increase or no change in the left ventricular stroke work index. In 6 patients, DBcAMP was given in incremental doses of 0.05, 0.1, and 0.2 mg/kg/min every 20 minutes, and 5 of 6 patients tolerated the full dose and showed dose-related hemodynamic changes for the incremental doses of DBcAMP. These data suggest that DBcAMP has powerful vasodilating effects on resistance vessels in patients with CHF; hence, it can be a useful vasodilating agent for treatment of CHF.
A 38-year-old woman with coronary arterial aneurysm, which resulted in myocardial infarction, was reported. By coronary arteriography, an aneurysm of the left anterior descending branch was found, but no arteriovenous shunt could be revealed. The patient has neither clinical history of severe febrile inflammatory disease nor any coronary risk factors. The etiology of her coronary arterial aneurysm was considered to be congenital. The patient underwent aorto-coronary saphenous vein bypass graft surgery successfully. We believe that this is the first case report in Japan on congenital aneurysm of the coronary artery without arteriovenous fistula, which was diagnosed during life by coronary arteriography.
A randomized prospective study was carried out and the therapeutical effects of intensive medical management in the acute stage of unstable angina were compared with those of urgent coronary bypass surgery on patients admitted to Kanazawa Medical University Hospital, who showed an ST elevation or depression during their attacks. Seventy patients with unstable angina were evaluated clinically, angiographically and hemodynamically: 41 of them had a transient ST elevation (26 treated medically; 15 surgically) and 29 had a transient ST depression (15 treated medically; 14 surgically). The hospital mortality rates were 12.2% for the medical group (3.8% in patients with an ST elevation; 26.7% in an ST depression) and 17.2% for the surgical group (6.7% in an ST elevation; 28.6% in an ST depression). These differences were not significant. The incidence of myocardial infarction among in-patients was 7.3% in the medical group (0% in the patients with an ST elevation; 20% in an ST depression) and 13.8% in the surgical group (13.3% in an ST elevation; 14.3% in an ST depression). These differences were also not significant. On their coronary angiograms, single vessel disease was significantly frequent in unstable angina with an ST elevation and so was triple vessel disease in patients with an ST depression. Left ventricular function was markedly improved in patients with an ST elevation after coronary bypass surgery. However, in unstable angina with an ST depression, there was no amelioration of left ventricular contractility and relaxation. It is concluded that by medical or surgical treatment, patients with unstable angina showing an ST elevation during their attacks had a fairly better prognosis than those showing an ST depression; the left ventricular function of the ST elevation group was improved considerably after AC bypass surgery, while those of the ST depression group showed no improvement.
The effects of a therapeutic dose of oral S-596 upon the cardiovascular response to intravenous isoproterenol and noradrenaline were studied in 2 hypertensive and 4 normotensive subjects in order to evaluate the drug's mode of action. After oral administration of S-596, mean blood pressure rose slightly and the heart rate decreased. In addition, cardiac output decreased considerably and total peripheral resistance increased. However pulmonary arterial end-diastolic pressure and right atrial pressure were not affected by S-596 administration. Before S-596, intravenous isoproterenol increased both heart rate and pulse pressure in a dose-dependent manner. Similarly, intravenous noradrenaline increased both systolic and diastolic pressures. Following 15 mg of S-596, the effects of isoproterenol were antagonized such that the cumulative log-dose-response curves of the mean isoproterenol-induced increases in heart rate and reductions in diastolic pressure were shifted in parallel to the right. At the same time, the mean noradrenaline-induced increases in blood pressure were also antagonized in a competitive manner. The mean ratio of alpha- and beta-components was calculated as: (formula: see text) From this result it can be suggested that the alpha-adrenoceptor blockade potency of this drug is approximately one-eight of its beta-adrenoceptor blockade potency.
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The effects of angiotensin II, thyroxine and 17 beta estradiol on plasma renin substrate concentration in rats and renin substrate production by perfused rat livers were investigated. The addition of angiotensin II (1-10 microgram) to the perfusion system did not affect the synthesis of renin substrate. After treatment with thyroxine (2.5 mg/kg/day), plasma renin substrate concentration, plasma renin activity, plasma aldosterone concentration and the rate of renin substrate synthesis were all significantly increased. 17 beta estradiol (2 mg) raised both plasma renin substrate concentration and the amount of renin substrate production by the liver. Isoelectric focusing profiles of renin substrate of liver perfusate and of plasma from estrogen-treated rats were different from that of liver perfusate from normal rats. But the profile of renin substrate in plasma was essentially similar to those to liver perfusates both in normal and estrogen-treated rats.
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