Eiki Murakami

Plasma Adrenomedullin Concentrations and Cardiac and Arterial Hypertrophy in Hypertension

It has been reported that plasma concentrations of adrenomedullin (AM), a novel vasodilator peptide, are higher in patients with essential hypertension than those in normotensive subjects. To clarify the clinical significance of increased levels of AM in patients with essential hypertension, in this study we examined the relationship between plasma concentrations of AM and the structure of the left ventricle or carotid artery. Plasma AM concentrations; renin activity; and norepinephrine, epinephrine, and creatinine concentrations in 50 patients with untreated essential hypertension without renal dysfunction and heart failure were measured. We also measured the mean wall thickness of the left ventricle and left ventricular mass index by M-mode echocardiography and intimal-medial thickness and arterial distensibility of the carotid artery by ultrasonography. Hypertensive patients were divided into two groups: hypertensives with and those without left ventricular hypertrophy. Plasma AM concentrations in hypertensive patients with left ventricular hypertrophy were significantly higher than in hypertensive patients without left ventricular hypertrophy (7.87+/-2.70 vs 5.74+/-1.65 fmol/mL, P<.01). In all hypertensive patients, plasma AM concentrations were not correlated with blood pressure, plasma renin activity, plasma norepinephrine, plasma epinephrine, or plasma creatinine concentration. Plasma AM concentrations were positively correlated with left ventricular mass index or mean wall thickness (r=.37, P=.009; r=.40, P=.004, respectively) and inversely correlated with carotid artery distensibility (r=-.33, P=.02), whereas plasma AM concentrations were not correlated with intimal-medial thickness. These results suggest that the observed elevation of plasma AM in patients with essential hypertension with normal renal function may be partly related to cardiac hypertrophy and decreased carotid artery distensibility.

Effect of age on left ventricular geometric patterns in hypertensive patients.

Objectives To investigate the effect of age on left ventricular structure and geometry in hypertensive patients, we studied the relationship between age and echocardiographic variables in patients with uncomplicated essential hypertension. Patients and methods We divided 168 patients with hypertension into three groups according to age: young (<40 years), middle-aged (40–59 years) and an elderly group (±60 years). They were further categorized according to relative wall thickness and the left ventricular mass index. We then evaluated the prevalence of left ventricular geometric patterns in these patients according to age. Results The left ventricular end-diastolic dimension decreased with age, both in normotensive control subjects and in hypertensive patients. The magnitude of this decrease was similar for both. The relative wall thickness and left ventricular mass index were greater in the hypertensive patients than in the normotensive control subjects, and these increased with age both in the controls and the hypertensives. The differences between normotensives and hypertensives in these variables remained unchanged with age. The prevalence of a normal left ventricle (normal relative wall thickness and left ventricular mass index) in the hypertensive patients decreased with age. Conversely, the prevalence of concentric remodeling (increased relative wall thickness with normal left ventricular mass index) and concentric hypertrophy (increased relative wall thickness and left ventricular mass index) increased with age. Conclusions These results demonstrate that age significantly affects left ventricular structure both in normotensive control subjects and in hypertensive patients. Thus, the differences in left ventricular geometric patterns with age may have important implications in assessing left ventricular structure and geometric patterns in hypertensive patients.

A highly potent and long-acting oral inhibitor of human renin.

An orally active renin inhibitor, ES 6864 (JV-(2R)-3-morpholinocarbonyl-2-(l-naphthylmethyl) propionyl]-(4-thiazoIyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a value of 7.3 × 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.

Clinical Characteristics in Japanese Patients with Coexistent Hypertrophic Cardiomyopathy and Coronary Vasospasm

There are only a few reports concerning coexistent hypertrophic cardiomyopathy (HCM) and vasospastic angina. Clinical characteristics in patients with both diseases have not been clarified yet. This study was designed to elucidate the relationship between chest pain and coronary vasospasm in HCM patients and to delineate clinical characteristics in patients with both HCM and coronary vasospasm. First, 36 patients with HCM underwent acetylcholine provocation test for coronary vasospasm and were divided into two groups on the basis of presence or absence of coronary vasospasm. Next, the following risk factors for coronary artery disease were compared between the two groups: hypertension, smoking, hyperlipidemia, diabetes mellitus, and hyperuricemia. Coronary vasospasm was induced in 10 (28%) of 36 patients with HCM. There were no significant differences in age and male gender between the two groups. Smoking was more prominent in HCM patients with than without coronary vasospasm (80% vs 35%, p<0.05), but there were no differences in the prevalence of other risk factors between the two groups. In conclusion, coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in Japanese patients with HCM, and smoking might be a major risk factor for coexistence of HCM and coronary vasospasm.

ES-8891, an orally active inhibitor of human renin.

A newly synthesized orally active renin inhibitor, jV-morpholinoacetyl-(l-naphthyl)-L-alanyl-(4-thiazolyl)-L-alanyl (3S,4S)-4-amino-3-hydroxy-5-cyclohexylpentanoyl-/i-hexylamide (ES-8891), was found to be a highly potent competitive inhibitor of human renin with an inhibition constant of 1.1 nM. This inhibitor was also active against monkey renin, although there was less inhibition of renin in pig, rabbit, and rat ES-8891 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10−5 M. A single oral administration of ES-8891 (10 or 30 mg/kg) to conscious, sodium-depleted marmosets caused a dose-related decrease in plasma renin activity and blood pressure. ES-8891 (30 mg/kg) produced an 80% inhibition of plasma renin activity, which lasted for more than 6 hours. Kidney renin messenger RNA was not significantly changed 6 hours after oral administration of ES-8891 (30 mg/kg). A single oral administration of 240 mg ES-8891 to healthy human volunteers (n=6) produced a significant inhibition of plasma renin activity (75% inhibition at 0.5 and 1 hour, 50% inhibition at 2 hours) with a good correlation of plasma levels of ES-8891. There were no significant changes in blood pressure or heart rate, and no adverse effects were observed. These results suggest that ES-8891 is an orally active human renin inhibitor that may be clinically useful.

THE EFFECT OF THE RENIN INHIBITOR ES-1005 ON THE EXPRESSION OF THE KIDNEY RENIN GENE IN SODIUM-DEPLETED MARMOSETS

The effect of the renin inhibitor ES-1005 or captopril on the expression of the kidney renin gene was investigated in sodium-depleted marmosets. We measured the level of kidney renin messenger RNA (mRNA) after continuous administration of ES-1005 (48 mg/kg per day) or captopril (2 mg/kg per day) intraperitoneally, via an osmotic mini-pump, for one week. The level of kidney renin mRNA was measured by densitometric Northern blot analysis using an alpha-32P-labelled human renin cDNA fragment as the hybridization probe. Captopril treatment markedly increased plasma renin activity and the level of kidney renin mRNA by 4.7-fold and 6.3-fold, respectively. ES-1005 treatment completely inhibited plasma renin activity and significantly decreased the level of kidney renin mRNA (46% of the normal control P less than 0.01). However, plasma immunoreactive renin concentration was significantly increased by the treatment with ES-1005 (P less than 0.05). These results suggest that the treatment with the renin inhibitor ES-1005 for one week has a paradoxical effect on kidney renin gene expression and renin release from the kidney in sodium-depleted marmosets.

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. his(I-naphthyl)methyl acetyl-histidyl-statine-2(S)-methylbutylamide, was found to he a highly potent human renin inhibitor that is species-specific and enzyme-specific. The replacement of the methylhutylamide of ES-305 with the Ieucyl-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 rahhit renins. It had moderate inhibitory potencies against cathepsin D and pepsin (IC of cathepsin D) and pepsin of 1.6 x 10-6 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 hut also a wide variety of nonprimate renins.

Brain glutathione and blood pressure control.

&NA; 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 [&Dgr; 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 < 0.001]. Intracerebroventricular administration of its reduced form (GSH, 33 nmol) produced a vasodepressor response (&Dgr; mean BP: ‐9 ± 2 mm Hg) accompanied by a corresponding decrease in SNA [192 ± 15 to 54 ± 22 spikes/ 10 s (n = 6), p < 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.

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.

Mortality and Causes of Death among Japanese School Personnel between 1992 and 1996.

Mortality and Causes of Death among Japanese School Personnel between 1992 and 1996: Hideo Tanaka, et al . Department of Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases—To examine mortality among Japanese school personnel working at primary and secondary schools, we studied mortality among members of the Mutual Aid Association of Public School Teachers (MAPST) aged 20 to 59 yr working at a primary or secondary school in six prefectures in Japan in 1992‐1996 (membership, approximately 180,000/yr). The observed number of deaths during the study period was obtained from the file of deceased members kept at the MAPST. The cause of death was determined by examining the death benefit application submitted by bereaved families. The sex‐ and‐cause‐specific mortality was examined by using age‐adjusted standardized mortality ratios (SMRs) in comparison with the general population, all workers, or professional and technical workers (peer group). During the study period, 719 deaths occurred. The male school personnel had a significantly lower risk of mortality from all causes than the general population [SMR: 0.45,95% confidence interval (95%CI)=0.41‐0.49], all workers (SMR: 0.61, 95%CI=0.56‐0.67), and the peer group (SMR: 0.70, 95%CI=0.64‐0.77). The female school personnel had a significantly lower risk of mortality from all causes than the general population (SMR: 0.46, 95%C 1=0.40‐0.53), and all workers (SMR: 0.81, 95%CI=0.71‐0.93), but the difference from the peer group was not statistically significant (SMR: 0.93, 95%CI=0.82‐1.07). Lower mortality in school personnel compared with the three populations was observed from all cancers (SMR: male,0.54‐0.68; female, 0.54‐0.93), heart diseases (SMR: male, 0.60‐0.94; female, 0.30‐0.90), cerebrovascular diseases (SMR: male, 0.33‐0.50; female, 0.31‐0.61), and suicide (SMR: male, 0.36‐0.68; female, 0.42‐0.91). These findings indicate that Japanese school personnel working at a primary or secondary school had only half the mortality of the general population in both sexes. The causes of the low mortality among school personnel, including lifestyle factors and work environment, need to be studied to develop health promotion activities for other occupational employees in Japan.