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Biomedical subjects

M Sasaguri

Publications and source records attributed to M Sasaguri.

At least 19 recordsLinked to original sources
PubMed2000

Effects of a slow-release nifedipine on 24-hour ambulatory blood pressure and ischemic changes on 24-hour ambulatory electrocardiogram in patients with severe coronary artery disease.

Calcium antagonists have long been used as first-line drugs for hypertension and angina. However, deleterious effects have also been reported in patients treated with calcium antagonists. Thus, we evaluated the effect of a slow-release twice-daily formulation of nifedipine in 10 patients with severe coronary artery disease. Twenty-four-hour ambulatory electrocardiography (AECG) and blood pressure monitoring (ABPM) were performed simultaneously to detect any association between ischemic episodes on the ECG and changes in blood pressure (BP) and heart rate with and without nifedipine. Increased oxygen demand due to an increased systolic BP and heart rate was associated with ischemic episodes without nifedipine, while those with nifedipine were accompanied by a fall in diastolic BP and a rapid increase in heart rate. This slow-release twice-daily formulation of nifedipine may induce myocardial ischemia through a heart-rate increase and a decrease in coronary blood flow due to lower diastolic BP in patients with severe coronary artery disease. A once-daily formulation of nifedipine might be of great value for such patients.

Aged↗
PubMed2000

Increased chymase activity in internal thoracic artery of patients with hypercholesterolemia.

Apart from ACE, various angiotensin II (Ang II)-forming serine proteinases (eg, chymase, kallikrein, and cathepsin G) are known to exist in human tissues, but their clinical significance or the regulatory mechanisms that control their activities are not well established. A recent clinical study has shown that chymase activity was significantly increased in human atherosclerotic or aneurysmal aorta. The association between vascular Ang II-forming activities (AIIFAs) in the human internal thoracic artery (ITA) and various clinical parameters was studied with the use of ITAs obtained from 32 patients who underwent coronary artery bypass graft surgery. Total and ACE- and chymase-dependent AIIFAs in homogenates of ITAs were determined. Total AIIFA was 8.67+/-0.86 (nmol Ang II formed. min(-1). mg protein(-1) [U]), and approximately 95% of the activities were due to chymase. Serum total cholesterol level, but no other risk factors, significantly correlated with chymase- (r=0. 60, P<0.001) and ACE- (r=0.35, P<0.05) dependent AIIFAs, respectively. LDL cholesterol level was also correlated with chymase-dependent AIIFAs (r=0.47, P<0.05). Mast cells identified through the use of toluidine blue or immunohistochemical staining appeared in the adventitia but not in the intima or media of ITAs. Our results suggest that an increased plasma LDL cholesterol level may induce increased arterial chymase and ACE activity.

Aged↗
PubMed2000

The regression of left ventricular hypertrophy by imidapril and the reduction of serum procollagen type III amino-terminal peptide in hypertensive patients.

Angiotensin-converting enzyme (ACE) inhibitors are known to be the most effective antihypertensive drugs for reducing left ventricular mass in hypertensives when compared to other classes of drugs. In the present study, we evaluated the effects of imidapril, an ACE inhibitor, on serum procollagen type III amino-terminal peptide (PIIIP) levels as well as the left ventricular mass index (LVMI). The subjects consisted of 15 patients (12 men and 3 women) in the outpatient clinic of our hospital who were diagnosed as essential hypertensives and who had not been treated with any antihypertensive medication prior to the study. Left ventricular hypertrophy was observed in all of the patients, ie., LVMI >110 g/m2 in men and >106 g/m2 in women. Blood pressure, LVMI, and serum PIIIP levels were measured before and after treatment with imidapril for 6 months. The starting dose of imidapril was 5 mg, and this was increased to 10 mg. Finally, 1 mg of trichlormethiazide was added to obtain adequate control of blood pressure. Blood pressure significantly decreased in 12 patients, and the mean LVMI decreased significantly from 153.1 +/- 9.0 to 135.4 +/- 6.3 (p< 0.01) after treatment. The changes in LVMI and PIIIP levels with treatment had significant correlation (r=0.639, p< 0.05). The present study showed that imidapril reduces the left ventricular mass in hypertensives after 6 months of treatment, and that this may at least in part be due to a decrease in the collagen content of the hypertrophied heart, suggesting that serum PIIIP levels are a useful marker of the regression of left ventricular hypertrophy.

Adult↗
PubMed2000

Roles of renal dopamine and kallikrein-kinin systems in antihypertensive mechanisms of exercise in rats.

We have previously shown that both renal dopamine (DA) and kallikrein-kinin systems are activated by exercise in mild hypertensives. We aimed to confirm the effects of exercise on the renal DA system and the stimulatory effects of DA on the renal kallikrein-kinin system in rats. In experiment 1, 12 male Dahl salt-sensitive (DS) rats given a 4% salt diet were divided into two groups. Rats in the exercise group were forced to run at 8 m/min, 60 min/day, 5 days/week for 4 weeks. Daily urinary volume, urinary excretion of sodium, free DA, and kallikrein activity were measured weekly. Renal aromatic-L-amino-acid decarboxylase (AADC) activities were assayed at the end of the experiment. In experiment 2, 15 male Sprague-Dawley (SD) rats were randomly divided into 3 groups, a DA-5 (5 microg of DA/kg/min), a DA-10 (10 microg of DA/kg/min), and a control group. DA or vehicle was administered subcutaneously with an osmotic pump for 2 weeks. Daily urinary volume, urinary excretion of sodium, aldosterone, DA, and kallikrein activity were measured weekly. Plasma renin activity, aldosterone concentration, and renal kallikrein mRNA levels were determined at the end of the experiment. In experiment 1, urinary excretion of free DA and renal AADC activities in the exercise group were significantly higher than those in the non-exercise group at week 4. In experiment 2, renal kallikrein mRNA levels and urinary volume were significantly increased in the DA-10 group compared to the control group, although there were no differences in urinary kallikrein activities. Plasma aldosterone concentration was significantly decreased in the DA-10 group compared to that in the control group despite a lack of differences in plasma renin activities. In conclusion, exercise increased the urinary excretion of free DA, probably through increased renal AADC activity in DS rats. DA amplified renal kallikrein mRNA levels and decreased plasma aldosterone levels, probably through its suppression of aldosterone in the adrenal glands. Activation of the kallikrein-kinin system might be counteracted by post-transcriptional modification of aldosterone. These results suggest that exercise enhances renal dopamine production by activating renal AADC activity, which in turn stimulates the renal kallikrein-kinin system.

Aldosterone↗
PubMed2000

A case of hyperreninemic hypertension after extracorporeal shock-wave lithotripsy.

A 53-year-old male was found to have hypertension caused by the significant secretion of renin from an atrophic left kidney. He had undergone extracorporeal shock-wave lithotripsy (ESWL) for left renal lithiasis 11 years previously. A renal dynamic study with 99mTc-diethylenetriaminepentaacetic acid (DTPA) indicated that the rate of renal excretion and uptake was decreased in the left kidney and normal in the right kidney. Renal angiography demonstrated a normal right renal artery and a small but nonstenotic left renal artery. The ratio of PRA in the left renal vein to that in the right renal vein was 1.7. Blood pressure could be lowered to the range of 140-150/80-90 mmHg with imidapril, an ACE inhibitor. ESWL may cause hypertension via the well-known Page kidney effect. In this case, the kidney, atrophic probably due to ESWL, released a significant amount of renin.

Angiography, Digital Subtraction↗
PubMed1999

Structure of a kallikrein-like enzyme and its tissue localization in the dog.

We previously purified a kallikrein-like enzyme from the dog heart and demonstrated that it is not only able to form kinins but can also convert angiotensin (Ang) I to Ang II. The aim of the present study was to clarify the structure and tissue localization of this enzyme. Western blot analysis of various canine tissues was performed with antiserum against the purified dog heart enzyme. The purified enzyme was subjected to a determination of its amino acid composition and a sequence analysis. Western blotting indicated that this enzyme was present in the heart, aorta, kidney, pancreas, lung, liver, spleen, small intestine, and skeletal muscle. The amino acid composition of the enzyme was different from that of dog urinary kallikrein. Amino acid sequence analysis indicated that it is likely to be N-terminally blocked. The present study showed that this kallikrein-like enzyme is different from previously reported kallikrein and is distributed not only in the heart, but also in other tissues such as the aorta, kidney, lung, liver, spleen, small intestine, and skeletal muscle. This enzyme may exert local effects by generating kinins and Ang II.

Amino Acids↗
PubMed1999

Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta.

Locally formed angiotensin II (Ang II) and mast cells may participate in the development of atherosclerosis. Chymase, which originates from mast cells, is the major Ang II-forming enzyme in the human heart and aorta in vitro. The aim of the present study was to investigate aortic Ang II-forming activity (AIIFA) and the histochemical localization of each Ang II-forming enzyme in the atheromatous human aorta. Specimens of normal (n=9), atherosclerotic (n=8), and aneurysmal (n=6) human aortas were obtained at autopsy or cardiovascular surgery from 23 subjects (16 men, 7 women). The total, angiotensin-converting enzyme (ACE)-dependent, and chymase-dependent AIIFAs in aortic specimens were determined. The histologic and cellular localization of chymase and ACE were determined by immunocytochemistry. Total AIIFA was significantly higher in atherosclerotic and aneurysmal lesions than in normal aortas. Most of AIIFA in the human aorta in vitro was chymase-dependent in both normal (82%) and atherosclerotic aortas (90%). Immunocytochemical staining of the corresponding aortic sections with antichymase, antitryptase or anti-ACE antibodies showed that chymase-positive mast cells were located in the tunica adventitia of normal and atheromatous aortas, whereas ACE-positive cells were localized in endothelial cells of normal aorta and in macrophages of atheromatous neointima. The density of chymase- and tryptase-positive mast cells in the atherosclerotic lesions was slightly but not significantly higher than that in the normal aortas, and the number of activated mast cells in the aneurysmal lesions (18%) was significantly higher than in atherosclerotic (5%) and normal (1%) aortas. Our results suggest that local Ang II formation is increased in atherosclerotic lesions and that chymase is primarily responsible for this increase. The histologic localization and potential roles of chymase in the development of atherosclerotic lesions appear to be different from those of ACE.

Aged↗
PubMed1998

Mild exercise activates renal dopamine system in mild hypertensives.

OBJECTIVE: The role of renal dopamine in the early depressor effect of exercise was evaluated in hypertensives. METHODS: After a general clinical observation period of 4 weeks, 29 essential hypertensives were divided into two groups. The exercise group (n=16) underwent blood lactate threshold exercise using a cycle ergometer for 60 min three times a week for 4 weeks. RESULTS: In the non-exercise group (n=13), blood pressure (BP) and humoral variables did not change significantly (from 150+/-3/93+/-2 to 145+/-2/94+/-1 mm Hg). In the exercise group (n=16), resting BP was significantly reduced from 158+/-2/92+/-2 at week 0 to 145+/-3/85+/-3 mm Hg at week 4. The increase in urinary free dopamine excretion (from 248+/-14 to 276+/-24 ng/mg Cr) at week 4 was significantly higher than that in the non-exercise group (from 220+/-31 to 196+/-27 ng/mg Cr). In the exercise group, urinary kallikrein activity also increased significantly from 173.0+/-35.4 at week 0 to 320.3+/-63.3 ng bradykinin/min/mg Cr at week 4. These changes in urinary free dopamine excretion and urinary kallikrein activity were negatively correlated with the change in BP. The change in urinary sodium excretion was also negatively correlated with the change in plasma volume index. Moreover, the change in urinary free dopamine excretion was positively correlated with the changes in urinary kallikrein activity and urinary sodium excretion. The change in renal decarboxylation rate of DOPA (3,4-dihydroxyphenylalanine) positively correlated with the changes in urinary free dopamine excretion and urinary sodium excretion, and was negatively correlated with the change in systolic BP. CONCLUSION: These results suggest that exercise triggered renal dopamine generation and activation of renal kallikrein-kinin system, resulting in natriuresis and BP reduction in the early phase (4 weeks) of mild exercise.

Adult↗
PubMed1998

Plasma renin activity could be a useful predictor of left ventricular hypertrophy in essential hypertensives.

To clarify the ability of clinical and laboratory parameters to reflect target organ damage, especially left ventricular hypertrophy (LVH), we investigated which of these parameters might correlate to LVH as determined by electrocardiographic voltage at the first clinic visit in 108 (53 males and 55 females, average age 52 +/- 10 years) untreated essential hypertensives. The sum of the amplitude of the S wave in lead V1 plus that of the R wave in lead V5 or V6 (SV1 + R(V5, V6)) was correlated with blood pressure in both males and females. In subjects with LVH (SV1 + R(V5, V6) > or = 3.5mV), a stepwise multiple regression analysis revealed that SV1 + R(V5, V6) was associated with plasma renin activity (PRA) in both males and females, and with creatinine concentration (Cr) in males. These results suggest that PRA at the first visit could be a useful predictor of LVH in patients with essential hypertension.

Biomarkers↗
PubMed1998

Genetic analysis of the epithelial sodium channel in Liddle's syndrome.

BACKGROUND: Liddle's syndrome is an autosomal inheritable disorder that causes hypertension due to excess function of sodium channel. OBJECTIVE: To analyze the DNA sequence of the amiloride-sensitive epithelial sodium channel (ENaC) in three patients who had low-renin hypertension with hypokalemia. The patients included a 24-year-old woman and her 20-year-old brother whose mother was hypertensive. The third patient was a 15-year-old girl with no family history of hypertension. METHODS: The DNA sequence of the ENaC was analyzed as follows. Venous blood samples were collected from the patients and total genomic DNA was prepared by standard methods. Specific primers were used for direct polymerase chain reaction; one set of primers for amplifying the C terminus (codon 523-638) of the , subunit of ENaC, and two sets of primers for amplifying the C terminus (codons 525-587 and 568-650) of the y subunit of ENaC. Polymerase chain reaction products were purified and subjected to direct DNA sequence analysis. RESULTS: Direct sequence analysis demonstrated the presence of a single-base substitution in one segment of the 0 subunit of ENaC, a C-T transition that changed the encoded Pro (CCC) at codon 616 to Ser (TCC) in the siblings (cases 1 and 2). In case 3, we found a missense mutation of Pro (CCC) to Leu (CTC) at codon 616. Case 3 is considered to be sporadic, since DNA sequencing of the PY motif of her parents gave normal results. CONCLUSIONS: The DNA sequences of the ENaC in three patients with Liddle's syndrome were analyzed. In one family case, we found a new missense mutation of Pro (CCC) to Ser (TCC) at codon 616 in the 0 subunit of ENaC. A genetic analysis of the amiloride-sensitive epithelial sodium channel is recommended in assessing patients with low-renin, salt-sensitive hypertension whose blood pressure is not responsive to spironolactone treatment.

Adolescent↗
PubMed1998

Differences in tissue angiotensin II-forming pathways by species and organs in vitro.

Angiotensin (Ang) II plays an important role in cardiovascular homeostasis, not only in the systemic circulation but also at the tissue level, and is involved in the remodeling of the heart and vasculature under pathological conditions. Although alternative Ang II-forming pathways are known to exist in various tissues, the details of such pathways remain unclear. The aim of this study was to examine tissue Ang II-forming activities and to identify the responsible enzyme in several organs (lung, heart, and aorta) in various species (human, hamster, rat, rabbit, dog, pig, and marmoset). Among the organs examined, the lung contained the highest Ang II-forming activity. The responsible enzyme for pulmonary Ang II formation was angiotensin I-converting enzyme (ACE) in all of the species except the human lung, in which a chymaselike enzyme was dominant. In the heart, the highest total Ang II-forming activity was observed in humans, and a chymaselike enzyme was dominant in all of the species except rabbit and pig. Aorta exhibited a relatively high total Ang II-forming activity, with a predominance of chymaselike activity in all of the species except rabbit and pig, in which ACE was dominant. Our results indicate that there were remarkable differences in Ang II-forming pathways among the species and organs we examined. To study the pathophysiological roles of ACE-independent Ang II formation, one should choose species and/or organs that have Ang II-forming pathways similar to those in humans.

Aged↗
PubMed1998

Function and expression of a novel rat salt-tolerant protein: evidence of a role in cellular sodium metabolism.

Higher dietary salt intake in humans is associated with higher BP, but the BP response to NaCl, so-called salt sensitivity, is heterogeneous among individuals. It has been postulated that modifications in cellular cation metabolism may be related to salt sensitivity in mammalian hypertension. The authors have isolated a novel rat complementary DNA, called salt-tolerant protein (STP), that can functionally complement Saccharomyces cervisiae HAL1, which improves salt tolerance by modulating the cation transport system. On high-salt (8% NaCl) diets, both Dahl salt-sensitive and salt-resistant rats displayed an elevated BP and increased STP mRNA expression. Immunohistochemistry using an anti-rat STP antibody demonstrated the presence of STP immunoreactivity in the proximal tubules. In cells that transiently expressed STP, the intracellular [Na+]/[K+] ratio was higher than that in control cells. STP contains predicted coiled-coil and Src homology 3 domains, and shows a partially high degree of nucleotide identity to human thyroid-hormone receptor interacting protein. These results suggest that STP may play an important role in salt sensitivity through cellular sodium metabolism by mediating signal transduction and a hormone-dependent transcription mechanism.

Amino Acid Sequence↗
PubMed1997

Amlodipine lowers blood pressure without increasing sympathetic activity or activating the renin-angiotensin system in patients with essential hypertension.

OBJECTIVE: Recent clinical studies suggest that the reflex increase in sympathetic nervous activity accompanying a reduction in blood pressure may contribute to the untoward effects of dihydropyridine calcium antagonists. The aim of this study was to examine whether plasma noradrenaline levels and renin activity are increased with the reduction of blood pressure during the initial phase of administration of the long-acting dihydropyridine calcium antagonist amlodipine. METHODS: The effects of amlodipine on ambulatory blood pressure and on diurnal variations in plasma noradrenaline and renin activity were examined 1, 4, and 7 days after the start of amlodipine administration in eight inpatients with essential hypertension. RESULTS: The 24-h mean systolic and diastolic blood pressure on day 7 was significantly lower than it was 1 day before the start of treatment. There was no change in the mean heart rate. The mean trough to peak ratios of systolic and diastolic blood pressure of seven patients were 61% and 71%, respectively. Diurnal patterns of plasma noradrenaline levels and renin activity 1, 4, and 7 days after the start of amlodipine administration were unchanged. CONCLUSION: The antihypertensive effects of amlodipine were of slow onset and long duration and were not accompanied by an increase in sympathetic activity or activation of the renin-angiotensin system.

Aged↗
PubMed1997

Purification and characterization of a kinin- and angiotensin II-forming enzyme in the dog heart.

OBJECTIVE: To purify and characterize a kinin-forming enzyme in the dog heart and to examine the ability of this enzyme to generate angiotensin (Ang) II from Ang I. METHODS: The enzyme was isolated from heart homogenate using a diethylaminoethyl-Sepharose column, an aprotinin affinity column and a wheat germ lectin-Sepharose 6MB column. Kininogenase activity was assessed with a kinin radioimmunoassay after samples had been incubated with bovine low-molecular-mass kininogen at 37 degrees C for 1 h. Ang I-converting activity was assessed by the quantitation of Ang II formed by incubation of the sample with Ang I at 37 degrees C for 3 h, using high performance liquid chromatography. The enzyme was subjected to 12.5% sodium dodecyl sulphate-polyacrylamide gel electrophoresis, stained by Coomassie brilliant blue and transferred electrically to a membrane with glycoprotein staining. RESULTS: The purified enzyme is a glycoprotein with an apparent relative molecular mass of 65 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. Its kininogenase activity was approximately 20 micrograms bradykinin/h per mg protein at an optimal pH of 8.0. The enzyme also converted Ang I to Ang II at an optimal pH of 6.5. Its specific activity was approximately 2 micrograms Ang II/h per mg protein. Both activities were inhibited by aprotinin, a tissue kallikrein inhibitor. Western blot analysis using polyclonal antibody against this enzyme demonstrated that this enzyme exists both in the myocardium and in the coronary artery. CONCLUSIONS: The present study showed that the kinin-forming enzyme in the dog heart is a kallikrein-like enzyme that is different from cathepsin D, cathepsin G and chymase. It is also able to Ang I to Ang II. This enzyme might play a role in regulating myocardial perfusion, mainly by generating kinins and in part by forming Ang II.

Angiotensin II↗
PubMed1996

Molecular cloning of a novel rat salt-tolerant protein by functional complementation in yeast.

To elucidate the genetic basis of salt-sensitivity in mammalian hypertension, we isolated six rat complementary DNAs by functional complementation in yeast. These genes were able to substitute for the salt-tolerant activity of HALI which confers salt tolerance by modulating the cation transport system in yeast. We identified these genes as beta-globin, lambda-crystallin, androgen-regulated protein, mitochondrial cytochrome b, a homologue of infant brain cDNA, and a novel gene, called salt-tolerant protein (STP). STP contains 1964 bp nucleotides and an open reading frame which encodes 496 amino acid residues. Northern blot analysis showed that STP mRNA is expressed in various rat tissues.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1996

Role of endogenous ouabain-like substance during graded exercise in hypertensive individuals.

Changes in plasma endogenous ouabain-like substance (EOLS) and plasma noradrenaline, along with changes in blood pressure (BP), heart rate, and blood lactate concentration, were investigated in hypertensive individuals during strenuous exercise testing. Thirteen (4 men and 9 women) middle-aged (34-63 years, mean 50 +/- 2 years) patients with mild essential hypertension underwent graded multistage submaximal exercise testing on a cycle ergometer. The workload in each exercise test was increased depending on the individual's physical fitness until they reached 75-80% of the predicted age-adjusted maximal heart rate prescribed by the American College of Sports Medicine. Systolic (S) BP rose by 67 +/- 9 mm Hg (P < 0.001), mean (M) BP by 28 +/- 3 mm Hg (P < 0.001), diastolic (D) BP by 9 +/- 2 mm Hg (P < 0.005) and heart rate by 79 +/- 6 beats/min (P < 0.001) after submaximal graded exercise. The blood lactate concentration and plasma noradrenaline increased significantly (+3.40 +/- 0.34 mmol/l and +895 +/- 94 pg/ml respectively, P < 0.001). Although the change in EOLS was not significant, it showed a strong positive correlation with the change in plasma noradrenaline (R = 0.760, P < 0.001). These results suggest that EOLS may participate in modifying sympathetic vasoconstriction during submaximal graded exercise.

Adult↗
PubMed1995

Human urinary kallikrein can generate angiotensin II from homologous renin substrates.

We previously proposed the "kinin-tensin system," a unique vasoregulatory system that can produce both angiotensin II and kinins. To verify whether tissue kallikrein is a part of this system in humans, we examined the ability of human urinary kallikrein (HUK) to generate angiotensin (ANG) II directly from homologous renin substrates such as purified human angiotensinogen (AOGEN) and authentic human tridecapeptide renin substrate (13 RS). HUK released ANG II not only from ANG I but also directly from both AOGEN and 13RS at an optimum pH of 7.0. The amount of generated ANG II from 7.5 nmol of each of the three substrates at pH 7.0 was as follows: ANG I, 292.7 +/- 67.2; 13 RS, 1951.7 +/- 239.6; AOGEN, 2.2 +/- 0.3 (pmol/3h, n = 3 mean +/- SE). HUK cleaved Phe-His and His-Leu bonds in 13 RS, and Tyr-Ile and Phe-His bonds in ANG I. These results suggest that HUK is a part of the "kinintensin system", i.e., HUK can not only release kinins, but can also generate ANG II mainly through ANG I conversion and from AOGEN, the latter being a minor source of ANG II. Furthermore, HUK may play a role in regulating vascular tone under certain conditions in vivo.

Angiotensin I↗