K Yamada

Oita University, Ōita, Ōita, Japan

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Publications (62)270.78 Total impact

  • A Goto, K Yamada
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    ABSTRACT: It is clear that defective renal sodium handling plays an important role in the development of hypertension and that this abnormality could be caused by heterogeneous hereditary factors in the kidney. It is likely that sodium pump inhibitors with or without whole-body autoregulation gradually produce a rise in blood pressure in response to retained body sodium. Accumulated evidence has suggested that several sodium pump inhibitors similar to cardiotonic steroids are present in the human body. Ouabainlike compound (OLC) has been found to be increased with high sodium intake and hypervolemia, and in essential hypertension, mineralocorticoid hypertension, and pregnancy-induced hypertension. Further, blocking the action of OLC with digibind or a novel anti-ouabain agent has been observed to lower blood pressure in several models of experimental and clinical hypertension. The blockade of OLC action may become the basis of novel rational antihypertensive agents and may help to solve the problems still present in the management of hypertensive patients.
    Hypertension Research 10/2000; 23 Suppl:S7-13. · 2.79 Impact Factor
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    ABSTRACT: In rat brain slices we examined the differences in the levels of high-energy phosphates in the presence of various energy substrates by using 31P NMR with a time resolution of 4 min at 25 degrees C. In parallel experiments we recorded population excitatory postsynaptic potentials (EPSPs) from granule cells in rat hippocampal slices. During high K(+) stimulation (8 min) phosphocreatine (PCr) decreased to a low level and recovered to the control level in standard artificial cerebrospinal fluid (ACSF) in about 10 min. Population EPSPs disappeared following high-K(+) stimulation and recovered in standard ACSF. In iodoacetic acid (IAA)-pretreated slices, whereas glucose was unable to support energy metabolism, the PCr level, which decreased following high-K(+) stimulation, recovered in ACSF containing lactate or pyruvate. The half-time of recovery of PCr levels in ACSF containing lactate was longer than that containing glucose. Population EPSPs in standard ACSF were maintained for more than 1 h, but those in ACSF containing lactate decreased gradually by about half in 40 min. In IAA-pretreated slices, when further treated with fluorocitrate (100 microM) for 2 h, the recovery of the PCr level in ACSF containing lactate after high-K(+) stimulation was completely abolished, whereas the recovery of the PCr level in ACSF containing pyruvate was unaffected. These results indicate that neurons can utilize pyruvate as well as glucose, but not lactate, as exogenous energy substrates, and that lactate may be metabolized to pyruvate in glial cells and transported to neurons to be utilized as an energy substrate.
    Neuroscience Research 04/2000; 36(3):215-26. · 2.20 Impact Factor
  • A Goto, K Yamada
    Nippon rinsho. Japanese journal of clinical medicine 02/2000; 58 Suppl 1:492-6.
  • H Hirai, K Yoshioka, K Yamada
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    ABSTRACT: A recent report has demonstrated that inositol 1,4,5-trisphosphate (IP3)-induced Ca2+ release plays a crucial role in neurite growth. Here, using 31P-NMR, we examine whether activation of the metabotropic glutamate receptor 1 (mGluR1), which induces the production of IP3, could modulate phospholipid metabolism in human embryonic kidney 293 cells. mGluR1alpha- but not ionotropic glutamate receptor 1-expressing cells stimulated with glutamate exhibited a drastic reduction in the phosphorylcholine level, with corresponding increases in the level of phosphatidylcholine, a major phospholipid component. Quantitative analysis of cell growth revealed that mGluR1alpha-expressing cells cultured with 100microM glutamate were statistically significantly longer than the nontransfected cells. The effect was no longer observed following coincubation with a metabotropic glutamate receptor antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine. These results suggest that mGluR1alpha activation triggers phosphatidylcholine biosynthesis and may contribute to neurite extension.
    Molecular and Cellular Neuroscience 01/2000; 14(6):444-54. · 3.84 Impact Factor
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    ABSTRACT: To investigate the relationships between the activity in potential operated Ca2+ channels (POC), blood pressure, and endothelium in hypertension, we tested the contractile responses to a Ca2+ channel agonist Bay K 8644 (BAY K) in aorta from deoxycorticosterone-acetate-saline (DOCA-S) and reduced renal mass-saline (RRM-S) hypertensive rats. The effects of mechanical rubbing, N omega-Nitro-L-Arginine Methyl Ester (l-NAME) and indomethacin were also examined. Sensitivity to BAY K increased in experimental rats before they became hypertensive and contractile responses were enhanced as hypertension developed. Force development to BAY K was correlated with blood pressure levels. Endothelium removal enhanced the contractile response to BAY K. L-NAME, but not indomethacin, potentiated the response to BAY K. Contractile response to BAY K was negatively correlated with relaxation to acetylcholine. An enhanced contractile response to BAY K was observed also in aged rats. Enhanced activation of vascular POC in hypertension results from elevated blood pressure and partly from diminished inhibitory action of endothelium. Senescence also enhances vascular POC activity.
    Japanese Heart Journal 04/1999; 40(2):209-25. · 0.40 Impact Factor
  • Source
    S Fujita, T Nawata, K Yamada
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    ABSTRACT: 1. Trinitrophenyl AMP (TNP-AMP) in the concentration range 10-300 microM induced an increase in fluorescence intensity at around 530 nm in skinned skeletal muscle fibres freshly obtained from rat psoas muscle. 2. The fluorescence intensity of the fibres depended on TNP-AMP concentration up to approximately 200 microM. The Kd of TNP-AMP binding to the muscle fibres was 38.0 +/- 8.4 microM (mean +/- s.d., n = 4 measurements) in three fibres. TNP-AMP fluorescence was readily washed out. 3. Various nucleotides affected the fluorescence of the fibres incubated in 20 microM TNP-AMP. MgATP (1 mM) and caged ATP (5 mM) reduced the fluorescence in 20 microM TNP-AMP by more than 40 % of the value measured in the absence of nucleotide. 4. When the fibres were stretched to almost no filament overlap, the extent of the quenching of the TNP-AMP (20 microM) fluorescence due to ATP binding was reduced by 14 %. This might be explained by assuming that the association of the thin filament affected the TNP-AMP fluorescence in muscle fibres. 5. The distance between the active site and the specific site for TNP was measured by the fluorescence resonance energy transfer between N-methylanthraniloyl-ATP (Mant-ATP) bound to the active site and the TNP-AMP bound to the TNP-specific site in muscle fibres. The results showed that the distance between the two may be less than 2 nm. 6. It may be concluded that the fluorescence intensity at 530 nm in skinned muscle fibres in low concentrations of TNP-AMP changes directly reflecting the conformational state of the nucleotide-binding region that is determined by the binding of nucleotides.
    The Journal of Physiology 04/1999; 515 ( Pt 3):869-80. · 4.38 Impact Factor
  • K Yamada
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    ABSTRACT: Results of microcalorimetric titrations of calcium-binding proteins with calcium or magnesium have been reviewed and evaluated. Results were analyzed mostly in terms of heat capacity changes, which is most closely related to the structural changes of the molecule on metal binding. Two high-affinity sites of rabbit skeletal troponin C are distinguishable in terms of their affinity to calcium and associated enthalpy changes. Heat capacity changes on calcium binding to one of the two high-affinity sites is negative and is in the range ascribed to the ligand binding. In contrast, that to the other of the high-affinity sites is large and positive, indicating that a substantial area of hydrophobic groups become exposed to the solvent. In frog skeletal troponin C, the anomalous positive heat capacity changes occur in one of the low-affinity calcium-specific sites, so that this may be involved in the regulation of contraction. Unlike skeletal troponin C, both of the two high-affinity sites of cardiac troponin C show negative heat capacity changes. In calmodulin, heat capacity changes are positive but small, indicating that calcium binding may induce clustering of the hydrophobic residues on the surface of the molecule. In parvalbumins, heat capacity changes are negative, characteristic of most ligand binding.
    Molecular and Cellular Biochemistry 02/1999; 190(1-2):39-45. · 2.33 Impact Factor
  • A Goto, K Yamada
    Trends in Pharmacological Sciences 07/1998; 19(6):201-4. · 9.25 Impact Factor
  • K Yamada, S Fujita
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    ABSTRACT: 2'(or 3')-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP), a fluorescent analog of ATP, and the derivatives were used to fluorescently label the myosin head in skinned skeletal muscle fibers. It has been known that a secondary site for TNP-ADP other than the active site exists in myosin S1. We found by fluorescence resonance energy transfer between mant ATP and TNP-AMP that the secondary site for TNP-nucleotides is located within 2 nm of the active site in skeletal muscle fibers. The changes in fluorescence intensity of muscle fibers in 20 microM TNP-AMP when nucleotides are bound may reflect changes of the structure of the active site of myosin heads. It was also shown that actin affected the extent of the fluorescence changes induced by ATP binding to the active site. Both ATP and caged ATP affected the fluorescence intensity, thus caged ATP interacts with the active site. When ATP was released from caged ATP by pulse photolysis in muscle fibers in TNP-AMP showed a transient increase in fluorescence intensity, and still greater fluorescence signal can be detected when the fiber actively contracted when Ca2+ was present.
    Advances in experimental medicine and biology 02/1998; 453:419-23. · 1.83 Impact Factor
  • A Goto, K Yamada
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    ABSTRACT: We detected two candidates for endogenous digitalis-like factors in human urine based on the inhibition of 3H-ouabain binding to human erythrocytes. Two ouabain-displacing compound(ODC)s were consistently eluted off the C18 reverse phase HPLC column with 18% and 31% acetonitrile. The more-polar ODC-1 was ubiquitously found in mammals, markedly increased after acute and chronic salt loading in humans, and was thought to be a natriuretic factor with vasoactive property. ODC-1 mostly resembled ouabain in biological, physicochemical, and chromatographic properties and may correspond to ouabainlike compound purified by other investigators. The less-polar ODC-2 was indistinguishable from digoxin in proton nuclear magnetic resonance(NMR) and fast atom bombardment(FAB) mass spectrum.
    Clinical and Experimental Hypertension 01/1998; 20(5-6):551-6. · 1.28 Impact Factor
  • A Goto, K Yamada, H Nagoshi, Y Dan, M Omata
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    ABSTRACT: A major biologically active Na,K-ATPase inhibitor in the mammalian body may be ouabain-like compound. We investigated the potential roles of circulating ouabain-like compound in the regulation of Na+ and K+ homeostasis in terms of Na+ and K+ distribution between the cells and the extracellular fluid (internal balance). First, we developed a population of rats immunized against ouabain to block the action of ouabain-like compound. We measured plasma and intracellular Na+ and K+ concentrations in skeletal muscle and determined Na+ (extracellular-to-intracellular concentration ratio) and K+ (intracellular-to-extracellular concentration ratio) gradients in immune rats. We examined also the ability to respond to hypertonic NaCl load in immune rats. Consistent lower plasma K+ levels and steeper Na+ and K+ gradients were observed in immune rats. K+ handling in response to hypertonic NaCl load was altered, and lower plasma K+ level was maintained in immune rats. Second, we used PST-2238, a newly developed anti-ouabain agent, to block the action of ouabain-like compound and examined its effect on plasma Na+ and K+ concentrations. Chronic administration of PST-2238 significantly lowered plasma K+ levels in rats with subtotal nephrectomy. These findings collectively suggest that ouabain-like compound may determine at least in part the internal Na+ and K+ distribution and the transmembrane cation gradients in vivo in rats.
    Hypertension 10/1997; 30(3 Pt 2):753-8. · 6.87 Impact Factor
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    ABSTRACT: A major biologically active endogenous digitalis-like factor in the mammalian body may be an isomer of ouabain (ouabainlike compound, OLC). However, the exact role of OLC in sodium homeostasis is still unclear, and acute isotonic volume expansion does not enhance the secretion of OLC. We tested the hypothesis that OLC may be more important in the response to acute hypertonic NaCl load rather than isotonic volume expansion. We injected intraperitoneally 2 mL of 20% NaCl solution into male Wistar rats (n=34) and measured OLC levels in plasma, hypothalamus, pituitary, and adrenal at baseline (n=10) and 1, 2, and 4 hours (n=8 for each). In response to hypertonic NaCl loading, plasma Na-K ratio was elevated at 2 and 4 hours (P<.01). OLC levels in pituitary increased (P<.01) at 1 hour. Thereafter, plasma OLC levels increased at 2 and 4 hours (P<.05; basal, 75+/-11 pmol/L [+/-SEM]; 1 hour, 55+/-11; 2 hours, 130+/-24; 4 hours, 156+/-20). Concomitantly, OLC levels in adrenal increased at 2 and 4 hours (P<.01; basal, 1.7+/-0.2 pmol/g; 1 hour, 4.5+/-0.9; 2 hours, 5.0+/-0.7; 4 hours, 6.8+/-2.2). A significant correlation was observed between OLC levels in plasma and adrenal (P<.05). Plasma Na-K ratio positively correlated with OLC levels in plasma (r=.51, P<.01) and adrenal (r=.48, P<.01). Similar injection of physiological saline solution or hypertonic sucrose solution in physiological saline did not increase OLC levels in plasma and tissues. These findings indicate the elevation of OLC levels in plasma, pituitary, and adrenal in response to acute hypertonic NaCl load in rats and suggest that OLC may be involved in the response to the hypernatremic state.
    Hypertension 07/1997; 30(1 Pt 1):94-8. · 6.87 Impact Factor
  • K Yamada, A Goto, M Omata
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    ABSTRACT: We examined the role of ouabain-like compound (OLC) in hypertension associated with corticotropin (ACTH) excess in rats. Physiological saline solution (1 mL/kg) or synthetic ACTH-Z (0.5 mg/kg) was injected intramuscularly for 15 days to 14 control and 13 male Wistar rats. Significant increases in blood pressure and plasma sodium/potassium ratio, and decreases in plasma potassium concentration and urinary sodium/potassium ratio were observed in ACTH-treated rats. The plasma OLC level was higher in ACTH-treated group (control; 76 +/- 13, ACTH; 202 +/- 48 pmol/L, P < .05). Plasma OLC level correlated with systolic blood pressure (SPB; r = 0.53, P < .01). Urinary OLC excretion was also higher in ACTH-treated group (control; 0.95 +/- 0.01, ACTH; 3.32 +/- 0.67 pmol/day, P < .01). A significant relation was also found between urinary OLC excretion and SBP (r = 0.66, P < .01). Plasma potassium concentration negatively correlated with SBP (r = -0.48, P < .01) and urinary sodium/potassium ratio also correlated inversely with urinary OLC excretion (r = -0.55, P < .01). Measurement of OLC levels after the fractionation of urine by reverse-phase high performance liquid chromatography showed that the major OLC peak in urine from both groups coincided with that of authentic ouabain. These results suggest the contribution of OLC to ACTH-induced hypertension in rats.
    American Journal of Hypertension 04/1997; 10(4 Pt 1):403-8. · 3.67 Impact Factor
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    ABSTRACT: The established associations between blood pressure (BP) and electrolytes are mostly based on either dietary intake or urinary excretion data. We measured office BP, ambulatory BP (ABP) using the automated oscillometric ABPM-630 device, and plasma electrolytes in 82 essential hypertensive patients to examine the relation between BP and plasma electrolytes. Significant negative correlations were observed between plasma potassium concentration and 24-h systolic BP (r = -0.336) and diastolic BP (r = -0.298) in our patients. Plasma potassium concentration inversely correlated also with both daytime and nighttime systolic and diastolic BPs. There was no relation between office BP and plasma potassium concentration. These findings indicate that in essential hypertensives plasma potassium concentration is inversely related to ABP including daytime and nighttime BPs and suggest that potassium may be a factor determining the whole day BP in essential hypertension.
    American Journal of Hypertension 04/1997; 10(3):337-40. · 3.67 Impact Factor
  • S Yanai, N Nisimaru, T Soeda, K Yamada
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    ABSTRACT: We observed simultaneous changes in lactate level and regional blood flow (rBF) in the brain of the anesthetized rabbit by using localized proton magnetic resonance spectroscopy (1H MRS) and laser Doppler flowmetry. The volume of interest of 0.5 ml for 1H MRS contained mostly thalamic nuclei. During hypoxia peak area for lactate increased up to 57% of that from N-Acetylaspartate. While the rBF increased during hypoxia up to 260% of the control, oxygen delivery (rBF x arterial oxygen content) decreased. In the normoxic recovery period following hypoxia, the rBF recovered slowly and a consequent overshoot of oxygen delivery was observed. The multiple and stepwise linear regression analyses revealed that the averaged decrease in oxygen delivery during hypoxia was the most significant independent variable for the increase in lactate during hypoxia (correlation coefficient; r2 = 0.68) and also that the increase in lactate during hypoxia was the most significant independent variable for the time for half-recovery of rBF (r2 = 0.75). These results suggest that the increase in lactate during hypoxia is due to the deficiency of oxygen delivery and that the increase in lactate during hypoxia prolongs the period of enhancement of rBF during recovery from hypoxia.
    Neuroscience Research 02/1997; 27(1):75-84. · 2.20 Impact Factor
  • A Goto, K Yamada, H Hazama, Y Uehara, K Atarashi, Y Hirata, K Kimura, M Omata
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    ABSTRACT: Molecular mechanisms related to sodium retention have been implicated in the pathogenesis of hypertension. It is unclear how sodium retention leads to a rise in blood pressure, but ouabainlike compound may act as a final common pathway in sodium-induced hypertension. In ectopic corticotropin syndrome, hypertension has been attributed to cortisol inactivation overload, giving rise to mineralocorticoid-type hypertension. We sequentially measured plasma and urinary levels of ouabainlike compound over 2 months to evaluate its role in the hypertensive mechanisms in a 64-year-old man with this syndrome caused by lung cancer. His data included hypokalemia and increased cortisol concentrations, corticotropin levels, and urinary 17-hydroxycorticosteroid excretion. Plasma renin activity was suppressed. Plasma and urinary levels of ouabainlike compound were markedly increased concomitantly with high blood pressure. The maximum plasma level was 40-fold the normal range of the subject. After chemotherapy, ouabainlike compound levels gradually decreased in parallel with the decline in blood pressure and rise in potassium concentration. A correlation was observed between plasma and urinary levels of ouabainlike compound (P < .05). Plasma and urinary levels of ouabainlike compound correlated with systolic (P < .01) and diastolic (P < .05) pressures, respectively. The peak of ouabainlike compound in plasma and urine coincided with that of authentic ouabain on high-performance liquid chromatography. Ouabainlike compound derived from urine inhibited [3H]ouabain binding to human erythrocytes. These findings suggest that ouabainlike compound with biological activity could partly account for hypertension in ectopic corticotropin syndrome.
    Hypertension 10/1996; 28(3):421-5. · 6.87 Impact Factor
  • K Yamada, A Goto, C Hui, M Omata
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    ABSTRACT: A major biologically active Na,K-ATPase inhibitor in the mammalian circulation may be ouabain-like compound(OLC). We developed a population of immunized rats against ouabain to block the actions of circulating OLC. To investigate the roles of OLC in the regulation of aldosterone secretion and/or production, we measured plasma aldosterone concentration after a week of low salt diet. No significant changes in serum Na and K concentrations were observed in immune rats. The plasma aldosterone concentration was significantly decreased by 30% in 17 immune rats as compared with 11 control rats(control: 455 +/- 53, immune: 315 +/- 21 pg/mL, p < 0.05). These data indicate that chronic blockade of the circulating OLC significantly decreases plasma aldosterone concentration during salt depletion and suggest that endogenous OLC may play an important role in the regulation of aldosterone secretion and/or production.
    Life Sciences 02/1996; 58(21):1833-7. · 2.56 Impact Factor
  • Marine Pollution Bulletin 01/1996; 33(7). · 2.79 Impact Factor
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    K Kagawa, K Horiuti, K Yamada
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    ABSTRACT: Using flash photolysis of caged ATP in skinned muscle fibers from rat psoas, we examined the inhibitory effects of 2,3-butanedione monoxime (BDM) on the contraction kinetics and the rate of ATP hydrolysis of the cross-bridges at approximately 10 degrees C. The hydrolysis rate was estimated from the stiffness records. The effects of BDM were compared with those of orthophosphate (P(i)) and of reduction in [Ca2+] (low Ca2+), and it was found that i) BDM and low Ca2+ inhibited ATPase activity to the same extent as they inhibited the steady tension, whereas P(i) inhibited ATPase activity much less than tension; ii) BDM and P(i) decreased tension per stiffness during the steady contraction more than did low Ca2+; iii) neither BDM nor low Ca2+ affected the initial relaxation of the fiber on release of ATP, but P(i) slightly slowed it; and iv) BDM hardly influenced the rate of contraction development after relaxation, although P(i) and low Ca2+ accelerated it. We concluded that BDM inhibits the Ca(2+)-regulated attachment of the cross-bridges and force-generation of the attached cross-bridges.
    Biophysical Journal 01/1996; 69(6):2590-600. · 3.67 Impact Factor
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    ABSTRACT: Recent observations demonstrate the presence of neurosteroids and their rapid increase in response to acute stress. In view of a steroidal nature of ouabainlike compound, we tested the hypothesis that ouabainlike compound may participate in a homeostatic response to acute stress. Male Wistar rats were subjected to acute stress by swimming in water (22 degrees C) for 10 minutes. The levels of ouabainlike compound in plasma, hypothalamus, pituitary, and adrenal at 10, 40, and 70 minutes (n = 8 for each) after the end of swim stress were compared with nonstressed control levels (n = 10). Ouabainlike compound was measured by a radioimmunoassay for ouabain. Plasma levels of corticosterone and catecholamines were also measured. Plasma corticosterone concentrations increased rapidly at 10 minutes (P < .01) and then declined. A trend for a rise in plasma catecholamines was found at 10 minutes. Adrenal levels of ouabainlike compound concomitantly increased at 10 minutes (P < .01, control: 58.9 +/- 5.9 pmol ouabain equivalents per gram; 10 minutes: 92.5 +/- 4.8; 40 minutes: 47.3 +/- 9.6; 70 minutes: 45.1 +/- 6.3). In contrast, the response of plasma ouabainlike compound was slow and doubled at 40 minutes (P < .01, control: 115 +/- 12 pmol ouabain equivalents per liter; 10 minutes: 132 +/- 23; 40 minutes: 226 +/- 53; 70 minutes: 117 +/- 16). Ouabainlike compound levels in hypothalamus and pituitary remained unaltered. These findings suggest that ouabainlike compound may function as a stress hormone.
    Hypertension 12/1995; 26(6 Pt 2):1173-6. · 6.87 Impact Factor

Publication Stats

503 Citations
270.78 Total Impact Points


  • 1992–2000
    • Oita University
      • Department of Physiology
      Ōita, Ōita, Japan
  • 1988–2000
    • The University of Tokyo
      • • Department of Internal Medicine
      • • Division of Internal Medicine
      • • Faculty & Graduate School of Medicine
      Tokyo, Tokyo-to, Japan