A free-ranging roundtable discussion on hypertension.
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Biomedical Research↗
Biomedical subjects
T Shimosawa
Publications and source records attributed to T Shimosawa.
Regulatory effects of senescence marker protein 30 on the proliferation of hepatocytes.
Senescence marker protein 30 (SMP 30) is preferentially expressed in the liver. One of its remarkable functions is the protection of cells against various injuries by enhancement of membrane calcium-pump activity. We analyzed the role of SMP 30 in hepatocyte proliferation. SMP 30 expression was decreased initially, then increased along with hepatic regeneration, after carbon tetrachloride (CCl4) administration. SMP 30 expression was decreased in the necrotic phase and then gradually increased. Its increase was slightly delayed just after the mitotic phase. These results lead us to speculate that mitoses of hepatic cells induce enhanced SMP 30 expression. In contrast, administration of lead nitrate (LN) as a hepatic mitogen induced a more stable increase of SMP 30 expression. To estimate the effect of SMP 30 on cell proliferation, we evaluated hepatic mitosis in wild-type and SMP 30-deficient knockout (KO) mice after CCl4 administration. We found an increase in mitotic numbers in hepatocytes of KO mice. This result suggests that SMP 30 has a suppressive effect on cell proliferation. Suppressive activity of SMP 30 cDNA was shown in cultured hepatoblastic cells. Our results suggest that SMP 30 performs a regulatory function in liver regeneration.
Animals↗
Regulatory effect of histamine H1 receptor antagonist on the expression of messenger RNA encoding CC chemokines in the human nasal mucosa.
BACKGROUND: Allergic rhinitis is characterized by tissue accumulation of inflammatory cells. CC chemokines, including monocyte chemotactic protein (MCP) 1, MCP-3, RANTES, and eotaxin, are thought to play an important role in inducing selective recruitment of these cells to the allergic inflammatory site. Furthermore, MCPs have been indicated as histamine-releasing factors. Histamine is an important mediator in the pathogenesis of nasal allergy. The regulation of histamine may have a role in the management of allergic inflammation. OBJECTIVE: The objectives of this study were to investigate the expression of MCP-1, MCP-3, RANTES, and eotaxin in the nasal mucosa of patients with allergic rhinitis and to clarify the effect of histamine and antihistamine on the regulation of the expression of these CC chemokines. METHODS: By using a semiquantitative reverse transcriptase PCR technique, the numbers of copies of messenger RNA encoding MCP-1, MCP-3, RANTES, and eotaxin were measured in explant cultures of human nasal mucosa. In culture medium, specific antigen or histamine was added. Furthermore, the effect of preincubation with the antihistamine carebastine was estimated. RESULTS: Mite antigen (1:2 x 10(4) dilution) and histamine (10(-4) to 10(-3) mol/L) upregulated the messenger RNA expression of these CC chemokines at 3- to 10-fold increases. Carebastine (10(-7) to 10(-6) mol/L) inhibited this upregulation. CONCLUSION: Our results suggest that histamine may induce CC chemokine production in the nasal mucosa of patients with allergic rhinitis. This indicates that there may be a prolonged inflammatory cycle in the histamine-MCP axis in allergic rhinitis. The regulation of histamine-CC chemokine interaction could lead to new therapeutic approaches in the treatment of nasal allergy.
Adult↗
Effects of ouabain on the growth and DNA synthesis of PC12 cells.
We investigated the effects of ouabain and serum from salt-loaded Dahl salt-sensitive (S) rats, which contain abundant ouabain-like compounds, on the growth and DNA synthesis of rat pheochromocytoma PC12 cells. Ouabain decreased the growth of PC12 cells, as evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, in a concentration-dependent fashion. A moderate concentration (10(-7) M) of ouabain increased DNA synthesis, as measured by 5-bromo-2'-deoxyuridine incorporation, and induced transcription of the proto-oncogenes c-myc and c-fos. Serum from salt-loaded Dahl S rats also enhanced DNA synthesis, but serum from Dahl salt-resistant rats did not. Thus ouabain-like compounds may modify the growth or differentiation of neural tissues. This effect may contribute to the development of salt-induced hypertension in Dahl S rats.
Animals↗
Blood pressure biofeedback treatment of white-coat hypertension.
OBJECTIVE: The objective of the study was to compare blood pressure (BP) biofeedback treatment (BF) effects between white-coat hypertension and essential hypertension. METHODS: Fifteen white-coat hypertensive out-patients and 23 essential hypertensive out-patients were randomly assigned to groups A or B. Subjects in group A underwent BF once a week for a total of four sessions. Those in group B visited the clinic only to measure BP and later underwent the same BF. RESULTS: In group A, BPs of white-coat hypertensives and essential hypertensives were significantly reduced by 22/11 and 14/8 mmHg, respectively. In group B, they were unchanged during the same period but later suppressed by BF. Under BF, pulse and respiratory rates were significantly higher, and elevation of diastolic BP due to mental stress testing was better suppressed in white-coat hypertensives than in essential hypertensives. CONCLUSION: This treatment was effective in both types of hypertension, and pressor response to stress seems to be important in the differentiated BF effect.
Biofeedback, Psychology↗
Adrenomedullin amidation enzyme activities in hypertensive patients.
Adrenomedullin (AM) is a potent vasodilating peptide secreted from the vasculature of various organs. It is biologically active when its C-terminus is amidated. Recently, an RIA method was developed for measurement of the active form of AM, or mature AM. We here employed this method to investigate the significance of amidation of AM in controlling cardiovascular function. Thirty-six patients under hemodialysis were recruited and divided into hypertensive (n = 25; 157/86 mmHg) and normotensive (n= 11; 116/66 mmHg) groups. Mature AM, immature AM and blood pressure were monitored during hemodialysis in all patients. There was a significant reduction in blood pressure during hemodialysis in both groups, although after hemodialysis blood pressure was still higher in hypertensives than in normotensives (139 +/-14.8/76 +/- 2.5 mmHg vs. 110 +/- 5.1/66.7 +/- 3.1 mmHg). Mature AM before hemodialysis were lower in hypertensives than normotensives and it decreased in both groups. Although mature AM decreased more in normotensives than in hypertensives (-27 +/- 8% vs. -17 +/- 5%), at the end point, its level was still higher in normotensives. The ratio of mature AM/immature AM decreased only in normotensives (-11.4 8.7%), whereas it remained stable in hypertensives (0.2 +/- 5.6%). Both groups showed similar changes in ANP, endothelin, catecholamines, cGMP, and NOx. The low level in mature AM level in hypertensives may have contributed to the higher blood pressure in this group. The attenuation of AM amidation in normotensives indicates that an unspecified amidative enzyme of AM was regulated in order to normalize blood pressure.
Adrenomedullin↗
5-HT(2A/2C) receptor agonist-induced increase in urinary isatin excretion in rats: reversal by both diazepam and dexamethasone.
Isatin, a stress-related biological substance, increases in rat urine in association with elevated catecholamine biosynthesis during stress. The goal of this study was to unravel how the biosynthetic pathway of isatin is related to stress response. The importance of the serotonergic compounds in anxiety, which is the major emotional process of stress response, has emerged. m-Chlorophenylpiperazine (m-CPP), a 5-HT(1A/1B/2A/2C) receptor agonist, and (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride [(+/-)-DOI], a 5-HT(2A/2C) agonist, both of which have anxiogenic properties, induced a marked increase in 24-hr urinary isatin excretion, whereas neither 1-(m-chlorophenyl)-biguanide (m-CPBG), a 5-HT3 agonist, nor 2-methyl-5-HT, a 5-HT(3,4) agonist, affected urinary isatin excretion. 5-HT(2A/2C) receptor antagonists such as ketanserin and ritanserin prevented the increase in urinary isatin excretion induced by the 5-HT(2A/2C) receptor agonist m-CPP. These findings are the first to provide evidence that pharmacological substances cause increases in urinary isatin excretion via specific 5-HT receptors, probably 5-HT(2A/2C) receptors. In addition, both the synthetic glucocorticoid dexamethasone and diazepam prevented the m-CPP-induced increase in urinary isatin excretion. These observations suggest that the mechanism by which m-CPP elicits enhancing effects on urinary isatin excretion has something in common with stress response involving activation of hypothalamic CRF cells and the sympathetic nervous system.
Animals↗
Hyperglycemia increases vascular adrenomedullin expression.
We have reported that plasma adrenomedullin (AM) in hyperglycemic patients was significantly increased compared with normal volunteers. In this report we examined the effects of hyperglycemia on AM expression in the vasculature, the main site of AM production. AM mRNA level in the aorta was higher in the diabetic rats than in the control rats. AM mRNA level and protein kinase C (PKC) activity in cultured vascular smooth muscle cells (VSMC) increased as the glucose concentration in the medium changed from 100mg/dl to 450mg/dl. PKC inhibitors blocked this increase of AM mRNA. Similar osmotic change with mannitol had no effect on AM expression. We conclude that (1) hyperglycemia increases vascular AM expression through PKC-dependent pathway, and (2) the elevated plasma AM in hyperglycemic patients originates from the glucose induced vascular AM expression. We propose the possible role of AM in the pathogenesis of diabetic vascular complications.
Adrenomedullin↗
Blood pressure biofeedback treatment, organ damage and sympathetic activity in mild hypertension.
BACKGROUND: Although biofeedback treatment is reported to be useful for patients with mild hypertension as an adjunct to medication, it is not certain whether the presence of organ damage affects its efficacy. The aim of this study is to clarify the clinical effects of biofeedback on mild hypertension in the absence and presence of organ damage. METHODS: Eleven mildly hypertensive outpatients without damage to the heart, brain, retina or kidney (4 men and 7 women), aged 40-65 years, and 11 mildly hypertensive outpatients with target organ damage and matching variables for age, sex and medication were included in this study. They underwent biofeedback treatment once a week for a total of four sessions. RESULTS: As a result of these sessions, mean blood pressures (MBP) in the organ-damage-negative (-) group and in the organ-damage-positive (+) group were significantly reduced by 12 +/- 11 and 12 +/- 8, respectively. The decrease was still significant 3 months after the treatment in the organ-damage (-) group, whereas no significant change was found 1 or 3 months after the treatment in the organ-damage (+) group. Throughout these sessions, the ratio of low frequency to high frequency of heart rate variance as well as systolic and MBP gradually decreased in each group (p < 0.01); this ratio of heart rate variance was smaller, and the alpha-wave amplitude on the electroencephalogram was larger in the organ-damage (-) group (p < 0.05). CONCLUSION: These results suggested that biofeedback intervention may be effective in mild hypertension, especially when the patient is organ damage (-). Sympathetic activity seems to play an important role in the differentiated response.
Adult↗
Senescence marker protein-30 (SMP30) rescues cell death by enhancing plasma membrane Ca(2+)-pumping activity in Hep G2 cells.
Senescence marker protein-30 (SMP30) has been reported to decrease with aging in the rat liver. SMP30 has been also suggested to play a role as a Ca(2+)-binding protein localized in cytosol of hepatocytes. To elucidate the functional significance of SMP30, we have generated Hep G2 cell lines that stably express large amounts of SMP30 by transfection with human SMP30 cDNA. Using these cell lines, in view of the intracellular Ca2+ homeostasis, we then investigated cytosolic free Ca2+ concentration ([Ca2+]i) and Na(+)-independent Ca2+ efflux from the cells after extracellular ATP stimulation. Although stimulation of cells with ATP caused transient [Ca2+]i increase in both SMP30 and mock transfectants, rate of decrease after peak in [Ca2+]i was enhanced 2-fold by transfection of SMP30. Correspondingly, Ca2+ efflux was significantly increased in SMP30 transfectants compared with mock transfectants. In addition, more SMP30 transfectants survived than mock transfectants when cell death was induced by Ca2+ ionophore treatment. These results suggest that SMP30 regulates [Ca2+]i by modulating plasma membrane Ca(2+)-pumping activity, and thus down-regulation of SMP30 during aging may contribute to deterioration of cellular functions.
Animals↗
Mental arithmetic is a useful diagnostic evaluation in white coat hypertension.
It remains unclear whether patients with white coat hypertension are more susceptible to mental stress than are those with essential hypertension. To compare the pressor responses to mental arithmetic between the two types of hypertension, 21 untreated female outpatients, aged 42 to 64 (mean 55) years, with hypertension, were studied. After 2 weeks of self-monitoring blood pressure, 11 patients were diagnosed as having white coat hypertension and the remaining 10 patients were diagnosed as having essential hypertension. The systolic and diastolic blood pressure responses to mental arithmetic testing were significantly greater in the patients with white coat hypertension (+38 +/- 18/+24 +/- 13 mm Hg) than in those with essential hypertension (+21 +/- 8/+13 +/- 6 mm Hg). These differences also were statistically significant in controlling for the effects of age and baseline blood pressures. These data suggest that mental arithmetic testing may be a useful tool for the diagnosis of white coat hypertension.
Adult↗
Plasma adrenomedullin in diabetes.
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Adrenomedullin↗
Proadrenomedullin N-terminal 20 peptide (PAMP) inhibits proliferation of human neuroblastoma TGW cells.
We investigated the effects of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) on the growth of human neuroblastoma TGW cells. Both PAMP and AM inhibited growth and DNA synthesis in neuroblastoma cells. Calcitonin gene-related peptide (CGRP)(8-37), an antagonist to CGRP, abolished the inhibitory effect of AM on growth and DNA synthesis of neuroblastoma cells but did not affect that of PAMP. AM(22-52), an antagonist to AM, also reversed the effect of AM. On the other hand, pertussis toxin (PTX) and omega-conotoxin GIVA blocked the effect of PAMP alone. Thus, PAMP inhibits the growth of neuroblastoma cells by inhibiting N-type Ca2+ channels through PTX-sensitive G protein-coupled receptors, which is different mechanism of AM-induced inhibition of the cell growth.
Adrenomedullin↗
Hemodynamic and endocrine responsiveness to mental arithmetic task and mirror drawing test in patients with essential hypertension.
To evaluate the reactivity to psychological stress in patients with essential hypertension we investigated hemodynamic and endocrinologic changes during a mental arithmetic task (MAT) and a mirror drawing test (MDT) in 10 hypertensive subjects. Hemodynamic changes were assessed continuously using an ambulatory radionuclide cardiac detector. There were significant increases in systolic blood pressure (deltaSBP: +37.8 +/- 11.1 and +41.0 +/- 9.4 mm Hg during MAT and MDT, respectively, P < .01) and diastolic blood pressure (deltaDBP: +17.5 +/- 3.1 and +21.2 +/- 3.9 mm Hg, P < .01) and in heart rate (deltaHR: +17.1 +/- 5.3 and +12.5 +/- 2.9 beats/min, P < .01) during both tasks in association with an increase in cardiac output (CO). The plasma levels of norepinephrine and epinephrine increased during both the MAT (deltaNE: +0.074 +/- 0.022 ng/mL, P < .01; deltaEP: +0.068 +/- 0.025 ng/mL, P < .01) and the MDT (deltaNE: +0.067 +/- 0.034 ng/mL, P < .01; deltaEP: +0.030 +/- 0.011 ng/mL, .05 < P < .1). Although the deltaNE was similar in response to the MAT and MDT, the deltaEP during the MDT tended to be less than half the deltaEP during the MAT (.05 < P < .10). The deltaEP was positively correlated with the deltaDBP and the deltaCO during both tasks and with the deltaSBP and the deltaHR during the MAT. These findings suggest that MAT- and MDT-induced increases in BP were attributable mainly to an increase in CO, possibly as the result of stimulation of the sympathoadrenomedullary system. However, the sympathoadrenomedullary system appeared to be more closely associated with the hemodynamic responses during the MAT than during the MDT.
Adrenocorticotropic Hormone↗
A newly identified peptide, proadrenomedullin N-terminal 20 peptide, induces hypotensive action via pertussis toxin-sensitive mechanisms.
Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) are novel hypotensive peptides. Although they are derived from the same gene product, proadrenomedullin, their hypotensive mechanisms are different; PAMP inhibits the release of norepinephrine from the peripheral sympathetic nerve endings, whereas AM fosters vasodilation by elevating intracellular cAMP, possibly via activation of cholera toxin-sensitive G proteins. In PC12 cells, PAMP inhibited N-type calcium channel via activation of pertussis toxin-sensitive mechanisms. To clarify the relationship between the hypotensive effect of PAMP and pertussis toxin-sensitive mechanisms, we administered pertussis vaccine intraperitoneally into rats for 3 consecutive days. By using mesenteric artery preparation, we showed that PAMP's ability to decrease norepinephrine overflow was significantly attenuated in pertussis toxin-treated rat (-18.5 +/- 6.9%; P<.05 versus control rats). In electrically stimulated pithed rat, PAMP (20 and 40 nmol/kg) showed a hypotensive effect (-13 +/- 5 and -18 +/- 7 mm Hg, respectively; P<.05, P<.01), whereas in pertussis vaccine-treated rat it did not (-2 +/- 3 and -8 +/- 9 mm Hg, respectively; P=NS). Also, in pithed rat, plasma norepinephrine level was significantly elevated by electrical stimulation in both control (0.323 +/- 0.035 ng/mL) and pertussis vaccine-treated groups (0.355 +/- 0.079 ng/mL). After injection of PAMP (40 nmol/kg), plasma norepinephrine level significantly decreased in the control group (0.225 +/- 0.044 ng/mL; P<.01) but not in the pertussis vaccine-treated group (0.392 +/- 0.021 ng/mL; P=NS). Moreover, in conscious rats, intravenous administration of PAMP (40 nmol/kg) did not evoke hypotension after pertussis vaccine treatment, although untreated controls had significantly decreased arterial pressure (-5 +/- 2 versus -20 +/- 3 mm Hg; P<.01). In contrast to PAMP, the administration of AM (1 nmol/kg) significantly reduced the blood pressure of pertussis vaccine-treated as well as control rats (-20 +/- 5 versus -18 +/- 7 mm Hg; P=NS). These results demonstrate that the ability of PAMP to inhibit norepinephrine release from peripheral sympathetic nerve endings and to decrease blood pressure is pertussis toxin sensitive. Our findings thus suggest that despite being derived from the same gene, PAMP and AM apparently produce hypotension by activating different signaling pathways.
Adrenomedullin↗
[Diagnostic criteria and staging for patients with hypertension].
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Blood Pressure Determination↗
Effect of insulin on norepinephrine overflow at peripheral sympathetic nerve endings in young spontaneously hypertensive rats.
To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 +/- 5 mm Hg v 198 +/- 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 +/- 7 mm Hg v 104 +/- 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 +/- 0.079 ng/g) than in WKY (0.723 +/- 0.022 ng/g; P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (-18.4% +/- 4.0% v -32.0% +/- 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (-8.8% +/- 4.0%, P < .05), but not in WKY (-32.5% +/- 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na(+)-K+ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings.
Adrenergic alpha-Antagonists↗
Hypotensive effect of a newly identified peptide, proadrenomedullin N-terminal 20 peptide.
Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM), which are both derived from proadrenomedullin, exhibit marked hypotensive effects. We recently reported that PAMP but not AM reduced the release of norepinephrine from peripheral sympathetic nerve endings. Our present objective was to clarify the involvement of the sympathetic nervous system in the hypotensive action of PAMP and AM. Intravenous administration of PAMP (10, 20, and 50 nmol/kg) to conscious rats induced less reflex tachycardia (5 +/- 5, 10 +/- 5, and 14 +/- 6 beats per minute [bpm]) than that of AM in 0.1, 0.5, and 1.0 nmol/kg doses (5 +/- 8, 20 +/- 7, and 38 +/- 5 bpm, P < .01) although both agents showed similar hypotensive effects. We evaluated the effect of PAMP on blood pressure in pithed rats whose sympathetic nervous systems were abolished. In pithed rats, AM (-2 +/- 1, -7 +/- 1, and -10 +/- 3 mm Hg; NS, P < .05, and P < .01, respectively) but not PAMP evoked hypotension. In contrast, administration of PAMP (-3 +/- 1, -11 +/- 2, and -14 +/- 4 mm Hg; P < .05, P < .01, and P < .01, respectively) as well as adrenomedullin (-2 +/- 2, -10 + 3, and -15 +/- 4 mm Hg; NS, P < .01, and P < .01) significantly reduced blood pressure in electrically stimulated, pithed rats, which had reached almost the same levels as in conscious rats. In electrically stimulated, pithed rats, plasma norepinephrine level was reduced by PAMP but not by vehicle or AM. These findings suggest that the hypotensive effect of PAMP is mainly due to inhibition of peripheral sympathetic nerve activity.
Adrenomedullin↗