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  • Kuwaki, Tomoyuki  (4)
  • English  (4)
  • 2000-2004  (4)
  • 1
    Online Resource
    Online Resource
    Vascular Abnormalities and Elevated Blood Pressure in Mice Lacking Adrenomedullin Gene
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Circulation Vol. 104, No. 16 ( 2001-10-16), p. 1964-1971
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 104, No. 16 ( 2001-10-16), p. 1964-1971
    Abstract: Background Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. Levels of AM are markedly increased in the fetoplacental circulation during pregnancy, although its function there remains unknown. To clarify the physiological functions of AM, we chose a gene-targeting strategy in mice. Methods and Results Targeted null mutation of the AM gene is lethal in utero: the mortality rate among AM −/− embryos was 〉 80% at E13.5. The most apparent abnormality in surviving AM −/− embryos at E13.5 to E14.0 was severe hemorrhage, readily observable under the skin and in visceral organs. Hemorrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vitelline vessels and hepatic capillaries, which allowed efflux of protoerythrocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells stood out from the wall of the lumen, only partially adhering to the basement structure. AM +/− mice survived to adulthood but exhibited elevated blood pressures with diminished nitric oxide production. Conclusions AM is indispensable for the vascular morphogenesis during embryonic development and for postnatal regulation of blood pressure by stimulating nitric oxide production.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/hc4101.097111
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
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  • 2
    Online Resource
    Online Resource
    Elevated Sympathetic Nervous Activity in Mice Deficient in αCGRP
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Circulation Research Vol. 89, No. 11 ( 2001-11-23), p. 983-990
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 89, No. 11 ( 2001-11-23), p. 983-990
    Abstract: α-Calcitonin gene-related peptide (αCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of αCGRP, we developed an α CGRP -null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained α CGRP -null mice than in corresponding wild-type mice. The elevated MAP in α CGRP -null mice was shown to be the result of elevated peripheral vascular resistance by α-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between α CGRP -null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in α CGRP -null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that αCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/hh2301.100812
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
    detail.hit.zdb_id: 1467838-X
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  • 3
    Online Resource
    Online Resource
    Role of endothelin-1 in stress response in the central nervous system
    American Physiological Society ; 2000
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 279, No. 2 ( 2000-08-01), p. R515-R521
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 279, No. 2 ( 2000-08-01), p. R515-R521
    Abstract: Endothelin (ET)-1 is a 21-amino acid peptide that induces a variety of biological activities, including vasoconstriction and cell proliferation, and its likely involvement in cardiovascular and other diseases has recently led to broad clinical trials of ET receptor antagonists. ET-1 is widely distributed in the central nervous system (CNS), where it is thought to regulate hormone and neurotransmitter release. Here we show that CNS responses to emotional and physical stressors are differentially affected in heterozygous ET-1-knockout mice, which exhibited diminished aggressive and autonomic responses toward intruders (emotional stressors) but responded to restraint-induced (physical) stress more intensely than wild-type mice. This suggests differing roles of ET-1 in the central pathways mediating responses to different types of stress. Hypothalamic levels of ET-1 and the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) were both increased in wild-type mice subjected to intruder stress, whereas MHPG levels were not significantly affected in ET-1-knockout mice. Furthermore, immunohistochemical analysis showed that ET-1 and tyrosine hydroxylase, an enzyme in the catecholamine synthesis pathway, were colocalized within certain neurons of the hypothalamus and amygdala. Our findings suggest that ET-1 modulates central coordination of stress responses in close association with catecholamine metabolism.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.2000.279.2.R515
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2000
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Hypotension and Resistance to Lipopolysaccharide-Induced Shock in Transgenic Mice Overexpressing Adrenomedullin in Their Vasculature
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Circulation Vol. 101, No. 19 ( 2000-05-16), p. 2309-2316
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 101, No. 19 ( 2000-05-16), p. 2309-2316
    Abstract: Background —Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature. Methods and Results —Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N G -monomethyl- l -arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice. Conclusions —A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.101.19.2309
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1466401-X
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