| Co-Investigator(Kenkyū-buntansha) |
NODA-ISGIHAR Neiko Kansai Medical University, Faculty of Medicine, Instructor, 医学部, 助手 (80333194)
MATSUSAKA Taiji Tokai University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (50317749)
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| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
In wild-type mice, a 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of piasma aldosterone greater than that seen with sodium restriction alone (2.75±0.35 vs. 1.38±0.16 ng/ml, P<0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 ±0.2 Eqm/liter), while potassium remained unchanged in mice with sodium restriction alone. To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtrla). When animals were fed a normal diet or chrontcally infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 ±0.27 ng/ml) and potassium remained on average at 4.5±0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5±0.1 mEq/liter) and aldosterone (1.84±0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.
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