Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic.
OBJECTIVE
We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats.


METHODS
We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues.


RESULTS
SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system.


CONCLUSIONS
Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.
Nishikimi
Toshio
T
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. nishikim@dokkyomed.ac.jp
Wang
Xin
X
Akimoto
Kazumi
K
Tadokoro
Kazuyoshi
K
Mori
Yosuke
Y
Ishikawa
Yayoi
Y
Ishimura
Kimihiko
K
Yoshihara
Fumiki
F
Minamino
Naoto
N
Kangawa
Kenji
K
Matsuoka
Hiroaki
H
D053607:Adrenomedullin; D000450:Aldosterone / Q000097:blood; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000235:genetics; D008297:Male; D010455:Peptides / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*
D024042:Collagen Type I; D004232:Diuretics; D008233:Lymphotoxin-alpha; D010455:Peptides; D012333:RNA, Messenger; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D000450:Aldosterone