Upregulation of ligand, receptor system, and amidating activity of adrenomedullin in left ventricular hypertrophy of severely hypertensive rats: effects of angiotensin-converting enzyme inhibitors and diuretic.
OBJECTIVE
We investigated the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand, receptor and amidating activity in the hypertrophied heart in severe hypertension.


METHODS
We studied the following four groups: control Wistar-Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), 8 weeks captopril-treated SHR-SP, and 8 weeks trichlormethiazide-treated SHR-SP. AM precursor is converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly is converted to active mature AM (AM-m) by enzymatic amidation. We measured AM-m, AM-total (AM-T; AM-T = AM-m + AM-Gly), and atrial natriuretic peptide (ANP) in the plasma and left ventricle (LV) by immunoradiometric assay. We also measured gene expression of AM and ANP was and gene expression and protein levels of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor-activity modifying protein (RAMP) 2 and RAMP3.


RESULTS
At 7 weeks old, SHR-SP had higher blood pressure and ANP mRNA levels and lower plasma AM-T compared with WKY, however, there were no differences in other indices between the two groups. At 17 weeks old, SHR-SP had increased blood pressure, LV weight, plasma and LV ANP levels and mRNA levels of ANP compared with WKY. AM-m and AM-T levels in plasma (AM-m: + 31%; AM-T: + 56%) and the LV (AM-m: + 84%; AM-T: + 31%) were significantly higher in SHR-SP than in WKY. The LV tissue AM-m/AM-T ratio was significantly higher in SHR-SP (93.2%) than in WKY. The mRNA levels of AM, CRLR, and RAMP2 in the LV were significantly higher in SHR-SP than in WKY. Captopril and trichlormethiazide similarly decreased blood pressure and LV hypertrophy with the reduction of the LV AM-m and AM-T levels and mRNA abundance of AM and its receptor component.


CONCLUSIONS
These results suggest that cardiac AM system is upregulated in the hypertrophied heart in this hypertension model. Considering that AM acts as an anti-remodeling autocrine and/or paracrine factor, upregulation of the AM system may modulate the pathophysiology in LV hypertrophy.
Wang
Xin
X
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan.
Nishikimi
Toshio
T
Akimoto
Kazumi
K
Tadokoro
Kazuyoshi
K
Mori
Yosuke
Y
Minamino
Naoto
N
D053607:Adrenomedullin; D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects; D058286:Calcitonin Receptor-Like Protein; D002216:Captopril / Q000494:pharmacology*; D004232:Diuretics; D004359:Drug Therapy, Combination; D015870:Gene Expression; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000097:blood* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D014237:Trichlormethiazide / Q000494:pharmacology; D015854:Up-Regulation
D000806:Angiotensin-Converting Enzyme Inhibitors; D058286:Calcitonin Receptor-Like Protein; D004232:Diuretics; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; D012333:RNA, Messenger; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D049993:Sodium Chloride Symporter Inhibitors; D053607:Adrenomedullin; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D002216:Captopril; D014237:Trichlormethiazide