Although it has been reported that the circulating
adrenomedullin (AM) level is elevated in
hypertension and
renal failure, the pathophysiological significance of circulating and intrarenal AM in
malignant hypertension remains unknown. We investigated the circulating and intrarenal AM system in rats with
malignant hypertension by measuring the plasma level, renal tissue level, and
mRNA abundance of AM and the
mRNA abundance of AM receptor. We also investigated the effects of intravenously infused
calcitonin gene-related peptide (CGRP)-(8-37), an antagonist of AM, on the hemodynamics and renal tubular function. We studied the following four groups: control Wistar-Kyoto rats (WKY), control spontaneously hypertensive rats (C-SHR),
salt-loaded SHR (S-SHR), and
DOCA-
salt SHR (D-SHR). After 3 wk of
DOCA treatment, D-SHR developed
malignant hypertension. D-SHR were characterized by higher blood pressure, kidney weight, urinary
protein excretion and blood
urea nitrogen, and lower
creatinine clearance compared with the other three groups. The plasma AM level and urinary excretion of AM were markedly higher in D-SHR than in the other three groups. In the kidney, the tissue AM level and the expression of AM
mRNA in the renal medulla were significantly increased in D-SHR compared with the other three groups, whereas there were no significant differences in these levels in the renal cortex among the four groups. In the renal AM receptor system, the expression of the gene for
receptor activity modifying protein 3 was significantly increased in the renal medulla in D-SHR compared with the other three groups. An immunohistochemical study revealed that AM immunostaining in renal collecting duct cells and distal tubules was more intense in D-SHR than in the other three groups. After
CGRP-(8-37) infusion, blood pressure increased significantly and urinary
sodium excretion and urine flow decreased significantly only in D-SHR. These results suggest that the increased circulating AM and renal AM and the increased expression of the
mRNA for AM and its receptor may at least partly compensate for the malignant hypertensive state in certain forms of
malignant hypertension via the hypotensive, natriuretic, and
diuretic actions of AM.