Previous studies have demonstrated that
adrenomedullin has inhibitory effects on the proliferation and
DNA synthesis of mesangial cells and vascular smooth muscle cells in vitro and that plasma
adrenomedullin levels are markedly elevated in
malignant hypertension. This study was designed to examine whether chronic
adrenomedullin infusion has renoprotective effects in malignant hypertensive rats. We studied the following 3 groups: control Wistar Kyoto rats,
deoxycorticosterone acetate-
salt spontaneously hypertensive rats, and
adrenomedullin-treated
deoxycorticosterone acetate-
salt spontaneously hypertensive rats. Chronic
adrenomedullin infusion using an osmotic minipump was started simultaneously with
deoxycorticosterone acetate-
salt treatment. After 3 weeks of the treatment, malignant hypertensive rats were characterized by higher blood pressure, kidney weight, urinary
protein excretion, glomerular injury score, plasma
renin concentration,
aldosterone level, endogenous rat plasma
adrenomedullin level, renal cortical tissue
angiotensin II level,
angiotensin-converting enzyme mRNA level, and
transforming growth factor-beta1 mRNA level in the renal cortex, and by lower
creatinine clearance, compared with the control rats. Chronic
adrenomedullin infusion significantly improved these parameters (kidney weight -6.5%, urinary
protein excretion -63.8%, glomerular injury score -38.3%, plasma
renin concentration -52.4%,
aldosterone -23.2%, rat
adrenomedullin -28.6%, renal
angiotensin II -28.1%, renal
angiotensin-converting enzyme mRNA -38.3%, renal
transforming growth factor-beta1 mRNA -56.2%, and
creatinine clearance +20.5%) without significant reduction of mean arterial pressure (-4%). Kaplan-Meier survival analysis showed that
adrenomedullin infusion significantly prolonged survival time. These results suggest that subdepressor dose of chronic
adrenomedullin infusion has renoprotective effects in this
malignant hypertension model, at least in part, via inhibition of the circulating and intrarenal renin-angiotensin system.