Adrenomedullin (AM) is a potent
vasodilator and
natriuretic peptide that plays an important role in cardiorenal function. In this study, we explored the potential protective role of AM in volume-dependent
hypertension by somatic gene delivery. Adenovirus containing the human AM
cDNA under the control of the cytomegalovirus promoter/enhancer was administered into
deoxycorticosterone acetate (
DOCA)-
salt hypertensive rats via tail vein injection. A single injection of the human AM gene resulted in a prolonged reduction of blood pressure with a maximal reduction of 41 mm Hg 9 days after gene delivery. Human AM gene delivery enhanced renal function, as indicated by a 3-fold increase in renal blood flow and a 2-fold increase in glomerular filtration rate (n=5, P<0.05). Histological examination of the kidney revealed a significant reduction in glomerular
sclerosis, tubular injury,
luminol protein cast accumulation, and interstitial
fibrosis as well as urinary
protein. Human AM gene delivery caused significant decreases in left ventricular weight and cardiomyocyte diameter, which were accompanied by reduced interstitial
fibrosis and extracellular matrix formation within the heart. Expression of human AM
mRNA was detected in the kidney, adrenal gland, heart, aorta, lung, and liver; immunoreactive human AM levels were measured in urine and plasma. Significant increases in urinary and cardiac cAMP levels were observed in
DOCA-
salt rats receiving the human AM gene, indicating activation of the AM receptor. These findings showed that AM gene delivery attenuates
hypertension, protects against cardiac remodeling and renal damage in volume-overload
hypertension, and may have significance in therapeutic applications in cardiovascular and renal diseases.