Renal injury and salt-sensitive hypertension after exposure to catecholamines.
We investigated whether chronic infusion of phenylephrine could induce structural and functional changes in the kidney of rats with the subsequent development of salt-sensitive hypertension. Rats were infused with phenylephrine (0.15 mmol/kg per day) by minipump, resulting in a moderate increase in systolic blood pressure (BP) (17 to 25 mm Hg) and a marked increase in BP variability as measured by an internal telemetry device. After 8 weeks, the phenylephrine infusion was stopped with the return of BP to normal, and a nephrectomy was performed for histological studies. Glomeruli were largely spared, but focal tubulointerstitial fibrosis was present, with the de novo expression of osteopontin by injured tubules, macrophage and "myofibroblast" accumulation, and focal increases in mRNA for transforming growth factor beta by in situ hybridization. Peritubular capillaries at sites of injury had distorted morphology with shrinkage, rounding, and focal rarefaction, and endothelial cell proliferation was also identified. Rats were randomized to a high (8% NaCl or 1.36 mol/kg) or low (0.1% NaCl or 17 mmol/kg) salt diet. After 4 to 8 weeks, phenylephrine-treated rats on a high salt diet developed marked hypertension, which was in contrast with phenylephrine-treated rats placed on a low salt diet or vehicle-treated rats given a high salt diet. Hypertension after phenylephrine exposure correlated with the initial mean systolic BP (r(2)=0.99) and the degree of BP lability (r(2)=0.99) during the phenylephrine infusion, the amount of osteopontin expressed in the initial biopsy/nephrectomy (r(2)=0.74), and the final glomerular filtration rate (r(2)=0.58). These studies provide a mechanism by which a markedly elevated sympathetic nervous system can induce salt-dependent hypertension even when the hyperactive sympathetic state is no longer engaged.
Division of Nephrology, University of Washington Medical Center, Seattle, 98195 WA, USA.
R J
RJ
Johnson
K L
KL
Gordon
S
S
Suga
A M
AM
Duijvestijn
K
K
Griffin
A
A
Bidani
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D004039:Diet, Sodium-Restricted; D004351:Drug Resistance; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D012965:Sodium Chloride
D000316:Adrenergic alpha-Agonists; D010656:Phenylephrine; D012965:Sodium Chloride