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1 Hypertension and Vascular Division, Henry Ford Hospital, Detroit, Michigan, United States
2 Hypertension and Vascular Division, Henry Ford Hospital, Detroit, Michigan, United States; Department of Physiology, Wayne State University School of Medicine, 5374 Scott Hall, Detroit, Michigan, 48202, United States
* To whom correspondence should be addressed. E-mail: jzhuo1{at}hfhs.org.
Using AT1a receptor-deficient mice (Agtr1a-/-) and in vivo autoradiography, we tested the hypothesis that intracellular uptake of angiotensin II (Ang II) in the kidney and adrenals is primarily mediated by AT1a receptors and the response is regulated by prevailing endogenous Ang II. Wild-type (Agtr1a+/+) and Agtr1a-/- mice were pretreated with captopril (25 mg/kg/day) or losartan (10 mg/kg/day) for 2 weeks before [125I]-Val5-Ang II was infused for 60 min. Intracellular uptake of [125I]-Val5-Ang II was determined by quantitative in vivo autoradiography after circulating [125I]-Val5-Ang II was washed out. Compared with wild-types, basal intracellular Ang II levels were 65% lower in the kidney (p<0.001), but plasma Ang II levels were 3-folds higher in Agtr1a-/- mice (p<0.01). While plasma [125I]-Val5-Ang II levels were similar, urinary excretion of [125I]-Val5-Ang II was 4-folds higher in Agtr1a-/- mice (p<0.001). By contrast, intracellular [125I]-Val5-Ang II levels were 80% lower in the kidney and adrenals of Agtr1a-/- mice (p<0.01). Captopril decreased endogenous plasma and renal Ang II levels (p<0.01), but it increased intracellular uptake of [125I]-Val5-Ang II in the kidney and adrenals of both wild-type and Agtr1a-/- mice (p<0.01). Losartan largely blocked renal and adrenal uptake of [125I]-Val5-Ang II in both wild-type and Agtr1a-/- mice. Thus 80% of intracellular Ang II uptake in the kidney and adrenals is mediated by AT1a receptors, whereas AT1b receptor- and other non receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT1a receptor-mediated uptake of extracellular Ang II may play a physiological role in the kidney and adrenals.
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