In vivo regulation of AT1a receptor-mediated intracellular uptake of [125I]Val5-ANG II in the kidneys and adrenals of AT1a receptor-deficient mice.
Using type 1a angiotensin receptor (AT1a) receptor-deficient (Agtr1a-/-) mice and in vivo autoradiography, we tested the hypothesis that intracellular uptake of ANG II in the kidney and adrenal glands is primarily mediated by AT1a receptors and that the response is regulated by prevailing endogenous ANG II. After pretreatment of wild-type (Agtr1a+/+) and Agtr1a-/- mice (n = 6-9 each group) with or without captopril (25 mg.kg(-1).day(-1)) or losartan (10 mg.kg(-1).day(-1)) for 2 wk, [125I]Val5-ANG II was infused for 60 min. Intracellular uptake of [125I]Val5-ANG II was determined by quantitative in vivo autoradiography after washout of circulating [125I]Val5-ANG II. Basal intracellular ANG II levels were 65% lower in the kidney (P < 0.001), but plasma ANG II levels were threefold higher, in Agtr1a-/- than wild-type mice (P < 0.01). Although plasma [125I]Val5-ANG II levels were similar, urinary excretion of [125I]Val5-ANG II was fourfold higher in Agtr1a-/- mice (P < 0.001). By contrast, intracellular [125I]Val5-ANG II levels were approximately 80% lower in the kidney and adrenal glands of Agtr1a-/- mice (P < 0.01). Captopril decreased endogenous plasma and renal ANG II levels (P < 0.01) but increased intracellular uptake of [125I]Val5-ANG II in the kidney and adrenal glands of wild-type and Agtr1a-/- mice (P < 0.01). Losartan largely blocked renal and adrenal uptake of [125I]Val5-ANG II in wild-type and Agtr1a-/- mice. Thus 80% of intracellular ANG II uptake in the kidney and adrenal glands 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 adrenal glands.
Li
Xiao C
XC
Zhuo
Jia L
JL
D000302:Adrenal Cortex / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism*; D000313:Adrenal Medulla / Q000378:metabolism; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004705:Endocytosis; D007262:Infusions, Intravenous; D007668:Kidney / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011188:Potassium / Q000652:urine; D020033:Protein Isoforms / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D012964:Sodium / Q000652:urine
D047228:Angiotensin II Type 1 Receptor Blockers; D020033:Protein Isoforms; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000450:Aldosterone; D002216:Captopril; D012964:Sodium; D019808:Losartan; D011188:Potassium