(Hypertension. 1997;30:42-49.)
© 1997 American Heart Association, Inc.
Articles |
Angiotensin II Type 1 (AT1) Receptor–Mediated Accumulation of Angiotensin II in Tissues and Its Intracellular Half-life In Vivo
From the Departments of Internal Medicine (J.P. van K., L.M. de L., M.A.D.H.S.), Experimental Cardiology (J.P. van K., J.R. van M., P.D.V.), and Pharmacology (L.M. de L., A.H.J.D.), Cardiovascular Research Institute Erasmus University Rotterdam (COEUR) (the Netherlands).
Correspondence to A.H.J. Danser, PhD, Department of Pharmacology, Room EE 1418 B, Erasmus University Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail danser{at}farma.fgg.eur.nl
Abstract Angiotensin II (Ang II) is internalized by various cell types via receptor-mediated endocytosis. Little is known about the kinetics of this process in the whole animal and about the half-life of intact Ang II after its internalization. We measured the levels of 125I–Ang II and 125I–Ang I that were reached in various tissues and blood plasma during infusions of these peptides into the left cardiac ventricle of pigs. Steady-state concentrations of 125I–Ang II in skeletal muscle, heart, kidney, and adrenal were 8% to 41%, 64% to 150%, 340% to 550%, and 680% to 2100%, respectively, of the 125I–Ang II concentration in arterial blood plasma (ranges of six experiments). The tissue concentrations of 125I–Ang I were less than 5% of the arterial plasma concentrations. 125I–Ang II accumulation seen in heart, kidney, and adrenal was almost completely blocked by a specific Ang II type 1 (AT1) receptor antagonist. Steady-state concentrations of 125I–Ang II were reached within 30 to 60 minutes in the tissues and within 5 minutes in blood plasma. The in vivo half-life of intact 125I–Ang II in heart, kidney, and adrenal was approximately 15 minutes, compared with 0.5 minute in the circulation. Thus, Ang II, but not Ang I, from the circulation is accumulated by some tissues, and this is mediated by AT1 receptors. The time course of this process and the long half-life of the accumulated Ang II support the contention that this Ang II has been internalized after its binding to the AT1 receptor, so that it is protected from rapid degradation by endothelial peptidases. The results of this study are in agreement with growing evidence of an important physiological role for internalized Ang II.
Key Words: angiotensin II • receptors, angiotensin • adrenal glands • endocytosis • heart • kidney
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