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(Hypertension. 1998;31:1171-1177.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Angiotensin AT_1B Receptor Mediates Calcium Signaling in Vascular Smooth Muscle Cells of AT_1A Receptor–Deficient Mice

Zhiming Zhu; Sunny H. Zhang; Charlotte Wagner; Armin Kurtz; Nobuyo Maeda; Thomas Coffman; ; William J. Arendshorst

From the Departments of Physiology (Z.Z., W.J.A.) and Pathology (S.H.Z., N.M.), University of North Carolina at Chapel Hill; the Department of Medicine, Duke University, Durham, NC (T.C.), and the Institute of Physiology, University of Regensburg (Germany) (C.W., A.K.).

Abstract—Our studies on angiotensin II receptor subtype 1A (AT_1A) knockout mice define how endogenous receptors other than AT_1A receptors stimulate changes in cytosolic calcium concentration ([Ca²⁺]_i) in cultured aortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT_1A/AT_1B receptor mRNA as determined by semiquantitative reverse transcriptase–polymerase chain reaction. Mutant cells express AT_1B receptor mRNA but not that for the AT_1A receptor. In wild-type cells with AT_1A present, Ang II (10^-7 mol/L) produces a characteristic rapid peak increase in [Ca²⁺]_i of 150 to 180 nmol/L, followed by a plateau phase characterized by a sustained 70 to 80 nmol/L increase in [Ca²⁺]_i. An unexpected finding was that the magnitude and time-dependent pattern of [Ca²⁺]_i changes produced by Ang II were similar in cells that lacked AT_1A receptors but possessed AT_1B receptors. The response in mutant cells indicates effective coupling of an Ang II receptor to one or more second messenger systems. The similarity of response patterns between cells with and without AT_1A receptors suggests that non-AT_1A receptors are functionally linked to similar signal transduction pathways in mutant cells. The fact that mutant and wild-type cells exhibit similar patterns of calcium mobilization and entry supports the notion that AT_1A and non-AT_1A receptors share common signal transduction pathways. The AT₂ receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT₂ receptors and/or an absence of their linkage to [Ca²⁺]_i pathways. The nonpeptide AT₁ receptor blocker losartan antagonizes Ang II–induced [Ca²⁺]_i increases in both cell groups, supporting mediation by native AT_1B receptors and effective coupling of this subtype to second messenger systems leading to calcium entry and mobilization. Our results demonstrate that Ang II causes calcium signaling in AT_1A–deficient VSMCs that is mediated by an endogenous losartan-sensitive AT_1B receptor.

Key Words: muscle, smooth, vascular • angiotensin II • receptors, angiotensin • calcium channels • antagonists • losartan • fura 2

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