Our studies on angiotensin II receptor subtype 1A (AT1A) knockout mice define how endogenous receptors other than AT1Areceptors 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 AT1A/AT1Breceptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction. Mutant cells express AT1Breceptor mRNA but not that for the AT1Areceptor. In wild-type cells with AT1Apresent, Ang II (10-7mol/L) produces a characteristic rapid peak increase in [Ca2+]iof 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+]ichanges produced by Ang II were similar in cells that lacked AT1Areceptors but possessed AT1Breceptors. 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 AT1Areceptors suggests that non-AT1Areceptors 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 AT1Aand non-AT1Areceptors share common signal transduction pathways. The AT2receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2receptors and/or an absence of their linkage to [Ca2+]ipathways. The nonpeptide AT1receptor blocker losartan antagonizes Ang II-induced [Ca2+]iincreases in both cell groups, supporting mediation by native AT1Breceptors 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 AT1Breceptor. (Hypertension. 1998;31:1171-1177.)