ANGIOTENSIN AT(1B) RECEPTOR MEDIATES CALCIUM SIGNALING IN VASCULAR SMOOTH-MUSCLE CELLS OF AT(1A) RECEPTOR-DEFICIENT MICE

Our studies on angiotensin II receptor subtype 1A (AT(1A)) knockout mi ce define how endogenous receptors other than AT(1A)receptors stimulat e changes in cytosolic calcium concentration ([Ca2+](i)) in cultured a ortic vascular smooth muscle cells (VSMCs). Wild-type cells have a 1.7 ratio of AT(1A)/AT(1B) receptor mRNA as determined by semiquantitativ e reverse transcriptase-polymerase chain reaction. Mutant cells expres s AT(1B) receptor mRNA but not that for the AT(1A) receptor. In wild-t ype cells with AT(1A) present, Ang II (10(-7) mol/L) produces a charac teristic rapid peak increase in [Ca2+](i) of 150 to 180 nmol/L, follow ed by a plateau phase characterized by a sustained 70 to 80 nmol/L inc rease in [Ca2+](i). An unexpected finding was that the magnitude and t ime-dependent pattern of [Ca2+](i) changes produced by Ang II were sim ilar in cells that lacked AT(1A) receptors but possessed AT(1B) recept ors. The response in mutant cells indicates effective coupling of an A ng 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 c ommon signal transduction pathways. The AT(2) receptor ligands PD-1233 19 and CGP-42112 do not alter Ang II effects in either VSMC type, sugg esting a paucity of AT(2) receptors and/or an absence of their linkage to [Ca2+](i) pathways. The nonpeptide AT(1) receptor blocker losartan antagonizes Ang II-induced [Ca2+](i) increases in both cell groups, s upporting mediation by native AT(1B) receptors and effective coupling of this subtype to second messenger systems leading to calcium entry a nd mobilization. Our results demonstrate that Ang II causes calcium si gnaling in AT(1A)-deficient VSMCs that is mediated by an endogenous lo sartan-sensitive AT(1B) receptor.