Angiotensin IV (Ang IV), an active Ang II fragment, has been shown to induce systemic and renal cortical effects by binding to AT₄ receptors and activating unique signaling transductions unrelated to classical AT₁ or AT₂ receptors. We tested whether Ang IV exerts systemic and renal cortical effects on blood pressure, renal microvascular smooth muscle cells (VSMC) and glomerular mesangial cells (MC), and, if so, whether AT₁ receptor-activated signaling is involved. In anesthetized rats, systemic infusion of Ang II, Ang III or Ang IV (0.01, 0.1 and 1.0 nmol/kg/min, i.v.) caused dose-dependent increases in mean arterial pressure (MAP) and decreases in renal cortical blood flow (CBF) (p < 0.01). Ang II also induced dose-dependent reductions in renal medullary blood flow (MBF) (p < 0.01), whereas Ang IV did not. Ang IV-increased MAP and decreased CBF were completely abolished by AT₁ receptor blockade with losartan (5 mg/kg, i.v.) (p < 0.05). When Ang IV (1 nmol/kg/min) was infused directly into the renal artery, CBF was reduced by more than 30% and the response was also blocked by losartan (p < 0.01). In the renal cortex, unlabeled Ang IV displaced ¹²⁵I-[Sar¹,Ile⁸]-Ang II binding, whereas unlabeled Ang II inhibited ¹²⁵I-Nle¹-Ang IV (AT₄) binding in a concentration-dependent manner (p < 0.01). In renal VSMCs, Ang IV (100 nM) increased [Ca²⁺]_i and the effect was blocked by losartan and U73122, a selective inhibitor of phospholipase C/IP₃/Ca²⁺ signaling (1 µM). In rat MCs, Ang IV (10 nM) induced mitogen-activated protein (MAP) kinase ERK1/2 phosphorylation via AT₁ receptor- and phospholipase C-activated signaling. These results suggest that at nanomolar concentrations, Ang IV can increase MAP and induce renal cortical vasoconstriction by interacting with AT₁ receptor-activated signaling.