The present study was designed to study the functional properties of Angiotensin II (Ang II) binding sites in vascular smooth muscle cells in the Milan hypertensive rat (MHS), a model of low renin hypertension. Smooth muscle cells from MHS rats exhibited increased growth in culture in comparison with the Milan normotensive strain (MNS) as determined by population doubling times (24.5±2 and 34.8±2 hours, n=4, respectively). Hormone receptor number, evaluated by binding assays using [12SI]Ang II, showed no difference in either receptor number or affinity for both cell types. The functional responsiveness of Ang U receptors was evaluated by measuring the activation of phospholipase C, Na+-H+ exchange, and cytosolic Ca2+ levels. Phospholipase C activity was determined as tritium-labeled inositol trisphosphate and bisphosphate release before and after 15-second exposure to 10″7 M Ang II. Ang II-stimulated phospholipase C activity in MNS (p< 0.02) but not in MHS cells. Na+-H+ exchange was measured as the dimethylamiloride-sensitive nNa+ influx into acid-loaded vascular smooth muscle cells with and without 10″7 M Ang II. In MNS cells, Ang II significantly stimulated (/?< 0.001) antiporter activity but not in MHS cells, which showed a uniformly blunted response. MHS cells exhibited higher basal cytosolic Ca2+ levels than MNS cells, but Ca3+ rapidly increased in the presence of Ang II in MNS but not in MHS cells. Direct activation of phospholipase C by GTP-y-S in permeabilized cells indicated that both strains exhibited similar coupling levels by guanine-nucleotide binding proteins. In summary, cultured smooth muscle cells from MHS rats exhibit blunted phospholipase C, Na+-H+ exchange, and cytosolic Ca3+ responses to Ang II despite having the same number of Ang II receptors as MNS cells. This suggests that, in this model of low renin hypertension, Ang II receptor response is blunted during increased growth rates.