In an attempt to elucidate whether there is a specific &agr;1-adrenergic receptor (&agr;1-AR) subtype involved in the genesis or maintenance of hypertension, the &agr;1D-AR subtype was evaluated in a model of salt-induced hypertension. The &agr;1D-AR–deficient (&agr;1D−/−) and control (&agr;1D+/+) mice (n=8 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intraarterial BP recording. The &agr;1D−/−mice had a significantly (P=0.0004) attenuated increase in BP response in this protocol (baseline 94.6±2.8 versus end point 107.4±4.5 mm Hg) compared with that of their wild-type counterparts (&agr;1D+/+), from a baseline 97.4±2.9 to an end point 139.4±4.5 mm Hg. Seven of 15 &agr;1D+/+mice died with edema, probably owing to renal failure, whereas 14 of 15 &agr;1D−/−mice were maintained for 35 days. Body weight, renal remnant weight, and residual renal function were similar in the 2 groups, whereas the values of plasma catecholamines (epinephrine, norepinephrine, and dopamine) were higher in &agr;1D+/+than in the &agr;1D−/−mice. These data suggest that &agr;1D-AR plays an important role in developing a high BP in response to dietary salt-loading, and that agents having selective &agr;1D-AR antagonism could have significant therapeutic potential in the treatment of hypertension.