A hindlimb preparation of 19 male rats was used to determine the responses to norepinephrine (NE) at different levels of hemodilution at a constant flow, at increased flow and maintained pressure, and after reversal of hemodilution. An initial series demonstrated that the preparation remained stable with unchanged blood pressure, plasma electrolytes, and blood gases; and had reproducible responses to NE throughout the experiment. Two levels of isovolumic hemodilution were achieved by blood/hetastarch exchanges equivalent to 1.5% and 3.0% body weight, which reduced hematocrit to 30.8 +/- 2% and 18.7 +/- 1.5%, respectively. Hemodilution reduced the perfusion pressure from 73.6 mmHg to 58.6 and 55.7 mmHg following 1.5% and 3.0% hemodilution, respectively. A dose-response relationship to NE (0.1, 0.3, 1.0 micrograms/kg) was obtained. The responses to NE were markedly reduced following both 1.5% and 3.0% hemodilution. Retransfusion of packed red blood cells increased the hematocrit from 21.1 +/- 2.2% during hemodilution to 41.2 +/- 2.1% (P less than .01). Concomitantly, perfusion pressure increased from 46.2 +/- 3.6 to 68.3 +/- 6.5 mmHg (P less than .001), close to prehemodilution levels (65.3 +/- 5.3 mmHg). Restoration of hematocrit levels restored responses to NE. In a third series, hemodilution was continued, but the blood flow was increased from 4.0 to 8.3 +/- 0.9 mL/min, and perfusion pressure returned to baseline values. This also restored the pressor responsiveness to NE to near normal.