The effect of endothelin-1 (ET-1), in concentrations well below threshold and near physiologic levels, has been examined on vasoconstrictor responses to perivascular nerve stimulation and norepinephrine in rat isolated kidney, perfused through the renal artery with physiologic salt solution. A 60-min exposure to ET-1 (1, 10, and 100 pM) had little or no effect on the basal perfusion pressure but enhanced responses to nerve stimulation (4 Hz, 10-s train) by 123 +/- 12% (n = 6), 125 +/- 8% (n = 6), and 226 +/- 49% (n = 7) of the control response, respectively. Responses to nerve stimulation were consistent in the absence of ET-1. Vasoconstrictor responses induced by norepinephrine (30-300 pmol) increased with time in control experiments, but the increase was markedly greater in the presence of 10 and 100 pM ET-1. The vasoconstrictor responses caused by nerve stimulation and norepinephrine were greatly increased by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (NOLA, 100 microM). In the presence of NOLA, ET-1 (1 pM) enhanced the responses to nerve stimulation (1-8 Hz, 10-s trains) by a significantly greater amount than in the absence of NOLA, suggesting that the enhancement by ET-1 is suppressed by NO release. The responses to norepinephrine (3-100 pmol) were also enhanced by 1 pM ET-1 in the presence of NOLA. The data suggest that ET-1 in physiologically relevant concentrations may have a role in the modulation of vascular reactivity in the renal circulation.