Sixteen healthy male subjects were investigated on four occasions when they received either placebo, 10 mg isosorbide dinitrate (ISDN), or 2.5 or 10 mg pirsidomine, a novel NO-donating drug. A constant-rate iv. infusion of a subsystemic dose (average 42 ng.min-1, SD 20.5) of noradrenaline in a dorsal hand vein was begun 1 h before drug treatment. It did not cause systemic changes but reduced the venous hand vein diameter by about 50%. This venoconstrictor response was approximately halved by 10 mg ISDN. Pirsidomine, in contrast, did not affect the in situ venoconstrictor responses to noradrenaline. ISDN and pirsidomine reduced systemic resting blood pressure. ISDN and 10 mg pirsidomine were approximately equipotent in reducing systolic blood pressure, both in terms of the duration and the extent of the effect (maximum average reduction of ISDN -6.7, 95% CI -10.3 to -3.0; and 10 mg pirsidomine -7.6, 95% CI -11.3 to -4.0 mmHg, respectively); 2.5 mg pirsidomine was less effective (-4.1, 95% CI -7.8 to -0.5). ISDN and 10 mg pirsidomine were also similarly effective in reducing diastolic blood pressure (ISDN -8.4 mmHg, 95% CI -10.5 to -6.2; 10 mg pirsidomine -6.0 mmHg, 95% CI -8.2 to -3.9; 2.5 mg pirsidomine -2.8 mmHg, 95% CI -5.0 to -0.6) but the effects of ISDN were longer lasting. Although similar with regard to their putative mechanism(s) of action and likely arterial/arteriolar effects, pirsidomine and ISDN seem to affect the venous vascular bed in distinctly different ways.