Nitrates are commonly used for rapid relief of ischemia in the initial management of unstable angina. However, their optimal dosage, route of administration, and therapeutic goals have not been fully established. This study was conducted to determine the optimal dosage and mode of administration (intravenous bolus versus sublingual spray) of nitrates and the therapeutic goals of their use in the immediate management of unstable angina. In a single-center prospective trial, 72 consecutive patients with unstable angina accompanied by typical ST-segment depression on electrocardiogram were randomly assigned to receive isosorbide dinitrate either as repeated intravenous boluses or as sublingual sprays while being delivered to the hospital by a mobile intensive care unit. Optimal nitrate dosage was tailored to pain relief while monitoring mean blood pressure reduction to an optimal range (5% to 20%) without dosage restriction. The mean nitrate dosage needed for ischemia control during the first hour of treatment was 7.8 +/- 3.8 mg. Optimal blood pressure reduction was achieved by significantly more intravenously treated patients than sublingually treated patients (68% v 41%, P = .037). Intravenously treated patients also experienced a more pronounced therapeutic effect, as assessed by reduction in chest pain score (67% v 39%, P = .0004) and decrease in ST-segment depressions (57% v 27%, P = .004). These results show that higher doses of nitrates than previously recommended are required for ischemia control during the initial management of unstable angina. The use of repeated intravenous boluses is safe and more easily controlled and, therefore, more efficacious than sublingual sprays in inducing the maximal anti-ischemic effect while avoiding significant hypotension.