Nitrate tolerance is a clinical problem in patients with coronary artery disease and heart failure. Human internal mammary arteries and saphenous veins obtained intraoperatively were suspended in organ chambers, and isometric tension was measured. In the artery, nitroglycerin elicited a potent relaxation, which was significantly diminished after prolonged incubation with nitroglycerin (10(-6) M, 1 h). In contrast, no tolerance occurred in saphenous vein under the same conditions. However, incubation with 10(-5) M nitroglycerin also developed tolerance. Compared to nitroglycerin, the new cysteine-containing mononitrate SPM 5185 exhibited a lower sensitivity but comparable maximal relaxation in arteries and veins. In nitroglycerin-tolerant arteries and veins, SPM 5185 caused relaxations similar to those under control conditions. Our results show that in isolated blood vessels, vascular nitrate tolerance occurs more readily in the mammary artery than in the saphenous vein. SPM 5185 seems to be less prone to the development of tolerance, which may be advantageous during chronic nitrate therapy.