Nitric oxide (NO) increments in exhaled air and changes in mean arterial pressure of anaesthetised rabbits were measured in order to study the NO generation from NO donors and tachyphylaxis in NO formation from nitroglycerin. Continuous infusions of isosorbide dinitrate, isosorbide-5-mononitrate and 3-morpholino-sydnonimine (SIN-1) evoked dose-dependent increases in exhaled NO, paralleled by decrements in mean arterial pressure. Repeated infusions of nitroglycerin resulted in attenuation (P<0.01) of the NO increase from a given dose. Concurrent infusions of isosorbide dinitrate, isosorbide-5-mononitrate or nitroglycerin reduced the amount of NO emanating from the bioconversion of a given dose nitroglycerin as measured in the expired air (P<0.01 for all drugs), indicating cross-tachyphylaxis. SIN-1 did not exhibit such cross-tachyphylaxis. In conclusion, measurements of exhaled NO can be a useful tool for exploration of nitrovasodilator tachyphylaxis. Cross-tachyphylaxis is only shared between some nitrovasodilators and is possibly not due to feedback from the generated NO.