We examined the development of tolerance to nitroglycerin (glyceryl trinitrate; GTN) in the rat when isosorbide-5-mononitrate (ISMN) or GTN was continuously infused. Under pentobarbital anesthesia (60 mg/kg, i.p.), mean arterial blood pressure was measured via the left common carotid artery. Bolus injection of ISMN (0.25—250 mg/kg) and GTN (0.25 μg/kg—2.5 mg/kg) was made into the right external jugular vein. ISMN (2.5 mg/h/rat for 7 d), GTN (1.3 μg/h/rat for 7 d), or GTN (0.2 mg/h/rat for 3 d) was infused continuously using an osmotic pump embedded subcutaneously. Bolus injection of ISMN and GTN decreased arterial blood pressure in a dose-dependent manner. The hypotensive effect of ISMN was 2000 times less potent than that of GTN. The GTN-induced hypotensive effect was not affected after continuous infusion of ISMN, whereas it was attenuated after continuous infusion of GTN at either dose. Chronic treatment with ISMN does not induce GTN tolerance as easily as treatment with GTN.