Tolerance to nitroglycerin induced by isosorbide-5-mononitrate infusion invivo

We examined the development of tolerance to nitroglycerin (glyceryl trinitr ate, GTN) in the rat when isosorbide-5-mononitrate (ISMN) or GTN was contin uously infused. Under pentobarbital anesthesia (60 mg/kg, i.p.), mean arter ial blood pressure was measured via the left common carotid artery. Bolus i njection of ISMN (0.25-250 mg/kg) and GTN (0.25 mug/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 mug/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 hypo tensive effect of ISMN was 2000 times less potent than that of GTN. The GTN -induced hypotensive effect was not affected after continuous infusion of I SMN, whereas it was attenuated after continuous infusion of GTN at either d ose. Chronic treatment with ISMN does not induce GTN tolerance as easily as treatment with GTN.