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Nitrate Tolerance: Comparison of Nicorandil, Isosorbide Dinitrate, and Nitroglycerin in Anesthetized Dogs

Development of tolerance to nicorandil (NCR), N-(2-hydroxyethyl)nicotinamide nitrate (ester), was compared with that to nitroglycerin (NTG) or isosorbide dinitrate (ISDN) in dogs. An intracoronary arterial (i.a.) injection of NCR (20 μg), ISDN (30 μg), or NTG (1 μg) caused coronary vasodilation. Development of tolerance (including cross-tolerance) was determined by examining whether the coronary vasodilating effect of i.a. injection of these drugs was attenuated by a 2-h infusion of NCR, ISDN, or NTG. The effect of i.a. injection of NCR was not affected by i.v. infusion of either NCR (10 μg/kg/min), ISDN (10 or 30 μg/kg/min), or NTG (1 or 3 μg/kg/min). The effects of i.a. injection of NTG and ISDN, however, were attenuated by the NTG or ISDN infusion, whereas they were unaffected by the NCR infusion. Additionally, the coronary vasodilating effect of NCR infusion (30 μg/kg/min, i.v.) was not attenuated by i.v. infusion of NTG (3 μg/kg/min) or ISDN (30 μg/kg/min). These results suggest that NCR does not produce tolerance, whereas NTG and ISDN do, and that there is no cross-tolerance between NCR and NTG, or ISDN in terms of the coronary vasodilating effect.