Comparison of development of tolerance between nicorandil and nitroglycerin in anesthetized, open-chest dogs

Development of tolerance to nicorandil (NCR), N-(2-hydroxyethyl) nicotinamide nitrate (ester), was compared with that to nitroglycerin (NTG) in dogs. An intra-coronary arterial (i.a.) injection of NCR (30 micrograms) or NTG (3 micrograms) produced 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 hr-infusion of NCR or NTG. The effect of i.a. injection of NCR was not affected by either NCR infusion (10 micrograms/kg/min, i.v.) or NTG infusion (1 or 3 micrograms/kg/min, i.v.). The effect of i.a. injection of NTG, however, was attenuated by the NTG infusion, while it was not affected by the NCR infusion. Additionally, the coronary vasodilating effect of NCR infusion (30 micrograms/kg/min, i.v.) was not attenuated by NTG infusion (3 micrograms/kg/min, i.v.). These results suggest that NCR does not produce tolerance, whereas NTG does, and that there is no cross-tolerance between NCR and NTG in terms of the coronary vasodilating effect.