Nitrate Tolerance Induced by Nicorandil or Nitroglycerin is Associated with Minimal Loss of Nicorandil Vasodilator Activity

Abstract

In the current study, the vasodilator and tolerance-inducing actions of a recently developed organic nitrate vasodilator, nicorandil, were compared to nitroglycerin (NTG) in an isolated coronary artery preparation. The order of potency for relaxing U46619-constricted bovine-isolated coronary artery rings was NTG > isosorbide dinitrate (ISDN) > nicorandil. NTG was ≤250-fold more potent than nicorandil (mean EC50 values for relaxation; 0.044 and 11.2 μM, respectively; n = 6–8). Coronary artery rings preexposed for 60 min to NTG (30 μM) were subsequently markedly less responsive to the relaxant effects of NTG (7.5-fold increase in mean EC50 value, 68.4% decrease in Emax; p < 0.001) and ISDN (14.1-fold increase in mean EC50 value; p < 0.001), although only marginally less responsive to nicorandil (1.75-fold increase in mean EC50 value; p < 0.05). Thus, the coronary artery relaxant actions of nicorandil were significantly less affected by NTG-induced tolerance than were the relaxant actions of the related organic nitrate compounds, NTG and ISDN. To compare the tolerance-inducing actions of NTG and nicorandil, the relaxant actions of a series of nitric oxide (NO)-containing vasodilators were determined in control coronary artery rings and in rings preexposed for 60 min to either 30 μM NTG or 5,000 μM nicorandil. Quantitatively, similar changes in coronary artery ring responsiveness were produced by tolerance induced by NTG and nicorandil; marked attenuation of responsiveness to NTG and to the nonnitrate compound 3-morpholinosydnonimine (SIN-1), but only marginal attenuation of responsiveness to nicorandil and NO. The results of the current study showed that although nicorandil had tolerance-inducing actions comparable to those of NTG, the vasodilator actions of nicorandil were only slightly attenuated by the development of nitrate tolerance. These properties of nicorandil may be useful in the maintenance of hemodynamic responsiveness during chronic therapy with nicorandil and/or NTG.