Differences between nitrates: role of isosorbide 2-mononitrate.

Nitrates are used in the treatment of coronary heart disease and heart failure. The major drawback of their therapeutic use is the rapid development of tolerance. To investigate the effect of different nitrates on isolated rabbit hearts and aortic strips and the mechanism responsible for nitrate tolerance, using nitroglycerine (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN). Preparations were stimulated by different spasmogenic agents: KCl, angiotensin II and noradrenaline; nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. In another series of experiments, preparations were preincubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance. Nitrates produced the following maximum inhibitions on noradrenaline-induced contraction: NTG 90% (10(-6) mol/l), ISDN 60% (10(-4) mol/l), 5MN 55% (10(-4) mol/l) and 2MN 80% (10(-4) mol/l). After incubation a loss of vasodilator effect of nearly 50-60% was observed for all the nitrates considered except 2MN, whose loss of effect was significantly lower (36%). The cyclic guanosine monophosphate (cGMP) levels measured in the preparations were lower in the presence of 2MN than the other compounds. These data suggest that 2MN is able to induce a lower cGMP increase and less tolerance induction; since these observations seem to be correlated, the vasodilator effect of 2MN probably also involves mechanisms other than stimulation of guanylate cyclase.