Organic Nitrates and Tolerance in Cardiovascular Diseases: Effects of Isosorbide-2-Mononitrate Compared to Traditional Nitrates

Abstract

Nitrates are a cornerstone in the treatment of coronary heart disease and heart failure. Although they are widely used in clinical practice, their therapeutic value is partially compromised by the rapid development of tolerance. The effect of different nitrates, nitroglycerin (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN) and the mechanism responsible for nitrate tolerance were investigated on isolated rabbit hearts and aortic strips. Preparation was stimulated by different spasmogenic agents: KCl, angiotensin II (A) and noradrenaline (NA); nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. Nitrates produced the following maximum inhibitions on NA-induced contraction: NTG 90% (10–⁶ M), ISDN 60% (10^-4 M), 5MN 55% (10–⁴ M) and 2MN 80% (10–⁴ M). In another series of experiments, preparations were pre-incubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance. After incubation a loss of vasodilator effect of nearly 50–60% was observed for all the nitrates considered except 2MN, in which the loss of effect was significantly lower (36%). The cyclic GMP (cGMP) levels measured in the preparations were lower in the presence of 2MN than in the other compounds. These data suggest that 2MN is able to induce a lesser cGMP increase and a lesser tolerance induction; since these observations seem to be correlated the vasodilator effect of 2MN probably involves mechanisms other than guanylyl cyclase stimulation.