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 fail- ure. Although they are widely used in clinical practice, their therapeutic value is partially com- promised 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 mech- anism 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-in- duced 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 in- duction; since these observations seem to be correlated the vasodilator effect of 2MN probably in- volves mechanisms other than guanylyl cyclase stimulation. (Heart International 2007; 3: 112-21)