Clinical comparison of nitrates and sydnonimines.

Organic nitrates and the sydnominine-derivative, molsidomine, exhibit similar pharmacodynamic actions. Venous vasodilatation leads to a decrease in ventricular pressures and volumes and, consequently, to a reduction in myocardial oxygen requirement; coronary vasodilatation enhances myocardial oxygen supply to hypoperfused poststenotic regions. At the molecular level, relaxation of vascular smooth muscle is due to nitric oxide (NO) delivery; with nitrates, this is coupled to the presence of thiol groups, the depletion of which is considered the cause of nitrate tolerance. At least one further site in the nitrate bioconversion cascade, possibly at the level of NO generation appears to be involved in tolerance development, which may also affect the non-nitrate vasodilator SIN-1. Nitrate tolerance is a clinically relevant problem incurred with multiple daily doses or continuous nitrate administration which lead to nearly constant, high plasma concentrations. Effective long-term therapy with nitrates can only be carried out with an interval treatment which is associated with relatively low and substantially fluctuating plasma concentrations. In contrast, during long-term treatment with molsidomine, tolerance development is not a clinically-relevant problem, so that with multiple daily doses, an effect can be provided over 24 h. With regard to maximal anti-ischaemic and haemodynamic effects, organic nitrates and molsidomine are similar. Molsidomine represents an alternative to nitrate interval treatment, or, respectively can be used as an adjunct to interval treatment should it be necessary to bridge the therapeutic gap.