Effect of isosorbide dinitrate and its metabolites on rabbit atrial myocardial force-frequency relationships in vitro

Isosorbide dinitrate (ISDN) and its two mononitrate metabolites were studied for their effects on the force-frequency relationship of isolated rabbit left atrial preparations. ISDN (4.9 and 15 microgram/ml) (50-150 times maximum therapeutic plasma concentrations) produced no significant effect on the frequency-dependent changes in contractile force. A concentration of 90 micrograms/ml (approximately 900 times therapeutic concentrations) produced a depression of contractility normally observed at frequencies of 80-400 beats/min. The two mononitrate metabolites of ISDN (endo- and exo-nitratoisosorbide) (90 micrograms/ml and 450 micrograms/ml) failed to alter the normal-force-frequency relationship over the range of 10-400 beats/min. These concentrations are several thousand times greater than plasma levels achieved in man with therapeutic dosing of ISDN. The basic lack of effect of ISDN and its metabolites on this fundamental property of myocardial contractility under the test conditions suggests that their therapeutic action is not mediated through direct effects on myocardial excitation-contraction coupling mechanisms.