EFFECTS OF CHRONIC ORAL-ADMINISTRATION OF ISOSORBIDE DINITRATE ON IN-VITRO CONTRACTILITY OF RAT ARTERIAL SMOOTH-MUSCLE

In this study, we examined the effects of in vitro and in vivo treatme nt with isosorbide dinitrate (ISDN) on the in vitro response of isolat ed rat aorta. The in vitro treatment of isolated aorta with ISDN (100 mu M) for 2 hr had no effect on the ISDN-induced relaxation of norepin ephrine-induced contraction. In the aorta isolated from the rats treat ed with a high dose (90 mg/kg) of ISDN for 7-14 days, in contrast, the relaxant effect of ISDN was significantly reduced. However, the relax ant effect of sodium nitroprusside was only slightly attenuated by the treatment with a high dose of ISDN for 14 days; and the relaxant effe cts of 8-bromo-cGMP, levcromakalim and verapamil were unchanged. These results suggest that tolerance to ISDN was obtained only after the in vivo chronic treatment with a high dose of ISDN. ISDN may desensitize the nitric oxide-generating step rather than inactivate guanylate cyc lase or the downstream pathways.