Chronic in vivo administration of high-dose isosorbide dinitrate induces tolerance in rat aorta, likely by desensitizing the nitric oxide-generating step.
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Chronic in vivo ISDN induces tolerance in rat aorta unlike short-term in vitro exposure; extends mechanistic models but leaves open human relevance.
In this study, we examined the effects of in vitro and in vivo treatment with isosorbide dinitrate (ISDN) on the in vitro response of isolated rat aorta. The in vitro treatment of isolated aorta with ISDN (100 microM) for 2 hr had no effect on the ISDN-induced relaxation of norepinephrine-induced contraction. In the aorta isolated from the rats treated 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 relaxant effect of sodium nitroprusside was only slightly attenuated by the treatment with a high dose of ISDN for 14 days; and the relaxant effects 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 cyclase or the downstream pathways.
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Trongvanichnam et al. (1996) studied this question.
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