THE ROLE OF ALDEHYDE DEHYDROGRENASE 2 IN NITRATE TOLERANCE: INVESTIGATION OF LOW POTENCY NITRATES AND CROSS TOLERANCE
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Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat cardiovascular disease. They are prodrugs that require bioactivation for pharmacological activity. Currently, there are two proposed pathways of organic nitrate activation: a high-affinity pathway for high-potency nitrates (GTN and pentaerythrityl tetranitate) and a low-affinity pathway for low-potency nitrates (isosorbide dinitrate (ISDN) and isosorbide mononitrate). A major limitation in the utility of organic nitrates is the rapid onset of tolerance during chronic treatment. Inhibition of the enzymes responsible for bioactivation has been put forward as the major cause of tolerance, and aldehyde dehydrogenase 2 (ALDH2) has been proposed as the primary enzyme responsible for bioactivation in the high-affinity pathway. ALDH2 activity is decreased in GTN-tolerant tissues and it has been suggested that ALDH2 inactivation is the underlying cause of GTN tolerance. However, several aspects of this hypothesis are problematic. My objective was to develop an in vivo model of ISDN tolerance and to use this model to examine the effects of chronic ISDN treatment on ALDH2 activity and on organic nitrate-induced vasodilation. The hypothesis of my research is that the reduced potency of GTN caused by ISDN tolerance is mediated by a mechanism independent of ALDH2 inactivation. ISDN tolerance was induced in rats using an in vivo model in which animals were exposed to 0.8 mg/hr ISDN for 24-96 hr. ALDH2 activity was measured in liver mitochondrial fractions and tolerance was assessed in isolated aortic preparations. There was no inhibition of mitochondrial ALDH2 activity in ISDN-treated animals. However, chronic treatment with ISDN resulted in parallel rightward shifts of both the ISDN and GTN concentration-response curves, which increased with increased duration of exposure iii to ISDN. Concentration-response curves for acetylcholine (ACh), sodium nitroprusside (SNP), and diethylamine NONOate were unchanged in ISDN-treated animals. The model of chronic ISDN treatment results in cross tolerance to GTN but does not affect ALDH activity. The data presented in this study indicate no role for ALDH2 in the development of nitrate tolerance.