THE ROLE OF ALDEHYDE DEHYDROGENASE 2 IN NITRATE TOLERANCE
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Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat myocardial ischemia and congestive heart failure. GTN is proposed to act as a prodrug that requires bioactivation for pharmacological activity. However, continuous administration results in tolerance development, limiting its clinical usefulness. Aldehyde dehydrogenase 2 (ALDH2) has been proposed to be the primary enzyme responsible for GTN bioactivation, and ALDH2 inactivation has been proposed as the sole basis of nitrate tolerance. In the present study, we utilized an in vivo GTN tolerance model to investigate the role of ALDH2 in GTN bioactivation and tolerance. We assessed changes in ALDH2 protein, mRNA and activity levels in rat blood vessels during chronic GTN exposure (0.4 mg/hr for 6, 12, 24 and 48 hr) in relation to changes in vasodilator responses to GTN. A time-dependent decrease in both ALDH2 expression and activity occurred (80% in tolerant veins and 30% in tolerant arteries after 48 hrs exposure to GTN), concomitant with decreased vasodilator responses to GTN. However, after a 24 hr drug-free period following 48 hr GTN exposure, the vasodilator responses to GTN had returned to control values, whereas ALDH2 expression and activity were still markedly depressed. The dissociation between reduced ALDH2 activity and expression, and the duration of the impaired vasodilator responses to GTN in nitrate-tolerant blood vessels, suggest factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance.