Escape from tolerance of organic nitrate by induction of cytochrome P450

The mechanism of organic nitrate tolerance is poorly defined. We studied th e rat P450-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified P450 isoforms relationship between P450 expression and nitrate tol erance Mowing continuous infusion of organic nitrates in rats. The hypotens ive effect of an nitroglycerin (NTG) bolus injection was abolished in rats that had been previously provided a continuous 48 h infusion of NTG. This e ffect was accompanied by a gradual but marked decrease in plasma and urinar y nitrate levels following a peak at 18-24 h. Nitrate tolerance was reversi ble; the decline in the hypotensive effect and P450 levels observed after 2 d of continuous infusion was followed by restoration to control levels 2 d after cessation of the infusion. Similarly, the hypotensive action disappe ared in P450-depleted, and -inhibited rats. At 48 h after infusion. NTG-ind uced NO generation of the vessels increased in acetone (a P450 inducer) -pr etreated rats. The appearance and disappearance of P450 paralleled the conv ersion of organic nitrates to NO. Our observations indicate that nitrate to lerance is in large part the result of decreased P450 expression and activi ty. Interventions that maintain or increase P450 activity may be a strategy to provide relief from ischemic conditions in humans. (C) 2001 Elsevier Sc ience Inc.