IN-VIVO NITRATE TOLERANCE IS NOT ASSOCIATED WITH REDUCED BIOCONVERSION OF NITROGLYCERIN TO NITRIC-OXIDE

Background In vitro data suggest that reduced bioconversion of nitrogl ycerin (NTG) to nitric oxide (NO) contributes to the development of va scular and hemodynamic tolerance to NTG. We examined the in vivo valid ity of this hypothesis by measuring NTG-derived NO formation by in viv o spin-trapping of NO in vascular tissues from nitrate-tolerant and -n ontolerant rats. Methods and Results Five groups (n=6 to 8 each) of co nscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received eit her NTG vehicle (placebo, for 72 hours) or were left untreated (contro l). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypo tensive response to NTG in vivo and a reduced relaxation to NTG in iso lated aortic rings. NTG-derived NO formation in aorta, vena cava, hear t, and liver was measured as NOFe(DETC)(2) and NO-heme complexes forme d in vivo during 35 minutes combined with ex vivo cryogenic electron s pin resonance spectroscopy. NO formation was significantly (P<.05) inc reased in all tissues in nitrate-tolerant rats in an NTG dose-dependen t manner. Furthermore, the amount of NO formed from a bolus dose of NT G (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -non tolerant rats. Conclusions The results suggest that vascular and hemod ynamic NTG tolerance occurs despite high and similar rates of NO forma tion by NTG in tolerant and nontolerant target tissues. This finding i s compatible with the assumption that reduced biological activity of N O, rather than reduced bioconversion of NTG to NO, contributes to in v ivo development of nitrate tolerance.