In Vivo Nitrate Tolerance Is Not Associated With Reduced Bioconversion of Nitroglycerin to Nitric Oxide

Author:

Laursen Jørn Bech1,Mu¨lsch Alexander1,Boesgaard Søren1,Mordvintcev Petr1,Trautner Simon1,Gruhn Nicolai1,Nielsen-Kudsk Jens Erik1,Busse Rudi1,Aldershvile Jan1

Affiliation:

1. Medical Department B, Division of Cardiology, Rigshospitalet, University of Copenhagen, Denmark, and Center of Physiology, Johann Wolfgang Goethe University Clinic, Frankfurt/Main, Germany.

Abstract

Background In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats. Methods and Results Five groups (n=6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC) 2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly ( P <.05) increased in all tissues in nitrate-tolerant rats in an NTG dose–dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats. Conclusions The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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