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Vascular and anti-platelet actions of 1,2- and 1,3-glyceryl dinitrate

Corresponding Author

Daniela Salvemini

The William Harvey Research Institute, St Bartholomew's Hospital Medical College, Charterhouse Square, London EC1M 6BQ

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.Search for more papers by this author

Alessandra Pistelli,

Alessandra Pistelli

The William Harvey Research Institute, St Bartholomew's Hospital Medical College, Charterhouse Square, London EC1M 6BQ

Department of Preclinical and Clinical Pharmacology ‘M. Aiazzi Mancini’, Viale G.B. Morgagni 65, 50134 Florence, Italy.

Search for more papers by this author

Erik Anggard,

Corresponding Author

Erik Anggard

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.Search for more papers by this author

Daniela Salvemini,

Corresponding Author

Daniela Salvemini

The William Harvey Research Institute, St Bartholomew's Hospital Medical College, Charterhouse Square, London EC1M 6BQ

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.Search for more papers by this author

Alessandra Pistelli,

Alessandra Pistelli

The William Harvey Research Institute, St Bartholomew's Hospital Medical College, Charterhouse Square, London EC1M 6BQ

Department of Preclinical and Clinical Pharmacology ‘M. Aiazzi Mancini’, Viale G.B. Morgagni 65, 50134 Florence, Italy.

Search for more papers by this author

Erik Anggard,

Corresponding Author

Erik Anggard

Monsanto Company, Department of Molecular Pharmacology, 800 North Lindbergh Boulevard, St Louis, Missouri 63167, U.S.A.Search for more papers by this author

First published: November 1993

https://doi.org/10.1111/j.1476-5381.1993.tb13903.x

Citations: 6

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Abstract

1
The aim of this study was to investigate whether two metabolites of glyceryl trinitrate (GTN), 1,2 and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) could account for the pharmacological effects of GTN. To this end the formation of nitric oxide (NO) from 1,2- and 1,3-GDN in the presence of bovine aortic smooth muscle cells (SMC) or endothelial cells (EC) was studied. The effects of various thiols on NO formation from these dinitrates was also evaluated.
2
1,2-GDN or 1,3-GDN (10⁻¹⁰–10⁻⁵ m) caused a dose-dependent relaxation of rabbit aortic strips denuded of endothelium and precontracted with phenylephrine. The dinitrates were less than one tenth as potent as GTN.
3
Incubation of 1,2-GDN or 1,3-GDN (75–2400 μm) with SMC for 30 min led to a concentration-dependent increase in nitrite (NO₂⁻) formation but this increase was less than that produced from GTN. Likewise incubation of 1,2-GDN or 1,3-GDN with N-acetylcysteine (NAC), glutathione (GSH) or thiosalicylic acid (TSA) (all at 1 mm) for 30 min at 37°C produced a concentration-dependent increase in NO₂⁻ formation.
4
Platelet aggregation induced by thrombin (40 mu ml⁻¹) was not modified by high concentrations of 1,2-GDN or 1,3-GDN (175–700 μm). However, aggregation was inhibited when platelets were exposed to 1,2-GDN or 1,3-GDN (700 μm) in the presence of SMC (0.24–1.92 × 10⁵ cells) or EC (0.8–3.2 × 10⁵ cells). These effects were abrogated by co-incubation with oxyhaemoglobin (OxyHb, 10 μm) indicating that they were due to NO release. The concentrations of the dinitrates required to inhibit platelet aggregation by 50% were about 15 times higher than for GTN in the presence of the same numbers of SMC or EC.
5
When NAC or TSA (both at 0.5 mm) were co-incubated with platelets for 3 min in the presence of 1,2-GDN or 1,3-GDN, a concentration-dependent inhibition of platelet aggregation was observed. These anti-platelet effects were abolished by co-incubation with OxyHb (10 μm). Glutathione had no potentiating effects.
6
Thus the dinitrate metabolites of GTN are metabolized to NO by SMC or EC and are acted upon by thiols to form NO at concentrations about 10 times higher than those of GTN. In vivo, after oral or intravenous GTN, GDN levels are reached which are more than 10 times higher than those of GTN. These data support the notion that part of the effects of GTN are due to the generation of NO from 1,2-GDN and 1,3-GDN by the cells of the vascular wall.

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Volume110, Issue3

November 1993

Pages 937-942

Vascular and anti-platelet actions of 1,2- and 1,3-glyceryl dinitrate

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Vascular and anti-platelet actions of 1,2- and 1,3-glyceryl dinitrate

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