Modulation of the pharmacological actions of nitrovasodilators by methylene blue and pyocyanin

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Abstract
1 In superfused precontracted strips of rabbit aorta, methylene blue (MeB) or pyocyanin (Pyo, 1-hydroxy-5-methyl phenazinum betaine) at concentrations of 1–10 μm inhibited relaxations induced by endothelium-derived relaxing factor (EDRF), glyceryl trinitrate (GTN), S-nitroso-N-acetyl-penicillamine (SNAP) or 3-morpholino-sydnonimine (SIN-1). However, the vasorelaxant actions of sodium nitroprusside (NaNP) or sodium nitrite (NaNO2) were enhanced by MeB or Pyo. Oxyhaemoglobin (HbO2, 1 μm) inhibited the activities of EDRF and all of the nitrovasodilators studied. Vascular preparations were not relaxed by Pyo unless pretreated with NaNP (0.05–10 μm). 2 In bathed, precontracted rings of rabbit aorta, Pyo (10 μm) produced a shift to the left of the cumulative concentration-response curve for NaNP (0.01–10 μm). The rise in guanosine-3′:5′-cyclic monophosphate (cyclic GMP) content of aortic tissue was also enhanced. 3 The vasorelaxant potency of NaNP (30 μm) at pH 5–8 and at 37°C remained unchanged over 2.5 h while a solution of SNAP (30 μm) progressively lost its biological activity over 60 min. The in vitro degradation of the biological activity of SNAP was accelerated by MeB (150 μm) or Pyo (150 μm), whereas the vasorelaxant potency NaNP (30 μm) was doubled when incubated with MeB or Pyo. 4 In human platelet-rich plasma, MeB or Pyo (0.3–3.0 μm) uncovered an anti-aggregatory action of subthreshold concentrations of NaNP (4–8 μm). This was abrogated by HbO2 (10 μm). In contrast to NaNP the anti-aggregatory effect of SNAP (2–20 μm) was antagonized by MeB (10 μm), Pyo (10 μm) or HbO2 (10 μm). 5 We conclude that MeB or Pyo differ from HbO2 in their mode of interaction with nitrovasodilators. HbO2 scavenges nitric oxide that is released from all types of nitrovasodilators. MeB and Pyo exert a similar action towards organic nitrovasodilators (e.g. SNAP, SIN-1). However, the pharmacological actions of inorganic nitrovasodilators (e.g. NaNP or NaNO2) are potentiated by MeB and Pyo owing to facilitation of the intracellular release of nitric oxide from the inorganic nitrovasodilators.