A common pathway of nitric oxide release from AZD3582 and glyceryl trinitrate

Georg Berndt, Nina Grosser, Janet Hoogstraate, Henning Schröder

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

4-(Nitrooxy)-butyl-(S)-2-(6-methoxy-2-naphthyl)-propanoate (AZD3582) is a cyclooxygenase (COX)-inhibiting nitric oxide donator (CINOD). It donates nitric oxide (NO) in biological systems through as yet unidentified mechanisms. cGMP, a marker of intracellularly generated NO, was increased up to 27-fold over basal levels by AZD3582 (1-30 μM) in LLC-PK1 kidney epithelial cells. A 5 h pretreatment with glyceryl tinitrate (GTN, 0.1-1 μM) attenuated the cGMP response to a subsequent challenge with AZD3582 or GTN. Similarly, AZD3582 (10-30 μM) pretreatment reduced the increase in cGMP on subsequent incubation with AZD3582 or GTN. In contrast, cGMP stimulation by SIN-1, which releases NO independently of enzymatic catalysis, remained unimpaired in cells pretreated with GTN or AZD3582. Our results demonstrate that AZD3582 decreases the sensitivity of the guanylyl cyclase/cGMP system to GTN and vice versa. This suggests that bioactivation pathways for organic nitrates, which involve enzymatic catalysis, may be responsible for NO donation from AZD3582.

Original languageEnglish (US)
Pages (from-to)331-335
Number of pages5
JournalEuropean Journal of Pharmaceutical Sciences
Volume21
Issue number2-3
DOIs
StatePublished - Feb 2004

Keywords

  • AZD3582
  • Glyceryl trinitrate
  • Linsidomine
  • Nitric oxide
  • Nitric oxide donator
  • cGMP

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