2. Academic Validation
  3. A common pathway of nitric oxide release from AZD3582 and glyceryl trinitrate

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

  • Eur J Pharm Sci. 2004 Feb;21(2-3):331-5. doi: 10.1016/j.ejps.2003.10.020.
Georg Berndt 1,  Nina Grosser,  Janet Hoogstraate,  Henning Schröder
Affiliations

Affiliation

  • 1 Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Street 4, 06099, Halle (Saale), Germany. schroeder@pharmazie.uni-halle.de
PMID: 14757506 DOI: 10.1016/j.ejps.2003.10.020
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 (1-30microM) in LLC-PK1 kidney epithelial cells. A 5h pretreatment with glyceryl tinitrate (GTN, 0.1-1microM) attenuated the cGMP response to a subsequent challenge with AZD3582 or GTN. Similarly, AZD3582 (10-30microM) 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.

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