A common pathway of nitric oxide release from AZD3582 and glyceryl trinitrate.
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.
Berndt
Georg
G
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Street 4, 06099, Halle (Saale), Germany. schroeder@pharmazie.uni-halle.de
Grosser
Nina
N
Hoogstraate
Janet
J
Schröder
Henning
H
D000818:Animals; D006152:Cyclic GMP / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018374:LLC-PK1 Cells; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009281:Naphthalenes / Q000378:metabolism*; D009288:Naproxen / Q000494:pharmacology / Q000031:analogs & derivatives; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism* / Q000494:pharmacology; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine
D016861:Cyclooxygenase Inhibitors; D009281:Naphthalenes; D020030:Nitric Oxide Donors; C111751:naproxen-n-butyl nitrate; D009569:Nitric Oxide; D009288:Naproxen; C002385:linsidomine; D008981:Molsidomine; D005996:Nitroglycerin; D006152:Cyclic GMP