TY - JOUR
T1 - A common pathway of nitric oxide release from AZD3582 and glyceryl trinitrate
AU - Berndt, Georg
AU - Grosser, Nina
AU - Hoogstraate, Janet
AU - Schröder, Henning
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
KW - AZD3582
KW - Glyceryl trinitrate
KW - Linsidomine
KW - Nitric oxide
KW - Nitric oxide donator
KW - cGMP
UR - http://www.scopus.com/inward/record.url?scp=0742269693&partnerID=8YFLogxK
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U2 - 10.1016/j.ejps.2003.10.020
DO - 10.1016/j.ejps.2003.10.020
M3 - Article
C2 - 14757506
AN - SCOPUS:0742269693
SN - 0928-0987
VL - 21
SP - 331
EP - 335
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 2-3
ER -