Article date: December 2000
By: Hanan D Gibraeil, Peter Dittrich, Samira Saleh, Bernd Mayer in Volume 131, Issue 8, pages 1757-1765
The 4‐amino analogue of tetrahydrobiopterin (4‐ABH4) is a potent pterin‐site inhibitor of nitric oxide synthases (NOS). Although 4‐ABH4 does not exhibit selectivity between purified NOS isoforms, a pronounced selectivity of the drug towards inducible NOS (iNOS) is apparent in intact cells. This work was carried out to investigate the potential iNOS selectivity of 4‐ABH4 in isolated pig pulmonary and coronary arteries.
Endothelium‐dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore A23187 were inhibited by 4‐ABH4 in a concentration‐dependent manner. Half‐maximal inhibition was observed at 60–65 μM (pulmonary artery) and 200–250 μM 4‐ABH4 (coronary artery).
Pig coronary artery strips precontracted with 0.1 μM 9, 11‐dideoxy‐9, 11‐methanoepoxy‐prosta‐glandin F2α (U46619) showed a time‐dependent relaxation (monitored for up to 18 h) upon incubation with 1 μg ml−1 lipopolysaccharide (LPS). Addition of 10 μM 4‐ABH4 1 h after LPS led to a pronounced inhibition of the LPS‐triggered relaxation, whereas the pterin antagonist had no effect when given4 h after LPS.
Incubation of pulmonary and coronary artery strips with 1 μg ml−1 LPS attenuated contractile responses to norepinephrine (1 μM) and U46619 (0.1 μM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4‐ABH4 in a concentration‐dependent manner [IC50=17.5±5.9 μM (pulmonary artery) and 20.7±3 μM (coronary artery)]. The effect of 0.1 mM 4‐ABH4 was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH4via a salvage pathway.
These results demonstrate that 4‐ABH4 is a fairly selective inhibitor of iNOS in an in vitro model of endotoxaemia, suggesting that this drug and/or related pterin‐site NOS inhibitors may be useful to increase blood pressure in severe infections associated with a loss of vascular responsiveness to constrictor agents caused by endotoxin‐triggered iNOS induction in the vasculature.
The 4‐amino analogue of tetrahydrobiopterin (4‐ABH4) is a potent pterin‐site inhibitor of nitric oxide synthases (NOS). Although 4‐ABH4 does not exhibit selectivity between purified NOS isoforms, a pronounced selectivity of the drug towards inducible NOS (iNOS) is apparent in intact cells. This work was carried out to investigate the potential iNOS selectivity of 4‐ABH4 in isolated pig pulmonary and coronary arteries.
Endothelium‐dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore A23187 were inhibited by 4‐ABH4 in a concentration‐dependent manner. Half‐maximal inhibition was observed at 60–65 μM (pulmonary artery) and 200–250 μM 4‐ABH4 (coronary artery).
Pig coronary artery strips precontracted with 0.1 μM 9, 11‐dideoxy‐9, 11‐methanoepoxy‐prosta‐glandin F2α (U46619) showed a time‐dependent relaxation (monitored for up to 18 h) upon incubation with 1 μg ml−1 lipopolysaccharide (LPS). Addition of 10 μM 4‐ABH4 1 h after LPS led to a pronounced inhibition of the LPS‐triggered relaxation, whereas the pterin antagonist had no effect when given4 h after LPS.
Incubation of pulmonary and coronary artery strips with 1 μg ml−1 LPS attenuated contractile responses to norepinephrine (1 μM) and U46619 (0.1 μM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4‐ABH4 in a concentration‐dependent manner [IC50=17.5±5.9 μM (pulmonary artery) and 20.7±3 μM (coronary artery)]. The effect of 0.1 mM 4‐ABH4 was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH4via a salvage pathway.
These results demonstrate that 4‐ABH4 is a fairly selective inhibitor of iNOS in an in vitro model of endotoxaemia, suggesting that this drug and/or related pterin‐site NOS inhibitors may be useful to increase blood pressure in severe infections associated with a loss of vascular responsiveness to constrictor agents caused by endotoxin‐triggered iNOS induction in the vasculature.
British Journal of Pharmacology (2000) 131, 1757–1765; doi:10.1038/sj.bjp.0703752
DOI: 10.1038/sj.bjp.0703752
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