Inhibition of endotoxin-induced vascular hyporeactivity by 4-amino-tetrahydrobiopterin.

Abstract

The 4-amino analogue of tetrahydrobiopterin (4-ABH(4)) is a potent pterin-site inhibitor of nitric oxide synthases (NOS). Although 4-ABH(4) 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-ABH(4) 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-ABH(4) in a concentration-dependent manner. Half-maximal inhibition was observed at 60 - 65 microM (pulmonary artery) and 200 - 250 microM 4-ABH(4) (coronary artery). Pig coronary artery strips precontracted with 0.1 microM 9, 11-dideoxy-9, 11-methanoepoxy-prosta-glandin F(2alpha) (U46619) showed a time-dependent relaxation (monitored for up to 18 h) upon incubation with 1 microg ml(-1) lipopolysaccharide (LPS). Addition of 10 microM 4-ABH(4) 1 h after LPS led to a pronounced inhibition of the LPS-triggered relaxation, whereas the pterin antagonist had no effect when given> or =4 h after LPS. Incubation of pulmonary and coronary artery strips with 1 microg ml(-1) LPS attenuated contractile responses to norepinephrine (1 microM) and U46619 (0.1 microM). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4-ABH(4) in a concentration-dependent manner [IC(50)=17.5+/-5.9 microM (pulmonary artery) and 20.7+/-3 microM (coronary artery)]. The effect of 0.1 mM 4-ABH(4) was antagonized by coincubation with 0.1 mM sepiapterin, which is known to supply intracellular BH(4) via a salvage pathway. These results demonstrate that 4-ABH(4) 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.

• Authors: H D Gibraeil, P Dittrich, S Saleh, B Mayer
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 131 Issue 8 Pg. 1757-65 (Dec 2000) ISSN: 0007-1188 [Print] England
• PMID: 11139456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Enzyme Inhibitors
• Hydrazines
• Lipopolysaccharides
• Nitric Oxide Donors
• Nitrogen Oxides
• Pteridines
• Pterins
• Vasoconstrictor Agents
• 4-amino-tetrahydrobiopterin
• Nitroarginine
• Biopterin
• Calcimycin
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• 1,1-diethyl-2-hydroxy-2-nitrosohydrazine
• sepiapterin
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• sapropterin
• Bradykinin
• Norepinephrine

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Animals
• Biopterin (analogs & derivatives, metabolism, pharmacology)
• Bradykinin (pharmacology)
• Calcimycin (pharmacology)
• Coronary Vessels (drug effects, physiology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (physiology)
• Endotoxins (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Hydrazines (pharmacology)
• In Vitro Techniques
• Lipopolysaccharides (pharmacology)
• Nitric Oxide Donors (pharmacology)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type II
• Nitroarginine (pharmacology)
• Nitrogen Oxides
• Norepinephrine (pharmacology)
• Pteridines (pharmacology)
• Pterins
• Pulmonary Artery (drug effects, physiology)
• Swine
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)
• Vasodilation (drug effects)