Cardiovascular effects of the new nitric oxide synthase inhibitor (4-amino-tetrahydrobiopterin)

Abstract

The 4-amino analogue of tetrahydrobiopterin (4-ABH,) is a potent pterin site inhibitor of nitric oxide synthases (NOS). Although 4-ABH, 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, in isolated pig pulmonary and coronary arteries.

Endothelium-dependent relaxations of pig pulmonary and coronary artery strips to bradykinin or calcium ionophore As7 were inhibited by 4-ABH, in a concentration-dependent manner. Half-maximal inhibition was observed at 60-65 M (pulmonary artery) and 200-250 [M 4-ABH, (coronary artery). Pig coronary artery strips precontracted with 0.1 M 9,11-dideoxy-9,11•

methanoepoxy-prostaglandin F5, (U4sst9) showed a time-dependent

relaxation (monitored for up to 18 hours) upon incubation with 1 µgmJ-1 lipopolysaccharide (LPS). Addition of 10 M 4-ABH, I hour after LPS led to a pronounced inhibition of the LPS-triggered relaxation, whereas the pterin antagonist had no effect when given 4 hours after LPS.

incubation of pulmonary and coronary artery strips with 1 µgmJ-1 LPS attenuated contractile responses to norepinephrine (I M) and U4ssro (0.I M). This hyporeactivity of the blood vessels to vasoconstrictor agents was inhibited by 4-ABH, in a concentration-dependent manner [IC,, = 17.5 ± 5.9 M (pulmonary artery) and 20.7 ± 3 M (coronary artery)]. The effect of 0.1 mM 4-ABH, was antagonized by coincubation with 0.1 mM