Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension

Congenital heart disease associated with increased pulmonary blood flow pro duces pulmonary hypertension. To characterize vascular alterations in the n itric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4-6 wk of age, w e assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shun ted lambs relaxed similarly to exogenous NO (S-nitrosyl-acetyl-penicillamin e), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atria l natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast w ere blunted in PAs isolated from shunted lambs relative to controls. Inhibi tors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pre treatment of shunt PAs with the substrates L-arginine and sepiapterin, a pr ecursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxati ons. However, pretreatment with superoxide dismutase and catalase significa ntly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxat ion that is selective to PAs. The impaired relaxation may be mediated in pa rt by excess superoxide production.