Influence of hypoxia on nitric oxide synthase activity and gene expression in children with congenital heart disease: A novel pathophysiological adaptive mechanism

Abstract

Background - Chronic hypoxia has been shown to modulate nitric oxide (NO) responses in different cell models, but the relationship between hypoxia and NO synthase (NOS) regulation in humans was not studied. We studied the relationship between endothelial and inducible NOS (eNOS and iNOS) activities and expression and chronic hypoxia in children with cyanotic and acyanotic congenital heart defects. Methods and Results - Right atrial tissue was excised from 18 patients during cardiac surgery. eNOS and iNOS activities were measured by conversion of L-[H3]arginine to L-[H3]citrulline. Gene expression of eNOS and iNOS was quantified by competitive reverse transcription-polymerase chain reaction. The eNOS activity and expression were significantly reduced in cyanotic hearts compared with acyanotic hearts: 0.38±0.14 versus 1.06±0.11 pmol · mg-1 · min-1 (P<0.0001) and 0.54±0.08 versus 0.80±0.10 relative optical density (ROD) of cDNA (P<0.0001), respectively. In contrast, iNOS activity and expression were significantly higher in cyanotic than in acyanotic children: 7.04±1.20 versus 4.17±1.10 pmol · mg-1 · min-1 (P<0.0001) and 2.55±0.11 versus 1.91±0.18 ROD of cDNA (P<0.0001), respectively. Conclusions - Hypoxia downregulates eNOS activity and gene expression in cardiac tissue from patients with cyanotic congenital heart defects. By contrast, iNOS activity and expression are increased in cyanotic children and may represent an alternative mechanism to counteract the effects of hypoxia in the cardiovascular system. Therefore, a novel adaptive mechanism during hypoxia is suggested.