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

Background-Chronic hypoxia has been shown to modulate nitric oxide (NO) res ponses in different cell models, but the relationship between hypoxia and N O synthase (NOS) regulation in humans was not studied. We studied the relat ionship between endothelial and inducible NOS (eNOS and iNOS) activities an d expression and chronic hypoxia in children with cyanotic and acyanotic co ngenital 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 -[H-3]arginine to L-[H-3]citrulline. Gene expression of eNOS and iNOS was q uantified by competitive reverse transcription-polymerase chain reaction. T he eNOS activity and expression were significantly reduced in cyanotic hear ts 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 optic al density (ROD) of cDNA (P<0.0001), respectively. In contrast, iNOS activi ty and expression were significantly higher in cyanotic than in acyanotic c hildren: 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 card iac tissue from patients with cyanotic congenital heart defects. By contras t, 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 hyp oxia is suggested.