RESUMO
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-[H(3)]arginine to L-[H(3)]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.
Assuntos
Cianose/enzimologia , Cardiopatias Congênitas/enzimologia , Hipóxia/enzimologia , Óxido Nítrico Sintase/metabolismo , Adaptação Fisiológica , Adolescente , Apêndice Atrial/enzimologia , Gasometria , Criança , Pré-Escolar , Cianose/etiologia , Regulação para Baixo , Feminino , Expressão Gênica , Átrios do Coração/enzimologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/cirurgia , Hemodinâmica , Humanos , Lactente , Recém-Nascido , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
One hundred and fifty patients with coronary artery disease (CAD) who refused bypass grafting were followed prospectively from 2 to 8 years. Mean age was 57 +/- 8 (standard deviation) years. Ejection fraction averaged 70 +/- 14%. Eight percent of patients had 1-vessel CAD and 92% had multiple-vessel CAD. Medical treatment included propranolol, nifedipine, isosorbide dinitrate, dipyridamole and aspirin. Annual mortality was 0% for 1- and 2-vessel CAD and 1.3% for left main equivalent disease, 3-vessel and left main CAD. Treatment significantly reduced the incidence of stable and unstable angina. Fifty-two patients (34%) had a second hemodynamic study 4.2 +/- 1.3 years after initial evaluation. Stenosis progression or new significant obstructions (greater than or equal to 70%) in previously normal coronary arteries occurred in 61% of 123 arteries studied, whereas new occlusions were observed in 12% of the arteries. Nonfatal acute myocardial infarction incidence was 8%. No significant changes occurred in ejection fraction. In conclusion, proper medical treatment in selected patients with advanced CAD but preserved ventricular function is associated with good long-term survival and remission of symptoms, although progression of coronary atherosclerosis does occur in some patients.