atrial-natriuretic-factor and Hyperlipidemias

Left ventricular dysfunction (LVD) occurs with myocardial ischemia and coronary artery disease (CAD). The natriuretic peptide system has compensatory vasodilatory, natriuretic and paracrine effects on LVD and subsequent heart failure. The aim of this study was to investigate the relationship between natriuretic peptide polymorphisms and risk of LVD in CAD patients.. We recruited 747 consecutive Southern Han Chinese patients with angiographically confirmed CAD, 201 had a reduced left ventricle ejection fraction (LVEF ≤45%, LVD group) and 546 had a preserved left ventricle ejection fraction (LVEF >45%). The reduced and preserved LVEF groups were matched by gender and age. Taqman assays were performed to identify five polymorphisms in the NPPA-NPPB locus (rs5065, rs5063, rs632793, rs198388 and rs198389).. Single-locus analyses found no significant difference in the allele and genotype frequencies of the reduced and preserved LVEF group, even after adjusting for confounding factors. Subgroup analyses performed by hyperlipidemia (HLP) demonstrated 3 polymorphisms, rs632793 (OR = 0.31, 95% CI 0.1-0.93, P = 0.04), rs198388 (OR = 0.26, 95% CI 0.09-0.79, P = 0.02) and rs198389 (OR = 0.26, 95% CI 0.09-0.80, P = 0.02) were associated with the reduced risk of LVD. No CAD-susceptible haplotypes were identified. Multifactor dimensionality reduction analysis did not detect any gene-to-gene interactions among the five loci. Three loci (rs5063, rs632793 and rs198388) formed the best model with the maximum testing accuracy (39.89%) and cross-validation consistency (10/10).. Three NPPA-NPPB polymorphisms (rs632793, rs198388 and rs198389) were associated with reduced risk of LVD in CAD patients with HLP.

Topics: Aged; Asian People; Atrial Natriuretic Factor; Case-Control Studies; Chi-Square Distribution; China; Coronary Angiography; Coronary Artery Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Hyperlipidemias; Logistic Models; Male; Middle Aged; Multivariate Analysis; Natriuretic Peptide, Brain; Odds Ratio; Phenotype; Polymorphism, Genetic; Protective Factors; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Abnormal neurohormonal regulation of renal sodium handling plays an important role in obesity-associated hypertension. We investigated the effect of experimental obesity on renal response to atrial natriuretic peptide (ANP).. The effect of ANP was studied in three groups of rats: (1) lean controls, (2) animals made obese by a highly palatable diet, (3) rats treated with adipose tissue hormone, leptin, for 7 days to reproduce hyperleptinemia observed in obesity.. ANP administered at a dose of 50 pmol/kg min(-1) induced about a 3-fold lower increase in Na+ and cGMP excretion in obese and leptin-treated rats than in the control group. ANP decreased Na+,K+-ATPase activity in the renal medulla only in the control group. Natriuretic effect of exogenous cGMP was also impaired in obese and leptin-treated rats. In contrast, hydrolysis-resistant cGMP derivative, 8-bromo-cGMP exerted comparable natriuretic effects in all groups. Neutral endopeptidase inhibitor, phosphoramidon, and ANP clearance receptor antagonist, C-ANP, increased urinary ANP excretion in all groups to a similar level, but their natriuretic effect was impaired in obese and leptin-treated groups. A specific inhibitor of cGMP-degrading phosphodiesterase, zaprinast, had comparable natriuretic and Na+,K+-ATPase-lowering effects in all groups and restored normal sensitivity to ANP.. (1) Dietary-induced obesity is accompanied by impaired natriuretic effect of ANP, (2) ANP resistance in obesity may be accounted for by increased leptin level, (3) accelerated degradation of cGMP may contribute to ANP resistance associated with obesity and hyperleptinemia, suggesting that inhibiting cGMP-specific phosphodiesterases may be useful in the treatment of obesity-associated hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Resistance; Hyperlipidemias; Kidney; Male; Obesity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Rats; Rats, Wistar; Sodium

This study was undertaken to examine the alterations in vascular relaxation responsiveness to endothelium-dependent or -independent vasodilators, including atrial natriuretic peptide (ANP) and acetylcholine, in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits during the progression of the atherosclerotic plaque. WHHL rabbits were divided into two groups according to age: group 1, 6-11 months, and group 2, 12-18 months. The isolated thoracic aortas obtained from both normal (control) and WHHL rabbits were suspended in a bath containing oxygenated Krebs' buffer for recording of isometric force. The endothelium-dependent relaxation evoked by acetylcholine was reduced in group 1 WHHL rabbits and decreased progressively in proportion to the degree of atherosclerosis progression when compared with age-matched control rabbits. ANP-induced relaxation was not significantly decreased in group 1 WHHL rabbits. However, ANP-induced relaxation was markedly impaired in group 2 WHHL rabbits. Thoracic aortas with severe atherosclerosis were less sensitive to ANP, with a significant increase in the median effective dose, although maximum relaxation induced by ANP was not reduced. Accumulation of cyclic GMP induced by ANP and acetylcholine was markedly reduced in atherosclerotic arteries obtained from group 2 WHHL rabbits compared with control rabbits. Vascular relaxation elicited by nitroglycerin or isoproterenol was not significantly impaired in atherosclerotic arteries from either group 1 or group 2 WHHL rabbits. From these results, we suggest that ANP-induced cyclic GMP formation and vascular relaxation via particulate guanylate cyclase in vascular smooth muscle cells are impaired in severely atherosclerotic arteries.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Arteriosclerosis; Atrial Natriuretic Factor; Cholesterol; Cyclic GMP; Endothelium, Vascular; Female; Hyperlipidemias; Isoproterenol; Male; Nitroglycerin; Rabbits; Triglycerides; Vasodilation