natriuretic-peptide--c-type and Hypercholesterolemia

Statins and angiotensin type 1 (AT1) receptor blockers reduce cardiovascular mortality and morbidity. In the Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress (EPAS) trial, impact of independent or combined statin and AT1 receptor blocker therapy on endothelial expression of anti-atherosclerotic and proatherosclerotic genes and endothelial function in arteries of patients with coronary artery disease were tested.. Sixty patients with stable coronary artery disease undergoing elective coronary artery bypass grafting (CABG) surgery were randomized 4 weeks before surgery to: (A) control without inhibition of renin-angiotensin system or statin; (B) statin (pravastatin 40 mg/d); (C) AT1 blockade (irbesartan 150 mg/d); or (D) combination of statin and AT1 blocker in same dosages. Primary end point was a priori therapy-dependent regulation of an anti-atherosclerotic endothelial expression quotient Q including mRNA expression (in arbitrary units measured by real-time polymerase chain reaction) of endothelial nitric oxide synthase and C-type natriuretic peptide, divided by expression of oxidized low-density lipoprotein receptor LOX-1 and NAD(P)H oxidase subunit gp91phox in left internal mammary arteries biopsies obtained by CABG surgery; 49 patients completed the study. Statin therapy increased lnQ from 3.2+/-0.4 to 4.4+/-0.4 significantly versus control. AT(1) blockade showed a trend to increase lnQ to 4.2+/-0.5. Combination of statin and AT1 blocker further increased lnQ to 5.1+/-0.6, but a putative interaction of both therapies in lnQ was not significant. Furthermore, preoperative therapy with statin, AT1 blocker and their combination improved endothelial function in internal mammary artery rings.. Statin and AT1 blocker therapy independently and in combination improve an anti-atherosclerotic endothelial expression quotient and endothelial function.

Topics: Angiotensin II Type 1 Receptor Blockers; Atherosclerosis; Biphenyl Compounds; Blood Pressure; Cholesterol; Cholesterol, LDL; Coronary Artery Bypass; Coronary Disease; Drug Therapy, Combination; Elective Surgical Procedures; Gene Expression Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Irbesartan; Mammary Arteries; Membrane Glycoproteins; Muscle, Smooth, Vascular; NADPH Oxidase 2; NADPH Oxidases; Natriuretic Peptide, C-Type; Nitric Oxide Synthase Type III; Oxidative Stress; Polymerase Chain Reaction; Pravastatin; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Scavenger Receptors, Class E; Tetrazoles

The natriuretic peptides, Brain Natriuretic Peptide (BNP), C-type Natriuretic Peptide (CNP), are mediators of cardiovascular homeostasis. The impairment of arterial ability to vasodilate, also known as endothelial dysfunction, represents the first stage of atherosclerotic damage and may be assessed as brachial flow mediated vasodilation (FMV) in human. Generally an altered brachial FMV is documented in association to several cardiovascular risk factors as hypercholesterolemia. Aim of the study was to evaluate the behaviour of BNP and CNP in hyperlipemia and the potential relationship to FMV.. Forty-four hyperlipemic patients (LDL-cholesterol > 130 mg/dl and/or triglycerides > 150, age 35-60 y) of both genders and 20 normolipemic patients, matched for age and sex were investigated.. Patients had lower values of brachial FMV in comparison to controls (3.9 +/- 3.5 vs 7.5 +/- 0.5%, p < 0.005), no differences were observed in BNP (4.6 +/- 4.6 vs 5.9 +/- 3.4 ng/mL, p = n.s) and CNP (4.1 +/- 5.8 vs 5.7 +/- 3.3 ng/mL, p = n.s). Univariate analysis showed a positive correlation between BNP and HDL-cholesterol values (r = 0.36, p = 0.001). In the multivariate analysis, LDL-cholesterol (beta = -0.57), HDL-cholesterol (beta = 0.26) and brachial artery diameter (beta = -0.33) were predictors of brachial FMV. The only predictive variable for CNP was HDL-cholesterol (beta = 0.37).. The present study suggested that natriuretic peptides, BNP and CNP, are not altered in patients affected by hypercholesterolemia. Nevertheless, the levels of HDL-cholesterol are strictly related to the values of CNP. This observation, in humans, adds another mechanism to the vascular control exerted by HDL.

Topics: Adult; Atherosclerosis; Blood Flow Velocity; Brachial Artery; Cholesterol, HDL; Cholesterol, LDL; Endothelium, Vascular; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Risk Factors; Statistics as Topic; Triglycerides; Vasodilation

Neutral endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter various functions of cells present in the arterial wall. Recently NEP has been found to exist in the vascular endothelium. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (candoxatril), an orally active NEP inhibitor (NEPI), on the development of atherosclerotic changes in high-cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks as follows: normal rabbit diet (Normal, n = 15), 1.5% cholesterol diet (Cholesterol, n = 15), or 1.5% cholesterol diet containing NEPI (20 mg.kg-1.d-1) (Cholesterol+NEPI, n = 15). At the end of the dietary period, NEPI treatment was found to suppress the surface area of the aorta covered by plaques (% surface area: Cholesterol, 59 +/- 6 versus Cholesterol+NEPI, 36 +/- 7, P < .01) and decreased contents of cholesterol and cholesterol esters in the aortas. NEPI also reduced plasma total cholesterol by 27% of Cholesterol rabbits (1781 +/- 130 mg/dL). The endothelial function, estimated by the endothelium-dependent relaxation of the isolated aortas in response to acetylcholine, was preserved in Cholesterol+NEPI rabbits compared with that in Cholesterol rabbits. NEP enzymatic activities in plasma and the particulate fraction of the homogenates from the aortas in Cholesterol rabbits were both increased, 3.1- and 3.9-fold, respectively, above those in Normal rabbits, but the activities in Cholesterol+NEPI rabbits were significantly lower than those in Cholesterol rabbits. UK73967, an active form of UK79300, or phosphoramidon partly reversed the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings from Cholesterol rabbits in response to exogenous additions of C-type natriuretic peptide (CNP) and substance P, which are NEP substrates known to exist endogenously in the vascular endothelium. The results suggest that the increased NEP activity plays a significant role in atherogenesis, and NEPIs might be therapeutically useful in the prevention of atherosclerosis. Reduction of plasma cholesterol and suppression of degradations in the arteries of endogenously released CNP, substance P, or possibly other kinins known to have anti-atherosclerotic actions may at least partially contribute to the inhibitory effects of NEPIs on atherosclerotic changes.

Topics: Administration, Oral; Animals; Aorta, Thoracic; Arteriosclerosis; Atrial Natriuretic Factor; Body Weight; Cholesterol, Dietary; Diet, Atherogenic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glycopeptides; Hemodynamics; Hypercholesterolemia; Indans; Lipids; Male; Natriuretic Peptide, C-Type; Neprilysin; Nitroprusside; Organ Culture Techniques; Propionates; Proteins; Rabbits; Substance P; Vasodilation