atrial-natriuretic-factor and Hypercholesterolemia

Lipid-apheresis (LA) is thought to improve microcirculation. However, limited data are available on the effects on peripheral microcirculation. We investigated upper limb microcirculation of 22 patients undergoing regular LA on a weekly basis before and after LA. Using standardized semiquantitative scales, we analyzed blood flow, vasomotor function, and erythrocyte aggregation by capillary microscopy. In addition, capillary blood flow in quiescence and under heat and cryo-stress was evaluated by photoplethysmographic and laser Doppler anemometry. Moreover, levels of vasoactive mediators adrenalin, noradrenalin, endothelin-1 (ET-1), atrial natriuretic peptide (ANP), asymmetrical dimethyl-arginine (ADMA), as well as total protein and fibrinogen were measured. We found a significant increase in blood flow, the number of perfused capillaries and an improvement of erythrocyte aggregation by capillary microscopy. Using laser Doppler anemometry, we were able to show that this increase was predominantly located in the superficial layer capillaries (Δ44.53 ± 135.81%, n.s.) and less so in deeper layer arterioles (Δ2.75 ± 24.84%, n.s.). Vascular response to heat and cryo stress was also improved after LA but failed to reach significance. LA significantly reduced levels of epinephrin (-33 ± 39.2%), ANP (-28.8 ± 20.2%), ADMA (-74.1 ± 23%), and fibrinogen (-45.4 ± 19.7%) when comparing before LA and after LA values. In summary, we found an improvement in the microcirculation of the upper limbs under LA, which may result from a decrease of vasoconstrictors, improvement of vasomotor function, and a decrease in blood viscosity or erythrocyte aggregation.

Topics: Adult; Aged; Arginine; Atrial Natriuretic Factor; Blood Component Removal; Blood Flow Velocity; Endothelin-1; Epinephrine; Erythrocyte Aggregation; Female; Fibrinogen; Hand; Humans; Hypercholesterolemia; Hyperlipoproteinemia Type II; Laser-Doppler Flowmetry; Lipids; Male; Microcirculation; Microscopic Angioscopy; Middle Aged; Norepinephrine; Photoplethysmography

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

Hypercholesterolemia and hypertension are frequently associated risk factors for cardiovascular diseases. The interactions between hypercholesterolemia and the regulatory mechanisms of blood pressure are poorly understood. In this study we investigated the effects of hypercholesterolemia on salt metabolism and its hormonal control mechanisms in spontaneously hypertensive rats (SHR). Six-week-old SHR were randomly assigned to either a high (1%) cholesterol diet or a matched regular diet for 6 weeks, followed by a 2-week dietary washout. A group of normotensive Wistar-Kyoto rats received the high cholesterol diet and was used as a control. Plasma cholesterol increased significantly (P < 0.001) in both cholesterol-fed SHR and Wistar-Kyoto rats. Blood pressure was unaffected by 6 weeks of a high cholesterol diet. Hypercholesterolemia caused a significant increase in aldosterone (by analysis of variance: F = 8.40; P < 0.01) associated with a significant decrease in corticosterone (F = 4.64; P < 0.05) in the SHR, but not in the normotensive rats. In addition, in the cholesterol-fed SHR, urinary sodium excretion was reduced (P < 0.01), and the urinary potassium/sodium ratio was increased (P < 0.01) compared to those in the remaining groups of rats. The hormonal and urinary differences between the hypertensive subgroups were not detectable after withdrawal of cholesterol. These results demonstrate that diet-induced hypercholesterolemia specifically promotes reversible mineralocorticoid accumulation and sodium retention in SHR.

Topics: Adrenal Cortex Hormones; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cholesterol, Dietary; Corticosterone; Hypercholesterolemia; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; Water-Electrolyte Balance