Effect of Low-Density Lipoprotein Cholesterol on Angiotensin II Sensitivity

Abstract

Abstract-Increased angiotensin II (Ang II) sensitivity predisposes to hypertension and plaque instability. Raised low-density lipoprotein cholesterol (LDL-c) may increase Ang II sensitivity, but evidence in humans for this effect of LDL-c is limited. In 28, healthy, nonsmoking subjects, aged 30Ϯ8 years, with familial hypercholesterolemia, we determined the difference in infusion rate of Ang II and norepinephrine required to increase systolic blood pressure by 20 mm Hg (Pd-20) after 4 weeks of placebo and fluvastatin 80 mg daily in a randomized, double-blind, placebocontrolled, crossover study. Before infusions were started, fasting blood samples were taken to measure lipids. After 4 weeks of placebo, the mean LDL-c concentration was 6.3Ϯ1.4 mmol/L. [2][3][4][5] Moreover, an AT 1 -receptor antagonist inhibited LDL oxidation and streak formation in hypercholesterolemic monkeys. 6 In vitro and animal data support the idea that raised LDL-c associates with increased AT 1 -receptor gene expression in vascular smooth muscle cells. 7,8 Evidence for a direct effect of raised LDL-c on the sensitivity to Ang II in humans is limited. In previous studies we analyzed older subjects with additional cardiovascular risk factors, like hypertension and the metabolic syndrome, that could explain the increased sensitivity to Ang II as well. 9 -11 Proof of a direct effect of LDL-c on Ang II sensitivity could have preventive implications. We hypothesized that raised LDL-c increases sensitivity to Ang II, and, conversely, lowering LDL-c levels should decrease this sensitivity.In the present randomized, double blind, placebo-controlled crossover study, the effect of fluvastatin on Ang II sensitivity was assessed in healthy, young subjects with familial hypercholesterolemia (FH). FH is a monogenetic disorder characterized by markedly raised LDL-c levels. Methods SubjectsWe used predefined criteria to recruit 30 healthy, young, nonsmoking FH subjects without signs of cardiovascular disease. The diagnosis FH was based on LDL-c above age-and sex-specific 95th percentiles during a cholesterol-lowering diet with triglycerides and HDL-cholesterol (HDL-c) within the normal limits and a molecular diagnosis or the presence of tendon xanthomas or hypercholesterolemia in Ն1 first-degree relative. 12 Exclusion criteria were secondary forms of hypercholesterolemia, hypertension, obesity, a history or signs of cardiovascular disease, smoking during the year before the trial, a history of alcohol or drug abuse, or noncompliance to treatment.To obtain normal reference values, we previously studied 10 untreated, healthy, normocholesterolemic volunteers (6 males) matched as group for age (28Ϯ11 years), blood pressure (123Ϯ10/75Ϯ10 mm Hg), and body mass (23.4Ϯ2.0 kg/m 2 ), who underwent an identical protocol as the subjects of the present study. 13 Their fasting values of LDL-c, high-density lipoprotein (HDL) cholesterol (HDL-c), triglycerides and glucose were, respectively, 2.2Ϯ0.7 mmol/L, 1.4Ϯ0.6 mmol/L, 0.9Ϯ 0.8 mmol/L, and 3.8Ϯ0.4 mmol/L. The study...

Augmentation Of The Renin–Angiotensin System By Hyper Cholesterolemia Promotes Vascular Diseases

“…Subsequently, reinfusion with Ang II attenuated the increased systolic blood pressure compared with that obtained in these patients prior to statin administration [27]. Administration of the HMG-CoA reductase inhibitor fluvastatin in patients with familial hypercholesterolemia also led to an attenuation of Ang II-induced increases in systolic blood pressure [28]. …”

MDR1 genotype-dependent regulation of the aldosterone system in humans

“…Angiotensin II doses were chosen from previously published studies, which demonstrated a dose-dependent increase in arterial pressure and serum aldosterone in patients infused with angiotensin II at 0.5-8 ng/kg/min [26]. A recent study demonstrated that baseline plasma angiotensin II was doubled after angiotensin II infusion at 2 ng/kg/min whereas plasma angiotensin II increased nine-fold after angiotensin II infusion at 4 ng/kg/min in healthy individuals [27]. A twofold increase above basal plasma angiotensin II was also observed as a physiological response during stress in healthy volunteers [28].…”

Glomerular filtration rate and blood pressure are unchanged by increased sodium intake in atorvastatin‐treated healthy men

“…In a study in rats, statin treatment reduced AVP, but the intake of sodium was not defined [19]. Our previous study showed that atorvastatin does not change ANP, BNP, Aldo, AVP, Ang II and PRC in healthy men in acute and shortterm studies [9], although plasma concentrations of Aldo, ANP, BNP and Ang II, but not PRC, were reduced in patients [20][21][22][23]. In the present study, Aldo and PRC were reduced after the addition of sodium to the diet, most likely secondary to expansion of the extracellular fluid volume.…”

“…It has not been clarified whether statins have an antihypertensive effect [13,23]. In a recent study of spontaneously hypertensive rats fed different diets, a reduction in BP was found only in the rats fed a highsalt diet, while those fed a low-salt or lipid-rich diet showed no modification of BP by statin treatment [5].…”