Efonidipine Simultaneously Improves Blood Pressure, Endothelial Function, and Metabolic Parameters in Nondiabetic Patients With Hypertension

Abstract

Hypertension is characterized by endothelial dysfunction and frequently clusters with metabolic disorders that are characterized by insulin resistance (1,2). These comorbidities may be explained, in part, by reciprocal relationships between endothelial dysfunction and insulin resistance (1). By contrast with calcium channel blockers (CCBs), treatment of hypertension with ␤-blockers and diuretics is associated with a higher risk of type 2 diabetes (3). This advantage of CCBs may relate to specific mechanisms that target the vicious synergy between endothelial dysfunction and insulin resistance. CCBs activate nitric oxide (NO) synthase in vitro and enhance NO production in vivo (4). This may impact on the roles of adiponectin, leptin, and resistin to influence metabolic signals, inflammation, and atherosclerosis (5-7).Efonidipine hydrochloride is a 1,4-dihydropyridine-type CCB with longlasting vasodilator actions and little reflex tachycardia (8). Efonidipine improves endothelial function in patients with hypertension when compared with doses of nifedipine that result in comparable decreases in mean blood pressure (9). Therefore, we hypothesized that efonidipine therapy may simultaneously improve endothelial dysfunction, adipocytokine profiles, and other metabolic parameters in nondiabetic patients with hypertension. RESEARCH DESIGN ANDMETHODS -We evaluated effects of efonidipine in a randomized, doubleblind, placebo-controlled, crossover study. Thirty-nine hypertensive patients (systolic blood pressure [SBP] Ͻ180 mmHg and diastolic blood pressure [DBP] Ͻ110 mmHg) were considered eligible for this study. We excluded patients with severe hypertension, unstable angina, acute myocardial infarction, or renal insufficiency. None of our subjects were diabetic (based on history or criteria according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus [10]) or smokers. To minimize acute side effects, during an initial run-in period, study medication was titrated from 40 to 80 mg efonidipine upwards over a 2-week period if no hypot e n s i o n ( S B P Ͻ 1 0 0 m m H g ) o r hypertension (SBP Ͼ140 mmHg) was noted. After the run-in period, all patients underwent a 3-week washout period. At the end of the washout period, participants were randomly assigned to either 40 -80 mg efonidipine or placebo daily during 8 weeks. Patients were then crossed over to the second treatment arm on completion of the first treatment arm (without washout phase). The Green Cross Pharmaceutical company (Yongin, Korea) provided the identical placebo (purchased by investigators). One patient suffered from facial flushing and was withdrawn. Thus, data from 38 patients were analyzed. This study was approved by the Gil Hospital Institute Review Board.Blood samples were obtained at 8:00 A.M. following an overnight fast before and after each treatment period. Assays for plasma insulin, malondialdehyde, adiponectin, leptin, and resistin were performed in duplicate by immunoradiometric assay or by enzymel i n k e ...

Carotid cross-sectional wall area is significantly associated with serum leptin levels, independent of body mass index: the SABPA study

“…41 Angiotensin II also increases the production of ROS 42 and induces the release of the vasoconstrictor, endothelin-1. 43 Leptin also stimulates the secretion of inflammatory markers such as C-reactive protein 10 and interleukin-6 11 that are directly involved in the development of endothelial dysfunction and atherosclerosis. However, our finding was independent of ROS and C-reactive protein.…”

“…On the one hand, it induces vasodilation by promoting nitric oxide release in the endothelium, 7 but on the other hand, leptin increases sympathetic nerve activity 6 and promotes the release of vasoconstrictive substances, 8 which could contribute to obesity-related hypertension. Furthermore, leptin also increases the production of damaging reactive oxygen species (ROS) 9 and the secretion of inflammatory markers, 10,11 which contribute to atherosclerosis. Selective leptin resistance observed in obese animal models and patients with hyperleptinemia include resistance to leptin's metabolic actions; however, the stimulatory effect on the sympathetic nervous system remained intact.…”

Simvastatin Improves Flow-Mediated Dilation but Reduces Adiponectin Levels and Insulin Sensitivity in Hypercholesterolemic Patients

“…The Quantitative I n s u l i n -S e n s i t i v i t y C h e c k I n d e x (QUICKI), a surrogate index of insulin sensitivity based on fasting glucose and insulin levels, was calculated as follows (insulin is expressed in microunits per milliliter and glucose in milligrams per deciliter): QUICKI ϭ 1/[log(insulin) ϩ log(glucose)] (20). Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (ATL-Philips, Bothell, WA) equipped with a 10 MHz linear-array transducer, based on a previously published technique (15)(16)(17)(18)(19).…”

“…Assays for lipids, glucose, and plasma adiponectin were performed in duplicate by ELISA (R&D Systems, Minneapolis, MN) for high-sensitivity C-reactive protein (CRP) levels by latex agglutination [CRP-Latex(II); Denka-Seiken, Tokyo, Japan], and assays for plasma insulin levels were performed by immunoradiometric assay (INSULIN-RIABEADII; SRL, Tokyo, Japan) as described previously (15)(16)(17)(18)(19). The interassay and intra-assay coefficients of variation were Ͻ6%.…”

“…In humans, plasma levels of adiponectin are negatively correlated with adiposity and insulin resistance. We recently reported that fenofibrate, candesartan, or efonidipine increases adiponectin levels and insulin sensitivity in patients without changing BMI (15)(16)(17). Thus, decreased levels of adiponectin may promote insulin resistance rather than simply serving as a biomarker for insulin sensitivity.…”