Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction

Abstract

Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro. Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro. These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca2+ channels may differ among cells.

ARDS following oesophagectomy: a comparison of two trials

“…Calcium channel blockade has been associated with immunomodulation, although mostly downregulating inflammatory processes. [24][25][26] It may be that dihydropyridine use is a marker of worse systemic disease and therefore perioperative risk, although we did not find an association with aspirin, beta-blockers or statins. It would be premature to recommend not using dihydropyridines in the perioperative period, but there is a need for further studies on the effects of concurrent medications on patients undergoing surgery.…”

Role of free fatty acids in endothelial dysfunction

“…This table shows the reported dietary nutrients/drugs that have been shown to be effective against FFAs-induced ED, and the potential mechanisms highlighted in these studies. Two differently-colored texts in the table have been used to highlight different studies on the same drug or the use of more than one study model used within the same articleDrug/dietary constituentEffects/relevant mechanismsNature of the studyω-3 PUFAs (EPA)AMPK/eNOS pathway ↑In vitro study on primary HUVECs [18]iNOS ↓EC apoptosis, Caspase-3,p53/MAPK, Bax ↓NADPH oxidase/ROS ↓NF-κB activation ↓ Astragalus membranaceus NO ↑Ex vivo study on rat aortic rings [134, 141]Endothelium-dependentvasodilation ↑NF-κB ↓Cyanidin-3-O-glucosideOxidative stress ↓In vitro study on primary HUVECs [131]NF-κB activation and adhesionmolecules ↓Nrf2/EpRE pathway ↑Dihydropyridine calcium channel blockers (Nifedipine and amlodipine)Forearm blood flow responses toClinical trial [128]ACh ↑Leucocyte activation ↓Oxidative stress ↓In vitro monocytic cells [128]NF-κB ↓TNF-α, IL-6 ↓In vitro study on HUVECs [131]IKKβ/NF-κβ phosphorylation ↓IRS-1 phosphorylation ↓NO production ↑L-carnitineEndothelium-dependent leg blood flow ↑Clinical trial [107]LosartanVasodilation ↑Clinical study [139]eNOS activity ↑IRS-1 phosphorylation ↓Study on rats [139]Olive oil polyphenolseNOS activity ↑In vitro study on ECV304 cells [102]ET-1 ↓PerindoprilVasodilation ↑Clinical study [141]SalidrosideeNOS activation, NO production ↑In vivo study on HFD-fed ApoE −/− mice [106]AMPK/PI3K/Akt/eNOS pathway,Cellular AMP/ATP ratio ↑Atherosclerotic lesion ↓Withaferin AROS, TNF-α, IL-6 ↓In vitro stu...…”

“…For example, dihydropyridine calcium channel blockers such as nifedipine and amlodipine possess preventive effects against FFAs-induced ED, leucocyte activation and oxidative stress as evidenced by studies in human subjects; by exploring the further mechanisms, through in vitro study, the authors showed a role of NF-κB in such mediation of FFAs-induced ED, and that the protective role of the drugs were through the suppression of NF-κB p65 phosphorylation [128]. A role of Withaferin A (WA), a steroidal lactone derived from Acnistus arborescens [129], against PA-induced insulin resistance and dysfunction of the endothelium has been shown, mediated through its anti-oxidant and anti-inflammatory properties [130].…”

Renin-Angiotensin System Inhibitors Can Prevent Intravenous Lipid Infusion-Induced Myocardial Microvascular Dysfunction and Leukocyte Activation

“…Adhesive leukocytes were defined as static leukocytes with a clear surface border on still images. [8][9][10] To determine the apparent relative viscosity of precapillary arteriolar whole blood and plasma, we measured the time required for 0.05 mL of whole blood and plasma to pass through BK 7-7-7 microchannels (7854-parallel, 7×7-μm equivalent cross-sections, 30 μm long; Kikuchi Microtechnology Co., Ltd. Ibaraki, Japan) under a constant vacuum of 30 cm H2O (2.94 kPa) after calibration according to the duration of saline passage through the channels. In a pilot study, microchannels became occluded at a frequency of <0.2% (by activated leukocytes or platelet aggregation) per 30 samples in 10 men even after lipid/heparin loading.…”

“…[7][8][9] Leukocytes are critical to modulating microvascular hemodynamics through transformation from resting to active states under conditions of inflammation or low shear stress, 10-12 such as a high-fat diet 13 and ischemia/ reperfusion. 14 Decreased leukocyte deformability and increased leukocyte adherence to postcapillary venular endothelium synergistically lead to increased capillary resistance, in part through increased blood viscosity.…”