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.
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Research Article|
May 10 2013
Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction
Takanori Yasu;
Takanori Yasu
1
*Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan
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Mayumi Kobayashi;
Mayumi Kobayashi
*Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan
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Akiko Mutoh;
Akiko Mutoh
*Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan
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Ken Yamakawa;
Ken Yamakawa
*Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan
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Shin-ichi Momomura;
Shin-ichi Momomura
†Department of First Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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Shinichiro Ueda
*Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan
Correspondence: Professor Shinichiro Ueda (email blessyou@med.u-ryukyu.ac.jp).
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Publisher: Portland Press Ltd
Received:
June 12 2012
Revision Received:
March 25 2013
Accepted:
March 27 2013
Accepted Manuscript online:
March 27 2013
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 125 (5): 247–255.
Article history
Received:
June 12 2012
Revision Received:
March 25 2013
Accepted:
March 27 2013
Accepted Manuscript online:
March 27 2013
Citation
Takanori Yasu, Mayumi Kobayashi, Akiko Mutoh, Ken Yamakawa, Shin-ichi Momomura, Shinichiro Ueda; Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction. Clin Sci (Lond) 1 September 2013; 125 (5): 247–255. doi: https://doi.org/10.1042/CS20120311
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