{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T22:12:37Z","timestamp":1779919957487,"version":"3.53.1"},"reference-count":50,"publisher":"Portland Press Ltd.","issue":"5","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,9,1]]},"abstract":"<jats:p>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\u00a02 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\u00a0days 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-\u03baB (nuclear factor \u03baB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in\u00a0vitro. 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\u00a0vitro. 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.<\/jats:p>","DOI":"10.1042\/cs20120311","type":"journal-article","created":{"date-parts":[[2013,3,28]],"date-time":"2013-03-28T09:21:12Z","timestamp":1364462472000},"page":"247-255","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Dihydropyridine calcium channel blockers inhibit non-esterified-fatty-acid-induced endothelial and rheological dysfunction"],"prefix":"10.1042","volume":"125","author":[{"given":"Takanori","family":"Yasu","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Mutoh","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Yamakawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Momomura","sequence":"additional","affiliation":[{"name":"Department of First Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, University of the Ryukyus School of Medicine, Okinawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2013,5,10]]},"reference":[{"key":"2021113010285984000_B1","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1161\/01.ATV.17.1.64","article-title":"Differences in insulin suppression of free fatty acid levels by gender and glucose tolerance status. Relation to plasma triglyceride and apolipoprotein B concentrations. Insulin Resistance Atherosclerosis Study (IRAS) Investigators","volume":"17","author":"Laws","year":"1997","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113010285984000_B2","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1172\/JCI118709","article-title":"Obesity\/insulin resistance is associated with endothelial dysfunction: implications for syndrome of insulin resistance","volume":"97","author":"Steinberg","year":"1996","journal-title":"J. Clin. Invest."},{"key":"2021113010285984000_B3","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1172\/JCI119636","article-title":"Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation","volume":"100","author":"Steinberg","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2021113010285984000_B4","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1161\/01.ATV.20.6.1588","article-title":"High levels of nonesterfied fatty acids are associated with increased familial risk of cardiovascular disease","volume":"20","author":"Carlsson","year":"2000","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113010285984000_B5","first-page":"3622","article-title":"Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease","volume":"90","author":"Pilz","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113010285984000_B6","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1210\/jcem.87.6.8596","article-title":"FFA-induced endothelial dysfunction can be corrected by vitamin C","volume":"87","author":"Pleiner","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113010285984000_B7","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1161\/01.ATV.0000187465.55507.85","article-title":"Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans","volume":"25","author":"Watanabe","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021113010285984000_B8","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.2337\/diabetes.49.11.1939","article-title":"High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells","volume":"49","author":"Inoguchi","year":"2000","journal-title":"Diabetes"},{"key":"2021113010285984000_B9","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1007\/s001250051668","article-title":"Saturated non-esterified fatty acids stimulate de novo diacylglycerol synthesis and protein kinase C activity in cultured aortic smooth muscle cells","volume":"44","author":"Yu","year":"2001","journal-title":"Diabetologia"},{"key":"2021113010285984000_B10","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1161\/HYPERTENSIONAHA.110.153056","article-title":"FFA causes leukocyte activation and resultant endothelial dysfunction through enhanced angiotensin II production in mononuclear and polymorphonuclear cells","volume":"56","author":"Azekosi","year":"2010","journal-title":"Hypertension"},{"key":"2021113010285984000_B11","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1126\/science.1106830","article-title":"Myeloperoxidase, a leukocyte-derived vascular NO oxidase","volume":"296","author":"Eiserich","year":"2002","journal-title":"Science"},{"key":"2021113010285984000_B12","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/01.HYP.37.2.240","article-title":"Nifedipine increases endothelial nitric oxide bioavailability by antioxidative mechanisms","volume":"37","author":"Berkels","year":"2001","journal-title":"Hypertension"},{"key":"2021113010285984000_B13","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1161\/01.HYP.37.1.34","article-title":"Synergistic antihypertensive effects of nifedipine on endothelium: concurrent release of NO and scavenging of superoxide","volume":"37","author":"Brovkovych","year":"2001","journal-title":"Hypertension"},{"key":"2021113010285984000_B14","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1161\/01.CIR.0000021924.02006.BA","article-title":"Nifedipine indirectly upregulates superoxide dismutase expression in endothelial cells via vascular smooth muscle cell-dependent pathways","volume":"16","author":"Fukuo","year":"2002","journal-title":"Circulation"},{"key":"2021113010285984000_B15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.bbrc.2011.06.137","article-title":"Antioxidant and anti-inflammatory mechanisms of amlodipine action to improve endothelial cell dysfunction induced by irreversibly glycated LDL","volume":"411","author":"Toma","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021113010285984000_B16","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1291\/hypres.28.431","article-title":"Nifedipine enhances the cardioprotective effect of an angiotensin II receptor blocker in an experimental animal model of heart failure","volume":"28","author":"Okuda","year":"2005","journal-title":"Hypertens. Res."},{"key":"2021113010285984000_B17","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/S0021-9258(18)45965-0","article-title":"Calcium channel blockers nifedipine and diltiazem inhibit Ca2+ release from intracellular stores in neutrophils","volume":"267","author":"Rosales","year":"1992","journal-title":"J. Biol. Chem."},{"key":"2021113010285984000_B18","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1046\/j.1365-2362.1996.126286.x","article-title":"Inhibited neutrophil functions in patients treated with nifedipine but not with verapamil or diltiazem","volume":"26","author":"Levy","year":"1996","journal-title":"Eur. J. Clin. Invest."},{"key":"2021113010285984000_B19","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1042\/cs0910459","article-title":"Suppression of oxidant production by diltiazem, nifedipine and verapamil in human neutrophils","volume":"91","author":"Feng","year":"1996","journal-title":"Clin. Sci."},{"key":"2021113010285984000_B20","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.1016\/0006-2952(86)90613-1","article-title":"Calcium channel antagonist induced inhibition of superoxide production in human neutrophils. Mechanisms independent of antagonizing calcium influx","volume":"35","author":"Irita","year":"1986","journal-title":"Biochem. Pharmacol."},{"key":"2021113010285984000_B21","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1161\/01.CIR.0000046488.52939.BF","article-title":"Effect of nifedipine and cerivastatin on coronary endothelial function in patients with coronary artery disease: the ENCORE I Study (Evaluation of Nifedipine and Cerivastatin on Recovery of Coronary Endothelial Function)","volume":"107","author":"ENCORE Investigators","year":"2003","journal-title":"Circulation"},{"key":"2021113010285984000_B22","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0008-6363(98)00341-1","article-title":"Nifedipine improves endothelial function in hypercholesterolemia, independently of an effect on blood pressure or plasma lipids","volume":"42","author":"Verhaar","year":"1999","journal-title":"Cardiovasc. Res."},{"key":"2021113010285984000_B23","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1161\/01.HYP.37.3.943","article-title":"Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension","volume":"37","author":"Taddei","year":"2001","journal-title":"Hypertension"},{"key":"2021113010285984000_B24","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1161\/01.HYP.33.1.575","article-title":"Effect of treatment on flow-dependent vasodilation of the brachial artery in essential hypertension","volume":"3","author":"Muiesan","year":"1999","journal-title":"Hypertension"},{"key":"2021113010285984000_B25","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0140-6736(04)16980-8","article-title":"Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial","volume":"364","author":"Poole-Wilson","year":"2004","journal-title":"Lancet"},{"key":"2021113010285984000_B26","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1001\/jama.292.18.2217","article-title":"Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial","volume":"292","author":"Nissen","year":"2004","journal-title":"JAMA, J. Am. Med. Assoc."},{"key":"2021113010285984000_B27","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1291\/hypres.27.351","article-title":"Methodological validity and feasibility of NO clamp research in human resistance vessels","volume":"27","author":"Ueda","year":"2004","journal-title":"Hypertens. Res."},{"key":"2021113010285984000_B28","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/S0022-2275(20)39687-5","article-title":"Analysis of techniques to obtain plasma for measurement of levels of free fatty acids","volume":"34","author":"Zambon","year":"1993","journal-title":"J. Lipid Res."},{"key":"2021113010285984000_B29","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1093\/jn\/131.12.3208","article-title":"Bioavailability and antioxidant activity of some food supplements in men and women using the d-ROMs test as a marker of oxidative stress","volume":"131","author":"Cornelli","year":"2001","journal-title":"J. Nutr."},{"key":"2021113010285984000_B30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ijcard.2005.08.046","article-title":"Elevated hydroperoxide levels as a prognostic predictor of mortality in a cohort of patients with cardiovascular disease","volume":"110","author":"Vassalle","year":"2006","journal-title":"Int. J. Cardiol."},{"key":"2021113010285984000_B31","doi-asserted-by":"crossref","first-page":"IV-6","DOI":"10.1161\/01.CIR.0000133444.17867.56","article-title":"Established and emerging plasma biomarkers in the prediction of first atherothrombotic events","volume":"109","author":"Ridker","year":"2004","journal-title":"Circulation"},{"key":"2021113010285984000_B32","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1161\/01.RES.0000133677.77465.38","article-title":"Contribution of fluid shear response in leukocytes to hemodynamic resistance in the spontaneously hypertensive rat","volume":"95","author":"Fukuda","year":"2004","journal-title":"Circ. Res."},{"key":"2021113010285984000_B33","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1253\/circj.CJ-09-0758","article-title":"Effects of submaximal exercise on blood rheology and sympathetic nerve activity","volume":"74","author":"Ikeda","year":"2010","journal-title":"Circ. J."},{"key":"2021113010285984000_B34","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1253\/circj.CJ-08-0917","article-title":"Effects of pitavastatin on postprandial endothelial function, oxidative stress, and hemorheology in patients with stable angina pectoris","volume":"73","author":"Arao","year":"2009","journal-title":"Circ. J."},{"key":"2021113010285984000_B35","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1161\/CIRCULATIONAHA.105.590083","article-title":"Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase","volume":"113","author":"Baldus","year":"2006","journal-title":"Circulation"},{"key":"2021113010285984000_B36","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev.immunol.15.1.351","article-title":"Redox regulation of cellular activation","volume":"15","author":"Nakamura","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2021113010285984000_B37","doi-asserted-by":"crossref","first-page":"E13","DOI":"10.1161\/01.RES.86.1.e13","article-title":"Mechanisms for regulation of fluid shear stress response in circulating leukocytes","volume":"86","author":"Fukuda","year":"2000","journal-title":"Circ. Res."},{"key":"2021113010285984000_B38","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1097\/00005344-200211000-00006","article-title":"Nicorandil and leukocyte activation","volume":"40","author":"Yasu","year":"2002","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"2021113010285984000_B39","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1161\/HYPERTENSIONAHA.108.111914","article-title":"Nifedipine improves endothelialfunction: role of endothelial progenitor cells","volume":"52","author":"Sugiura","year":"2008","journal-title":"Hypertension"},{"key":"2021113010285984000_B40","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1291\/hypres.28.147","article-title":"Nifedipine-induced vascular endothelial growth factor secretion from coronary smooth muscle cells promotes endothelial tube formation via the kinase insert domain-containing receptor\/fetal liver kinase-1\/NO pathway","volume":"28","author":"Miura","year":"2005","journal-title":"Hypertens. Res."},{"key":"2021113010285984000_B41","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.cardiores.2006.04.013","article-title":"The calcium channel blocker amlodipine promotes the unclamping of eNOS from caveolin in endothelial cells","volume":"71","author":"Batova","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"2021113010285984000_B42","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1016\/j.bcp.2003.07.005","article-title":"A non-voltage-gated calcium channel with L-type characteristics activated by B cell receptor ligation","volume":"66","author":"Grafton","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"2021113010285984000_B43","doi-asserted-by":"crossref","first-page":"7297","DOI":"10.1074\/jbc.271.13.7297","article-title":"Anti-Ig-induced calcium influx in rat B lymphocytes mediated by cGMP through a dhydropyridine-sensitive channel","volume":"271","author":"Akha","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021113010285984000_B44","doi-asserted-by":"crossref","first-page":"46949","DOI":"10.1074\/jbc.M309268200","article-title":"Identification and functional characterization of voltage-dependent calcium channels in T lymphocytes","volume":"278","author":"Kotturi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021113010285984000_B45","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1046\/j.1523-1755.2003.00311.x","article-title":"Amlodipine reverses the elevation in [Ca2+]i and the impairment of phagocytosis in PMNLs of NIDDM patients","volume":"64","author":"Krol","year":"2003","journal-title":"Kidney Int."},{"key":"2021113010285984000_B46","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.bbrc.2006.02.173","article-title":"Simultaneous measurement of superoxide generation and intracellular Ca2+ concentration reveals the effect of extracellular Ca2+ on rapid and transient contents of superoxide generation in differentiated THP-1 cells","volume":"344","author":"Ishibashi","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021113010285984000_B47","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/ajh.2007.13","article-title":"Calcium channel blockers suppress cytokine-induced activation of human neutrophils","volume":"21","author":"Shima","year":"2008","journal-title":"Am. J. Hypertens."},{"key":"2021113010285984000_B48","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1096\/fj.00-0733fje","article-title":"Protein kinase C-mediated calcium entry dependent upon dihydropyridine sensitive channels: a T cell receptor-coupled signaling pathway involved in IL-4 synthesis","volume":"15","author":"Savignac","year":"2001","journal-title":"FASEB J."},{"key":"2021113010285984000_B49","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1182\/blood-2002-09-2785","article-title":"Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-\u03baB","volume":"102","author":"El Bekay","year":"2003","journal-title":"Blood"},{"key":"2021113010285984000_B50","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1016\/S0024-3205(00)00849-3","article-title":"Nifedipine inhibits activation of transcription factor NF-\u03baB","volume":"67","author":"Matsumori","year":"2000","journal-title":"Life Sci."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/125\/5\/247\/442423\/cs1250247.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/125\/5\/247\/442423\/cs1250247.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T11:09:58Z","timestamp":1638270598000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/125\/5\/247\/69158\/Dihydropyridine-calcium-channel-blockers-inhibit"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,5,10]]},"references-count":50,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2013,9,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20120311","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,5,10]]}}}