Horm Metab Res 2016; 48(04): 257-262
DOI: 10.1055/s-0035-1565180
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Nifedipine Treatment for Hypertension is Associated with Enhanced Lipolytic Activity and Accelerated Clearance of Postprandial Lipemia

I. Grosskopf
1   The Bert Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel
,
A. Shaish
1   The Bert Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel
,
G. Charach
2   Department of Medicine, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
D. Harats
1   The Bert Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
,
Y. Kamari
1   The Bert Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel
3   Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
4   Hypertension Unit, Sheba Medical Center, Tel Hashomer, Tel Hashomer, Israel
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Publikationsverlauf

received 20. Mai 2015

accepted 16. Oktober 2015

Publikationsdatum:
05. Februar 2016 (online)

Abstract

Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPARγ. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70–75 years and 40–45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1 288±798 vs. 501±260 mg·dl−1·h, p<0.05), as was retinyl palmitate (surrogate marker for intestinally-derived cholesterol) in the chylomicrons (45.0±26.5 vs. 23.4±10.6 mg·l−1·h, p<0.05) and chylomicron remnant (15.2±5.4 vs. 11.7±4.7 mg·l−1·h, p<0.05) fractions. Importantly, while the level of chylomicron remnants in the group of younger subjects remained unchanged after treatment, nifedipine was associated with a significantly decreased chylomicron remnants retinyl palmitate in the elderly group, which dropped to levels, observed in younger subjects. This was accompanied by enhanced insulin sensitivity and augmented plasma lipolytic activity. The present work suggests that nifedipine has favorable metabolic effects that are beyond the known enhancement of insulin sensitivity. The improvement in postprandial lipidemia by nifedipine may add to its anti-atherogenic effects in hypertensive patients.

 
  • References

  • 1 Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298: 299-308
  • 2 Kim J, Nam KH, Kim SO, Choi JH, Kim HC, Yang SD, Kay JH, Ryu YH, Oh GT, Yoo SE. KR 31378 ameliorates atherosclerosis by blocking monocyte recruitment in hypercholestrolemic mice. FASEB J 2004; 18: 714-716
  • 3 Jackson KG, Poppitt SD, Minihane AM. Postprandial lipemia and cardiovascular disease risk: Interrelationships between dietary, physiological and genetic determinants. Atherosclerosis 2012; 220: 22-33
  • 4 Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109: 433-438
  • 5 Cohn JS, McNamara JR, Cohn SD, Ordovas JM, Schaefer EJ. Postprandial plasma lipoprotein changes in human subjects of different ages. J Lipid Res 1988; 29: 469-479
  • 6 Jackson KG, Knapper-Francis JM, Morgan LM, Webb DH, Zampelas A, Williams CM. Exaggerated postprandial lipaemia and lower post-heparin lipoprotein lipase activity in middle-aged men. Clin Sci (Lond) 2003; 105: 457-466
  • 7 Iaina A, Silverberg DS, Wollman Y, Judevics R, Baruch R, Levhar C, Peer G, Blum M, Grosskopf I, Weintraub MS. Postprandial intestinal-derived chylomicron and chylomicron remnants in essential hypertensive patients before and after prolonged captopril therapy. Am J Hypertens 1995; 8: 34-39
  • 8 Halter JB, Musi N, McFarland Horne F, Crandall JP, Goldberg A, Harkless L, Hazzard WR, Huang ES, Kirkman MS, Plutzky J, Schmader KE, Zieman S, High KP. Diabetes and cardiovascular disease in older adults: current status and future directions. Diabetes 2014; 63: 2578-2589
  • 9 Gong L, Zhang W, Zhu Y, Zhu J, Kong D, Pagé V, Ghadirian P, LeLorier J, Hamel P. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996; 14: 1237-1245
  • 10 Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366-372
  • 11 Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, Just H, Fox KAA, Pocock S, Clayton TC, Motro M, Parker JD, Bourassa MG, Dart AM, Hildebrandt P, Hjalmarson Å, Kragten JA, Molhoek GP, Otterstad J-E, Seabra-Gomes R, Soler-Soler J, Weber S. on behalf of the ACTION Investigators . Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364: 849-857
  • 12 Elliott HL, Meredith PA. Preferential benefits of nifedipine GITS in systolic hypertension and in combination with RAS blockade: further analysis of the ‘ACTION’ database in patients with angina. J Hum Hypertens 2011; 25: 63-70
  • 13 Sugiura T, Kondo T, Kureishi-Bando Y, Numaguchi Y, Yoshida O, Dohi Y, Kimura G, Ueda R, Rabelink TJ, Murohara T. Nifedipine improves endothelial function: role of endothelial progenitor cells. Hypertension 2008; 52: 491-498
  • 14 Ishii N, Matsumura T, Kinoshita H, Fukuda K, Motoshima H, Senokuchi T, Nakao S, Tsutsumi A, Kim-Mitsuyama S, Kawada T, Takeya M, Miyamura T, Nishikawa T, Araki E. Nifedipine induces peroxisome proliferator-activated receptor-gamma activation in macrophages and suppresses the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2010; 30: 1598-1605
  • 15 Olefsky JM, Saltiel AR. PPAR gamma and the treatment of insulin resistance. Trends Endocrinol Metab 2000; 11: 362-368
  • 16 Koyama Y, Kodama K, Suzuki M, Harano Y. Improvement of insulin sensitivity by a long-acting nifedipine preparation (nifedipine-CR) in patients with essential hypertension. Am J Hypertens 2002; 15: 927-931
  • 17 Raghavan VA. Insulin resistance and atherosclerosis. Heart Fail Clin 2012; 8: 575-587
  • 18 Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. Am J Hypertens 2001; 14: 241-247
  • 19 Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar S, Hamburger RJ, Fye C, Laksman R, Gottdiener J, Ramirez EA, Henderson WG. for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents . Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993; 328: 914-921
  • 20 Kuwajima I, Suzuki Y, Shimosawa T, Otsuka K, Kawamura H, Kuramoto K. Effect of nifedipine tablets on ambulatory blood pressure in patients aged less than 60 and greater than 65 years with systemic hypertension. Am J Cardiol 1991; 68: 1351-1356
  • 21 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Struijker Boudier HAJ, Zanchetti A. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105-1187
  • 22 Weintraub MS, Grosskopf I, Rassin T, Miller H, Charach G, Rotmensch HH, Lira M, Rubinstein A, Iaina A. Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years. BMJ 1996; 312: 935-939
  • 23 Nilsson-Ehle P, Schotz MC. A stable, radioactive substrate emulsion for assay of lipoprotein lipase. J Lipid Res 1976; 17: 536-541
  • 24 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462-1470
  • 25 Stančáková A, Javorsky M, Kuulasmaa T, Haffner SM, Kuusisto J, Laakso M. Changes in insulin sensitivity and insulin release in relation to glycemia and glucose tolerance in 6,414 Finnish men. Diabetes 2009; 58: 1212-1221
  • 26 Zhang X, Hintze TH. Amlodipine releases nitric oxide from canine coronary microvessels: an unexpected mechanism of action of a calcium channel-blocking agent. Circulation 1998; 97: 576-580
  • 27 Stepien O, Gogusev J, Zhu DL, Iouzalen L, Herembert T, Drueke TB, Pierre M. Amlodipine inhibition of serum-, thrombin-, or fibroblast growth factor-induced vascular smooth-muscle cell proliferation. J Cardiovasc Pharmacol 1998; 31: 786-793
  • 28 Bjorkbacka H. Atherosclerosis: cell biology and lipoproteins. Curr Opin Lipidol 2011; 22: 74-75
  • 29 Yu KC, Cooper AD. Postprandial lipoproteins and atherosclerosis. Front Biosci 2001; 6: D332-D354
  • 30 Wilhelm MG, Cooper AD. Induction of atherosclerosis by human chylomicron remnants: a hypothesis. J Atheroscler Thromb 2003; 10: 132-139
  • 31 Brunzell JD, Hazzard WR, Porte Jr D, Bierman EL. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest 1973; 52: 1578-1585
  • 32 Barzilai N, Ferrucci L. Insulin resistance and aging: a cause or a protective response?. J Gerontol A Biol Sci Med Sci 2012; 67: 1329-1331
  • 33 Semenkovich CF. Insulin resistance and atherosclerosis. J Clin Invest 2006; 116: 1813-1822