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Horm Metab Res 2002; 34(9): 499-503
DOI: 10.1055/s-2002-34789
Original Clinical
© Georg Thieme Verlag Stuttgart · New York

Effects of Acute Administration of Doxazosin on Fasting and Postprandial Haemodynamics and Lipid Metabolism in Healthy Subjects

T.  J.  Ulahannan 1 , F.  Karpe 1 , S.  M.  Humphreys 1 , D.  R.  Matthews 1 , K.  N.  Frayn 1
  • 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Infirmary, Oxford, UK
Further Information

Publication History

Received: 15 January 2002

Accepted after revision: 15 May 2002

Publication Date:
17 October 2002 (online)

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Abstract

The selective α1-adrenoceptor antagonist doxazosin has apparently beneficial effects on insulin sensitivity and on plasma lipid concentrations. In order to understand these effects better, we investigated the acute effects of doxazosin on adipose tissue and forearm blood flow and on postprandial lipid metabolism in healthy subjects. Nine subjects were studied in a balanced, placebo-controlled design. Pulse rate, blood pressure, forearm and subcutaneous adipose tissue blood flow were measured before and for 6 h after a mixed meal, with concomitant measurements of blood metabolites and insulin. Doxazosin increased pulse rate (p = 0.02) and forearm blood flow (p < 0.01 in fasting state), and decreased vascular resistance in forearm (p < 0.05 for fasting values) and subcutaneous abdominal adipose tissue (p = 0.04). Fasting plasma non-esterified fatty acid concentrations were increased by 40 % (p < 0.05). No other metabolic effects were detected. The effects on adipose tissue vascular resistance and lipolysis (reflected in elevated non-esterified fatty acid concentrations) were unexpected, as these are usually considered to be mediated by the balance of α2- and β-adrenoceptor activity in humans. We conclude that α1-adrenoceptor activity may be more important in regulation of human lipid metabolism than previously recognized.

Key words

α1-Adrenoceptors - Adipose Tissue - Forearm - Blood Flow - Vascular Resistance - Non-Esterified Fatty Acids

References

  • 1 Andersson P E, Johansson J, Berne C, Lithell H. Effects of selective alpha 1 and beta 1-adrenoreceptor blockade on lipoprotein and carbohydrate metabolism in hypertensive subjects, with special emphasis on insulin sensitivity.  J Hum Hypertens. 1994;  8 219-226
    PubMedGoogle Scholar
  • 2 Andersson P E, Lithell H. Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men. Relationship to changes in skeletal muscle blood flow.  Am J Hypertens. 1996;  9 323-333
    CrossrefPubMedGoogle Scholar
  • 3 Grimm R HJ, Flack J M, Grandits G A, Elmer P J, Neaton J D, Cutler J A, Lewis C, McDonald R, Schoenberger J, Stamler J. Long-term effects on plasma lipids of diet and drugs to treat hypertension. Treatment of Mild Hypertension Study (TOMHS) Research Group.  J Am Med Assoc. 1996;  275 1549-1556
    CrossrefPubMedGoogle Scholar
  • 4 Maheux P, Facchini F, Jeppesen J, Greenfield M S, Clinkingbeard C, Chen Y D, Reaven G M. Changes in glucose, insulin, lipid, lipoprotein, and apoprotein concentrations and insulin action in doxazosin-treated patients with hypertension. Comparison between nondiabetic individuals and patients with non-insulin-dependent diabetes mellitus.  Am J Hypertens. 1994;  7 416-424
    PubMedGoogle Scholar
  • 5 Rabkin S W, Huff M W, Newman C, Sim D, Carruthers S G. Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.  Hypertension. 1994;  24 241-248
    PubMedGoogle Scholar
  • 6 Jeng J R, Sheu W H, Jeng C Y, Huang S H, Shieh S M. Effect of doxazosin on fibrinolysis in hypertensive patients with and without insulin resistance.  Am Heart J. 1996;  132 783-789
    CrossrefPubMedGoogle Scholar
  • 7 Clark M G, Colquhoun E Q, Rattigan S, Dora K A, Eldershaw T PD, Hall J L, Ye J. Vascular and endocrine control of muscle metabolism.  Am J Physiol. 1995;  268 E797-E812
    PubMedGoogle Scholar
  • 8 Samra J S, Simpson E J, Clark M L, Forster C D, Humphreys S M, Macdonald I A, Frayn K N. Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism.  Am J Physiol. 1996;  271 E834-E839
    PubMedGoogle Scholar
  • 9 Hagström-Toft E, Enoksson S, Moberg E, Bolinder J, Arner P. β-Adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo.  Am J Physiol. 1998;  275 E909-E916
    PubMedGoogle Scholar
  • 10 Simonsen L, Bülow J, Astrup A, Madsen J, Christensen N J. Diet-induced changes in subcutaneous adipose tissue blood flow in man: effect of ß-adrenoceptor inhibition.  Acta Physiol Scand. 1990;  139 341-346
    PubMedGoogle Scholar
  • 11 Samra J S, Frayn K N, Giddings J A, Clark M L, Macdonald I A. Modification and validation of a commercially available portable detector for measurement of adipose tissue blood flow.  Clin Physiol. 1995;  15 241-248
    PubMedGoogle Scholar
  • 12 Coppack S W, Evans R D, Fisher R M, Frayn K N, Gibbons G F, Humphreys S M, Kirk M J, Potts J L, Hockaday T DR. Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal.  Metabolism. 1992;  41 264-272
    CrossrefPubMedGoogle Scholar
  • 13 Summers L KM, Samra J S, Humphreys S M, Morris R J, Frayn K N. Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity.  Clin Sci. 1996;  91 679-683
    PubMedGoogle Scholar
  • 14 Hjemdahl P, Linde B. Influence of circulating NE and Epi on adipose tissue vascular resistance and lipolysis in humans.  Am J Physiol. 1983;  245 H447-H452
    PubMedGoogle Scholar
  • 15 Cosenzi A, Sacerdote A, Bocin E, Molino R, Mangiarotti M, Bellini G. Metabolic effects of atenolol and doxazosin in healthy volunteers during prolonged physical exercise.  J Cardiovasc Pharmacol. 1995;  25 142-146
    PubMedGoogle Scholar
  • 16 Arner P, Kriegholm E, Engfeldt P, Bolinder J. Adrenergic regulation of lipolysis in situ at rest and during exercise.  J Clin Invest. 1990;  85 893-898
    CrossrefPubMedGoogle Scholar
  • 17 Galitzky J, Lafontan M, Nordenström J, Arner P. Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue.  J Clin Invest. 1993;  91 1997-2003
    PubMedGoogle Scholar
  • 18 Hellström L, Blaak E, Hagström-Toft E. Gender differences in adrenergic regulation of lipid mobilization during exercise.  Int J Sports Med. 1996;  17 439-447
    PubMedGoogle Scholar
  • 19 Langin D, Lucas S, Lafontan M. Millennium fat-cell lipolysis reveals unsuspected novel tracks.  Horm Metab Res. 2000;  32 443-452
    PubMedGoogle Scholar
  • 20 Flechtner-Mors M, Jenkinson C P, Alt A, Adler G, Ditschuneit H H. In vivo α1-adrenergic lipolytic activity in subcutaneous adipose tissue of obese subjects.  J Pharmacol Exp Ther. 2002;  301 229-233
    CrossrefPubMedGoogle Scholar
  • 21 Ulahannan T J, Karpe F, Humphreys S M, Matthews D R, Frayn K N. Selective alpha-1 adrenoreceptor blockade alters free fatty acid and triglyceride metabolism with concomitant changes in adipose tissue and forearm blood flow.  Diab Med. 2000;  17 (Suppl. 1) 64
    CrossrefPubMedGoogle Scholar
  • 22 Greenfield A DM, Whitney R J, Mowbray J F. Methods for the investigation of peripheral blood flow.  Br Med Bull. 1963;  19 101-109
    PubMedGoogle Scholar
  • 23 Baron A D, Clark M G. Role of blood flow in the regulation of muscle glucose uptake.  Annu Rev Nutr. 1997;  17 487-499
    CrossrefPubMedGoogle Scholar
  • 24 Lafontan M, Berlan M. Fat cell adrenergic receptors and the control of white and brown fat cell function.  J Lipid Res. 1993;  34 1057-1091
    PubMedGoogle Scholar
  • 25 Kissebah A H, Alfarsi S, Adams P W, Seed M, Folkard J, Wynn V. Transport kinetics of plasma free fatty acid, very low density lipoprotein triglycerides and apoprotein in patients with endogenous hypertriglyceridaemia. Effects of 2,2-dimethyl, 5(2,5-xylyloxy) valeric acid therapy.  Atherosclerosis. 1976;  24 199-218
    PubMedGoogle Scholar
  • 26 Frayn K N, Coppack S W, Fielding B A, Humphreys S M. Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization.  Adv Enz Reg. 1995;  35 163-178
    PubMedGoogle Scholar
  • 27 Frayn K N, Shadid S, Hamlani R, Humphreys S M, Clark M L, Fielding B A, Boland O, Coppack S W. Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition.  Am J Physiol. 1994;  266 E308-E317
    PubMedGoogle Scholar
  • 28 Engeli S, Sharma A M. Role of adipose tissue for cardiovascular-renal regulation in health and disease.  Horm Metab Res. 2000;  32 485-499
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Skurk T, Lee Y M, Rohrig K, Hauner H. Effect of angiotensin peptides on PAI-1 expression and production in human adipocytes.  Horm Metab Res. 2001;  33 196-200
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Group A CR. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).  J Am Med Assoc. 2000;  283 1967-1975
    CrossrefPubMedGoogle Scholar
  • 31 Frayn K N, Williams C M, Arner P. Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases?.  Clin Sci. 1996;  90 243-253
    PubMedGoogle Scholar

Prof. K. N. Frayn

Oxford Lipid Metabolism Group

Radcliffe Infirmary · Oxford OX2 6HE · UK

Phone: + 44 (1865) 224 180

Fax: + 44 (1865) 224 652

Email: keith.frayn@oxlip.ox.ac.uk

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