Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 373, Issue 4, pp 245–258

Metabolic effects of antihypertensive agents: role of sympathoadrenal and renin-angiotensin systems



Reports of beneficial, neutral and adverse impacts of antihypertensive drug classes on glucose and lipid metabolism can be found in human data. Furthermore, mechanisms for these diverse effects are often speculative and controversial. Clinical trial data on the metabolic effects of antihypertensive agents are highly contradictory. Comparisons of clinical trials involving different agents are complicated by differences in the spectrum of metabolic disturbances that accompany hypertension in different groups of patients. Two physiological systems are predominant at the interface between metabolic and cardiovascular regulation: the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS). These two systems are major targets of antihypertensive drug actions, and also mediate many of the beneficial and adverse effects of antihypertensive agents on glucose and lipid metabolism. Thiazides and β-adrenergic antagonists can adversely affect glucose and lipid metabolism, which are frequently compromised in human essential hypertension, and increase the incidence of new cases of diabetes. Laboratory studies confirm these effects, and suggest that compensatory activation of the SNS and RAS may be one mechanism. Other antihypertensives directly targeting the SNS and RAS may have beneficial effects on glucose and lipid metabolism, and may prevent diabetes. Resolution of the controversies surrounding the metabolic effects of antihypertensive agents can only be resolved by further laboratory studies, in addition to controlled clinical trials.


Glucose Insulin resistance Obesity Triglycerides Cholesterol Hypertension Sympathetic nervous system Renin-angiotensin system Angiotensin receptor antagonists 


  1. Ahren B, Lundquist I (1987) Alpha-adrenoceptor blockade by phentolamine inhibits beta-adrenergically and cholinergically induced glucagon secretion in the mouse. Horm Metab Res 19:600–603PubMedGoogle Scholar
  2. Anichkov DA, Shostak NA, Schastnaya OV (2005) Comparison of rilmenidine and lisinopril on ambulatory blood pressure and plasma lipid and glucose levels in hypertensive women with metabolic syndrome. Curr Med Res Opin 21:113–119PubMedGoogle Scholar
  3. Antonaccio MJ, High J, DeForrest JM, Sybertz E (1986) Antihypertensive effects of 12 beta adrenoceptor antagonists in conscious spontaneously hypertensive rats: relationship to changes in plasma renin activity, heart rate and sympathetic nerve function. J Pharmacol Exp Ther 238:378–387PubMedGoogle Scholar
  4. Aoki VS, Brody MJ (1969) The effect of thiazide on the sympathetic nervous system of hypertensive rats. Arch Int Pharmacodyn Ther 177:423–434PubMedGoogle Scholar
  5. Asai T, Kushiro T, Fujita H, Kanmatsuse K (2005) Different effects on inhibition of cardiac hypertrophy in spontaneously hypertensive rats by monotherapy and combination therapy of adrenergic receptor antagonists and/or the angiotensin II type 1 receptor blocker under comparable blood pressure reduction. Hypertens Res 28:79–87PubMedGoogle Scholar
  6. Assimacopoulos-Jeannet FD, Blackmore PF, Exton JH (1982) Studies of the interaction between glucagon and alpha-adrenergic agonists in the control of hepatic glucose output. J Biol Chem 257:3759–3765PubMedGoogle Scholar
  7. Barbieri C, Ferrari C, Caldara R, Testori G, Dal Bo GA, Bertazzoni A (1980) Clonidine-induced hyperglycemia: evidence against a growth hormone-mediated effect. J Pharmacol Exp Ther 214:433–436PubMedGoogle Scholar
  8. Belahsen R, Deshaies Y (1993) Alpha-1 adrenergic blockade interacts with dietary carbohydrates on triacylglycerol metabolism in rats. J Nutr 123:520–528PubMedGoogle Scholar
  9. Bernobich E, De Angelis L, Lerin C, Bellini G (2002) The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications. Drugs 62:1295–1314PubMedGoogle Scholar
  10. Bjorkman O, Miles P, Wasserman D, Lickley L, Vranic M (1988) Regulation of glucose turnover during exercise in pancreatectomized, totally insulin-deficient dogs. Effects of beta-adrenergic blockade. J Clin Invest 81:1759–1767PubMedCrossRefGoogle Scholar
  11. Brandi LS, Santoro D, Natali A, Altomonte F, Baldi S, Frascerra S, Ferrannini E (1993) Insulin resistance of stress: sites and mechanisms. Clin Sci (Colch) 85:525–535Google Scholar
  12. Bray GA (2002) Sibutramine and blood pressure: a therapeutic dilemma. J Hum Hypertens 16:1–3PubMedGoogle Scholar
  13. Brors O, Lilleng R, Soyland K, Holm H (1987) Effect of acute potassium depletion and thiazide treatment on blood glucose in the normal rat. Res Commun Chem Pathol Pharmacol 58:277–280PubMedGoogle Scholar
  14. Bruss M, Bonisch H, Gothert M, Molderings GJ (2003) Molecular structure of the rabbit alpha(2A)-adrenoceptor: a contribution to the alpha(2A)-adrenoceptor versus I(1) imidazoline receptor controversy. N-S Arch Pharmacol 367:328–331Google Scholar
  15. Carlsson PO, Berne C, Jansson L (1998) Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia 41:127–133PubMedGoogle Scholar
  16. Carmen GY, Victor SM (2006) Signalling mechanisms regulating lipolysis. Cell Signal 18:401–408PubMedGoogle Scholar
  17. Chan SL, Mourtada M, Morgan NG (2001) Characterization of a KATP channel-independent pathway involved in potentiation of insulin secretion by efaroxan. Diabetes 50:340–347PubMedGoogle Scholar
  18. Chu CA, Sindelar DK, Neal DW, Cherrington AD (1996) Direct effects of catecholamines on hepatic glucose production in conscious dog are due to glycogenolysis. Am J Physiol 271:Google Scholar
  19. Chu CA, Sindelar DK, Neal DW, Allen EJ, Donahue EP, Cherrington AD (1997) Comparison of the direct and indirect effects of epinephrine on hepatic glucose production. J Clin Invest 99:1044–1056PubMedGoogle Scholar
  20. Chu CA, Sindelar DK, Igawa K, Sherck S, Neal DW, Emshwiller M, Cherrington AD (2000) The direct effects of catecholamines on hepatic glucose production occur via alpha(1)- and beta(2)-receptors in the dog. Am J Physiol Endocrinol Metab 279:E463–E473PubMedGoogle Scholar
  21. Chu KY, Lau T, Carlsson PO, Leung PS (2006) Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes 55:367–374PubMedGoogle Scholar
  22. Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M, Thone-Reineke C, Unger T, Kintscher U (2005) PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension 46:137–143PubMedGoogle Scholar
  23. D’Eletto RD, Javitt NB (1989) Effect of doxazosin on cholesterol synthesis in cell culture. J Cardiovasc Pharmacol 13 Suppl 2:S1–S4PubMedCrossRefGoogle Scholar
  24. Daae LN, Westlie L (1998) A 5-year comparison of doxazosin and atenolol in patients with mild-to-moderate hypertension: effects on blood pressure, serum lipids, and coronary heart disease risk. Blood Press 7:39–45PubMedGoogle Scholar
  25. Damas J, Garbacki N, Lefebvre PJ (2004) The kallikrein-kinin system, angiotensin converting enzyme inhibitors and insulin sensitivity. Diabetes Metab Res Rev 20:288–297PubMedGoogle Scholar
  26. De Champlain J (2005) Do angiotensin II antagonists provide benefits beyond blood pressure reduction? Adv Ther 22:117–136PubMedGoogle Scholar
  27. Del Rio G, Marrama P, Della C (1992) High urinary excretion of adrenaline in insulin dependent diabetic subjects. Horm Metab Res Suppl 26:106–108PubMedGoogle Scholar
  28. De Luca N, Izzo R, Fontana D, Iovino G, Argenziano L, Vecchione C, Trimarco B (2000) Haemodynamic and metabolic effects of rilmenidine in hypertensive patients with metabolic syndrome X. A double-blind parallel study versus amlodipine. J Hypertens 18:1515–1522PubMedGoogle Scholar
  29. Deshaies Y, Belahsen R (1993) Postprandial plasma triacylglycerols in rats under alpha 1-adrenergic blockade. Am J Physiol 264:E541–E547PubMedGoogle Scholar
  30. Di Filippo C, Lampa E, Tufariello E, Petronella P, Freda F, Capuano A, D’Amico M (2005) Effects of irbesartan on the growth and differentiation of adipocytes in obese zucker rats. Obes Res 13:1909–1914PubMedGoogle Scholar
  31. Ditullio NW, Cieslinski L, Matthews WD, Storer B (1984) Mechanisms involved in the hyperglycemic response induced by clonidine and other a2-adrenoceptor agonists. J Pharmacol Exp Ther 228:168–173PubMedGoogle Scholar
  32. Efendic S, Efanov AM, Berggren PO, Zaitsev SV (2002) Two generations of insulinotropic imidazoline compounds. Diabetes 51 Suppl 3:S448–S454PubMedGoogle Scholar
  33. Elfellah MS, Reid JL (1987) The role of skeletal muscle beta-adrenoreceptors in the regulation of plasma potassium. J Auton Pharmacol 7:175–184PubMedGoogle Scholar
  34. Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiera F, Sharma AM (2003) The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol 35:807–825PubMedGoogle Scholar
  35. Erlich Y, Rosenthal T (1995) Effect of angiotensin-converting enzyme inhibitors on fructose induced hypertension and hyperinsulinaemia in rats. Clin Exp Pharmacol Physiol Suppl 22:S347–S349PubMedGoogle Scholar
  36. Erlich Y, Rosenthal T (1998) Contribution of bradykinin to the beneficial effects of ramipril in the fructose-fed rat. J Cardiovasc Pharmacol 31:581–584PubMedGoogle Scholar
  37. Ernsberger P, Koletsky RJ, Collins LA, Bedol DL (1996) Sympathetic nervous system in salt-sensitive and obese hypertension: Amelioration of multiple abnormalities by a central sympatholytic agent. Cardiovasc Drugs Ther 10:275–282PubMedGoogle Scholar
  38. Ernsberger P, Friedman JE, Koletsky RJ (1997) The I(1)-imidazoline receptor: From binding site to therapeutic target in cardiovascular disease. J Hypertens 15 (Suppl. 1):S9–S23Google Scholar
  39. Ernsberger P, Koletsky RJ, Friedman JE (1998) Contribution of sympathetic nervous system overactivity to cardiovascular and metabolic disease. Rev Contemp Pharmacother 9:411–428Google Scholar
  40. Ernsberger P, Ishizuka T, Liu S, Farrell CJ, Bedol D, Koletsky RJ, Friedman JE (1999) Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB). J Pharmacol Exp Ther 288:139–147PubMedGoogle Scholar
  41. Exton JH (1987) Mechanisms of hormonal regulation of hepatic glucose metabolism. Diabetes Metab Rev 3:163–183PubMedCrossRefGoogle Scholar
  42. Facchini FS, Stoohs RA, Reaven GM (1996) Enhanced sympathetic nervous system activity. The linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am J Hypertens 9:1013–1017PubMedGoogle Scholar
  43. Fink GD (1997) Long-term sympatho-excitatory effect of angiotensin II: a mechanism of spontaneous and renovascular hypertension. Clin Exp Pharmacol Physiol 24:91–95PubMedGoogle Scholar
  44. Fisher SJ, Lekas MC, McCall RH, Shi ZQ, Giacca A, Vranic M (1996) Determinants of glucose turnover in the pathophysiology of diabetes: an in vivo analysis in diabetic dogs. Diabetes Metab 22:111–121PubMedGoogle Scholar
  45. Friedman JE, Ishizuka T, Liu S, Farrell CJ, Koletsky RJ, Bedol D, Ernsberger P (1998) Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive rats. Blood Press Suppl 3:32–39Google Scholar
  46. Furberg CD, Psaty BM, Pahor M, Alderman MH (2001) Clinical implications of recent findings from the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) and other studies of hypertension. Ann Intern Med 135:1074–1078PubMedGoogle Scholar
  47. Giugliano D, Torella R, Cacciapuoti F, Gentile S, Verza M, Varricchio M (1980) Impairment of insulin secretion in man by nifedipine. Eur J Clin Pharmacol 18:395–398PubMedGoogle Scholar
  48. Gletsu N, Doan TN, Cole J, Sutliff RL, Bernstein KE (2005) Angiotensin II-induced hypertension in mice caused an increase in insulin secretion. Vascul Pharmacol 42:83–92PubMedGoogle Scholar
  49. Goyal RK (1999) Hyperinsulinemia and insulin resistance in hypertension: differential effects of antihypertensive agents. Clin Exp Hypertens 21:167–179PubMedCrossRefGoogle Scholar
  50. Granneman JG, Li P, Zhu Z, Lu Y (2005) Metabolic and cellular plasticity in white adipose tissue I: effects of beta3-adrenergic receptor activation. Am J Physiol Endocrinol Metab 289:E608–E616PubMedGoogle Scholar
  51. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL (2000) Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 342:905–912PubMedGoogle Scholar
  52. Guthrie GP Jr, Miller RE, Kotchen TA, Koenig SH (1983) Clonidine in patients with diabetes and mild hypertension. Clin Pharmacol Ther 34:713–717PubMedCrossRefGoogle Scholar
  53. Haenni A, Lithell H (1999) Moxonidine improves insulin sensitivity in insulin-resistant hypertensives. J Hypertens 17 Suppl 3:S29–S35Google Scholar
  54. Haffner SM (1997) Epidemiology of hypertension and insulin resistance syndrome. J Hypertens Suppl 15:S25–S30PubMedGoogle Scholar
  55. Henriksen EJ, Jacob S (1995) Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats. Metabolism 44:267–272PubMedGoogle Scholar
  56. Hirose H, Maruyama H, Itoh K, Koyama K, Kido K, Saruta T (1992) Alpha-2 adrenergic agonism stimulates islet glucagon release from perfused rat pancreas: Possible involvement of alpha- 2A adrenergic receptor subtype. Acta Endocrinol (Copenh) 127:279–283Google Scholar
  57. Holtzman E, Rosenthal T, Goldbourt U, Segal P (1987) Do beta-blockers alter lipids and what are the consequences? J Cardiovasc Pharmacol 10 Suppl 2:S86–S92PubMedGoogle Scholar
  58. Hsieh PS, Tai YH, Loh CH, Shih KC, Cheng WT, Chu CH (2005) Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. Metabolism 54:157–164PubMedGoogle Scholar
  59. Iaccarino G, Trimarco V, Lanni F, Cipolletta E, Izzo R, Arcucci O, De Luca N, Di Renzo G (2005) beta-Blockade and increased dyslipidemia in patients bearing Glu27 variant of beta2 adrenergic receptor gene. Pharmacogenomics J 5:292–297PubMedGoogle Scholar
  60. Izzo JL Jr, Black HR (2003) Hypertension Primer. Lippincott, Williams & Wilkins, DallasGoogle Scholar
  61. Jacob S, Balletshofer B, Henriksen EJ, Volk A, Mehnert B, Loblein K, Haring HU, Rett K (1999a) Beta-blocking agents in patients with insulin resistance: effects of vasodilating beta-blockers. Blood Press 8:261–268PubMedGoogle Scholar
  62. Jacob S, Fogt DL, Dietze GJ, Henriksen EJ (1999b) The beta2-adrenergic modulator celiprolol reduces insulin resistance in obese Zucker rats. Life Sci 64:2071–2079PubMedGoogle Scholar
  63. Jacob S, Klimm HJ, Rett K, Helsberg K, Haring HU, Godicke J (2004) Effects of moxonidine vs. metoprolol on blood pressure and metabolic control in hypertensive subjects with type 2 diabetes. Exp Clin Endocrinol Diabetes 112:315–322PubMedGoogle Scholar
  64. Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO (1993) Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 21:618–623PubMedGoogle Scholar
  65. Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME (2005) Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens 23:463–473PubMedCrossRefGoogle Scholar
  66. Jansen H, Lammers R, Baggen MG, Penders JM, Birkenhager JC (1989) Inhibition of hepatic cholesterol synthesis by the alpha 1-adrenoceptor blocker doxazosin in the hypercholesterolemic golden hamster. Life Sci 44:1013–1017PubMedGoogle Scholar
  67. Julius S (1995) The defense reaction: A common denominator of coronary risk and blood pressure in neurogenic hypertension. Clin Exp Hypertens 17:375–386PubMedGoogle Scholar
  68. Julius S (2000) Five decades of antihypertensive treatment: the unresolved issues. J Hypertens Suppl 18:S3–S7PubMedGoogle Scholar
  69. Julius S, Gudbrandsson T, Jamerson K, Andersson O (1992) The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. Blood Press 1:9–19PubMedGoogle Scholar
  70. Kakuta H, Sudoh K, Sasamata M, Yamagishi S (2005) Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers. Int J Clin Pharmacol Res 25:41–46PubMedGoogle Scholar
  71. Kanatsuna T, Nakano K, Mori H, Kano Y, Nishioka H, Kajiyama S, Kitagawa Y, Yoshida T, Kondo M, Nakamura N (1985) Effects of nifedipine on insulin secretion and glucose metabolism in rats and in hypertensive type 2 (non-insulin dependent) diabetics. Arzneimittelforschung 35:514–517PubMedGoogle Scholar
  72. Kawai Y, Arinze IJ (1983) beta-Adrenergic receptors in rabbit liver plasma membranes. Predominance of beta 2-receptors and mediation of adrenergic regulation of hepatic glycogenolysis. J Biol Chem 258:4364–4371PubMedGoogle Scholar
  73. Keltikangas-Jarvinen L, Ravaja N, Raikkonen K, Lyytinen H (1996) Insulin resistance syndrome and autonomically mediated physiological responses to experimentally induced mental stress in adolescent boys. Metabolism 45:614–621PubMedGoogle Scholar
  74. Kjeldsen SE, Rostrup M, Moan A, Mundal HH, Gjesdal K, Eide IK (1992) The sympathetic nervous system may modulate the metabolic cardiovascular syndrome in essential hypertension. J Cardiovasc Pharmacol 20 Suppl 8:S32–S39Google Scholar
  75. Kjeldsen SE, Moan A, Petrin J, Weder AB, Julius S (1996) Effects of increased arterial epinephrine on insulin, glucose and phosphate. Blood Press 5:27–31PubMedGoogle Scholar
  76. Klein C, Morton N, Kelley S, Metz S (1985) Transdermal clonidine therapy in elderly mild hypertensives: effects on blood pressure, plasma norepinephrine and fasting plasma glucose. J Hypertens Suppl 3:S81–S84PubMedGoogle Scholar
  77. Koh KK, Quon MJ, Han SH, Chung WJ, Lee Y, Shin EK (2006) Anti-inflammatory and metabolic effects of candesartan in hypertensive patients. Int J Cardiol 108:96–100PubMedGoogle Scholar
  78. Koletsky RJ, Velliquette RA, Ernsberger P (2003) The role of I(1)-imidazoline receptors and alpha(2)-adrenergic receptors in the modulation of glucose and lipid metabolism in the SHROB model of metabolic syndrome X. Ann N Y Acad Sci 1009:251–261PubMedGoogle Scholar
  79. Kulcsar-Gergely J, Posan E, Kulcsar A (1994) Metabolic actions of a single atenolol and metoprolol dose. Arzneimittelforschung 44:1183–1185PubMedGoogle Scholar
  80. Kurtz TW (2005) Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta Diabetol 42 Suppl 1:S9–S16PubMedGoogle Scholar
  81. Kurtz TW, Pravenec M (2004) Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens 22:2253–2261PubMedGoogle Scholar
  82. Lacey RJ, Berrow NS, Scarpello JH, Morgan NG (1991) Selective stimulation of glucagon secretion by beta 2-adrenoceptors in isolated islets of Langerhans of the rat. Br J Pharmacol 103:1824–1828PubMedGoogle Scholar
  83. Lacey RJ, Chan SLF, Cable HC, James RFL, Perrett CW, Scarpello JHB, Morgan NG (1996) Expression of a2- and b-adrenoceptor subtypes in human islets of Langerhans. J Endocrinol 148:531–543PubMedGoogle Scholar
  84. Lee AD, Hansen PA, Schluter J, Gulve EA, Gao J, Holloszy JO (1997) Effects of epinephrine on insulin-stimulated glucose uptake and GLUT-4 phosphorylation in muscle. Am J Physiol 273:C1082–C1087PubMedGoogle Scholar
  85. Leineweber K, Buscher R, Bruck H, Brodde OE (2004) Beta-adrenoceptor polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369:1–22PubMedGoogle Scholar
  86. Leung PS, Carlsson PO (2005) Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus. Pancreas 30:293–298PubMedGoogle Scholar
  87. Li Y-Q, Ji H, Ding DY, Ye XL (2006) Metabolic effects of telmisartan in spontaneously hypertensive rats. Naunyn-Schmiedeberg’s Archives of Pharmacology DOI 10.1007/s00210-006-0069-yGoogle Scholar
  88. Lind L, Berne C, Pollare T, Lithell H (1995) Metabolic effects of anti-hypertensive treatment with nifedipine or furosemide: a double-blind, cross-over study. J Hum Hypertens 9:137–141PubMedGoogle Scholar
  89. Lithell H (1992) Insulin resistance and cardiovascular drugs. Clin Exp Hypertens A 14:151–162Google Scholar
  90. Liu YL, Toubro S, Astrup A, Stock MJ (1995) Contribution of beta 3-adrenoceptor activation to ephedrine-induced thermogenesis in humans. Int J Obes Relat Metab Disord 19:678–685PubMedGoogle Scholar
  91. Ljung B, Ablad B, Drews L, Fellenius E, Kjellstedt A, Wallborg M (1976) Anti-hypertensive effect of metoprolol in spontaneously hypertensive rats. Clin Sci Mol Med Suppl 3:443S–445SPubMedGoogle Scholar
  92. Lorrain J, Angel I, Duval N, Eon MT, Oblin A, Langer SZ (1992) Adrenergic and nonadrenergic cotransmitters inhibit insulin secretion during sympathetic stimulation in dogs. Am J Physiol 263:E72–E78PubMedGoogle Scholar
  93. Lumb PJ, McMahon Z, Chik G, Wierzbicki AS (2004) Effect of moxonidine on lipid subfractions in patients with hypertension. Int J Clin Pract 58:465–468PubMedGoogle Scholar
  94. Mackintosh VS, Elsegood CL, Redgrave TG (1991) Effects of adrenoreceptor antagonists and agonists on clearance of emulsion models of triacylglycerol-rich lipoproteins from plasma in rats. Clin Exp Pharmacol Physiol 18:775–788PubMedGoogle Scholar
  95. Mancia G, Brown M, Castaigne A, de Leeuw P, Palmer CR, Rosenthal T, Wagener G, Ruilope LM (2003) Outcomes with nifedipine GITS or Co-amilozide in hypertensive diabetics and nondiabetics in Intervention as a Goal in Hypertension (INSIGHT). Hypertension 41:431–436PubMedGoogle Scholar
  96. Mancia G, Dell’oro R, Quarti-Trevano F, Scopelliti F, Grassi G (2006) Angiotensin-sympathetic system interactions in cardiovascular and metabolic disease. J Hypertens 24 Suppl 1:S51–S56Google Scholar
  97. Masuo K, Mikami H, Ogihara T, Tuck ML (1997) Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens 10:77–83PubMedGoogle Scholar
  98. McKenney JM, Goodman RP, Wright JT Jr (1985) Use of antihypertensive agents in patients with glucose intolerance. Clin Pharm 4:649–656PubMedGoogle Scholar
  99. Mervaala EM, Teravainen TL, Malmberg L, Laakso J, Vapaatalo H, Karppanen H (1997) Cardiovascular effects of a low-dose combination of ramipril and felodipine in spontaneously hypertensive rats. Br J Pharmacol 121:503–510PubMedGoogle Scholar
  100. Metz SA, Halter JB, Robertson RP (1978) Induction of defective insulin secretion and impaired glucose tolerance by clonidine: Selective stimulation of metabolic α-adrenergic pathways. Diabetes 27:554–562PubMedGoogle Scholar
  101. Moratinos J, Reverte M (1993) Effects of catecholamines on plasma potassium: the role of alpha- and beta-adrenoceptors. Fundam Clin Pharmacol 7:143–153PubMedCrossRefGoogle Scholar
  102. Morgan NG, Exton JH, Blackmore PF (1983) Angiotensin II inhibits hepatic cAMP accumulation induced by glucagon and epinephrine and their metabolic effects. FEBS Lett 153:77–80PubMedGoogle Scholar
  103. Moser M (1998) Why are physicians not prescribing diuretics more frequently in the management of hypertension? J Am Med Assoc 279:1813–1816Google Scholar
  104. Murray DP, Watson RD, Zezulka AV, Murray RG, Littler WA (1988) Plasma catecholamine levels in acute myocardial infarction: influence of beta-adrenergic blockade and relation to central hemodynamics. Am Heart J 115:38–44PubMedGoogle Scholar
  105. Navarro-Cid J, Maeso R, Perez-Vizcaino F, Casal MC, Cachofeiro V, Ruilope LM, Tamargo J, Lahera V (1996) Effects of antihypertensive drugs on blood pressure and metabolic alterations in the fructose-induced hypertensive rat. Am J Hypertens 9:669–674PubMedGoogle Scholar
  106. Nevzorova J, Evans BA, Bengtsson T, Summers RJ (2006) Multiple signalling pathways involved in beta2-adrenoceptor-mediated glucose uptake in rat skeletal muscle cells. Br J Pharmacol 147:446–454PubMedGoogle Scholar
  107. Nonogaki K (2000) New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549PubMedGoogle Scholar
  108. Nonogaki K, Iguchi A (1997) Role of central neural mechanisms in the regulation of hepatic glucose metabolism. Life Sci 60:797–807PubMedGoogle Scholar
  109. Nonogaki K, Moser AH, Feingold KR, Grunfeld C (1994) Alpha-adrenergic receptors mediate the hypertriglyceridemia induced by endotoxin, but not tumor necrosis factor, in rats. Endocrinology 135:2644–2650PubMedGoogle Scholar
  110. Olubadewo JO, Heimberg M (1993) Effects of adrenergic agonists and antagonists on the metabolism of [1–14C]oleic acid by rat hepatocytes. Biochem Pharmacol 45:2441–2447PubMedGoogle Scholar
  111. Opie LH, Schall R (2004) Old antihypertensives and new diabetes. J Hypertens 22:1453–1458PubMedGoogle Scholar
  112. Ostlund-Lindqvist AM, Eklund A, Sjoblom L, Jonsson L (1989) Effect of metoprolol on plasma lipids and arterial intimal lipid deposition in spontaneously hypertensive rats. Atherosclerosis 80:135–142PubMedGoogle Scholar
  113. Paquot N, Schneiter P, Jequier E, Tappy L (1995) Effects of glucocorticoids and sympathomimetic agents on basal and insulin-stimulated glucose metabolism. Clin Physiol 15:231–240PubMedGoogle Scholar
  114. Park SC, Radin MJ, Hoepf T, McCune SA (1999) Comparison of verapamil and felodipine treatment on lipid and glucose metabolism in obese female SHHF/Mcc-facp rats. Proc Soc Exp Biol Med 221:224–233PubMedGoogle Scholar
  115. Pelleg A, Katchanov G, Xu J (1997) Autonomic neural control of cardiac function: modulation by adenosine and adenosine 5′-triphosphate. American Journal of Cardiology 79:11–14PubMedGoogle Scholar
  116. Penicaud L, Berthault MF, Morin J, Dubar M, Ktorza A, Ferre P (1998) Rilmenidine normalizes fructose-induced insulin resistance and hypertension in rats. J Hypertens Suppl 16:S45–S49PubMedGoogle Scholar
  117. Pitre M, Gaudreault N, Santure M, Nadeau A, Bachelard H (1999) Isradipine and insulin sensitivity in hypertensive rats. Am J Physiol 276:E1038–E1048PubMedGoogle Scholar
  118. Ramracheya RD, Muller DS, Wu Y, Whitehouse BJ, Huang GC, Amiel SA, Karalliedde J, Viberti G, Jones PM, Persaud SJ (2006) Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans. Diabetologia 49:321–331PubMedGoogle Scholar
  119. Ran J, Hirano T, Adachi M (2004) Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats. Am J Physiol Endocrinol Metab 287:E227–E232PubMedGoogle Scholar
  120. Ran J, Hirano T, Fukui T, Saito K, Kageyama H, Okada K, Adachi M (2006) Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance. Metabolism 55:478–488PubMedGoogle Scholar
  121. Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283PubMedGoogle Scholar
  122. Randle PJ, Garland PB, Newsholme EA, Hales CN (1965) The glucose fatty acid cycle in obesity and maturity onset diabetes mellitus. Ann N Y Acad Sci 131:324–333PubMedGoogle Scholar
  123. Reaven GM (1993) Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 44:121–131PubMedGoogle Scholar
  124. Reaven GM, Lithell H, Landsberg L (1996) Hypertension and associated metabolic abnormalities–the role of insulin resistance and the sympathoadrenal system. N Engl J Med 334:374–381PubMedGoogle Scholar
  125. Reinhart PH, Taylor WM, Bygrave FL (1982) Studies on alpha-adrenergic-induced respiration and glycogenolysis in perfused rat liver. J Biol Chem 257:1906–1912PubMedGoogle Scholar
  126. Rodrigues B, Grassby PF, Battell ML, Lee SY, McNeill JH (1994) Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction. Can J Physiol Pharmacol 72:447–455PubMedGoogle Scholar
  127. Rosen SG, Clutter WE, Shah SD, Miller JP, Bier DM, Cryer PE (1983) Direct alpha-adrenergic stimulation of hepatic glucose production in human subjects. Am J Physiol 245:E616–E626PubMedGoogle Scholar
  128. Rosen P, Ohly P, Gleichmann H (1997) Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat. J Hypertens 15(Suppl. 1):S31–S38Google Scholar
  129. Ruffolo RR, Jr, Nichols AJ, Hieble JP (1991) Metabolic regulation by a1- and a2-adrenoceptors. Life Sci 49:171–183PubMedGoogle Scholar
  130. Salem HA, Abdel Rahman MS, Dahab GM (1993) Influence of diltiazem and/or propranolol on rat blood glucose levels in normal and diabetic animals. J Appl Toxicol 13:85–89PubMedGoogle Scholar
  131. Schupp M, Janke J, Clasen R, Unger T, Kintscher U (2004) Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 109:2054–2057PubMedGoogle Scholar
  132. Sechi LA, Catena C, Zingaro L, De Carli S, Bartoli E (1997) Hypertension and abnormalities of carbohydrate metabolism possible role of the sympathetic nervous system. Am J Hypertens 10:678–682PubMedGoogle Scholar
  133. Semple CG, Smith M, Furman BL (1988) Inhibition of glucose-induced insulin secretion by calcium channel blocking drugs in-vitro but not in-vivo in the rat. J Pharm Pharmacol 40:22–26PubMedGoogle Scholar
  134. Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC (2002) Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 40:609–611PubMedGoogle Scholar
  135. Sica DA (2004) Diuretic-related side effects: development and treatment. J Clin Hypertens (Greenwich) 6:532–540Google Scholar
  136. Szabo B (2002) Imidazoline antihypertensive drugs: a critical review on their mechanism of action. Pharmacol Ther 93:1–35PubMedGoogle Scholar
  137. Tahmasebi M, Puddefoot JR, Inwang ER, Vinson GP (1999) The tissue renin-angiotensin system in human pancreas. J Endocrinol 161:317–322PubMedGoogle Scholar
  138. Tavernier G, Barbe P, Galitzky J, Berlan M, Caput D, Lafontan M, Langin D (1996) Expression of b3-adrenoceptors with low lipolytic action in human subcutaneous white adipocytes. J Lipid Res 37:87–97PubMedGoogle Scholar
  139. Toda N (2003) Vasodilating beta-adrenoceptor blockers as cardiovascular therapeutics. Pharmacol Ther 100:215–234PubMedGoogle Scholar
  140. Tolentino-Silva FP, Haxhiu MA, Waldbaum S, Dreshaj IA, Ernsberger P (2000) alpha(2)-adrenergic receptors are not required for central anti-hypertensive action of moxonidine in mice. Brain Res 862:26–35PubMedGoogle Scholar
  141. Tomiyama H, Kushiro T, Abeta H, Ishii T, Takahashi A, Furukawa L, Asagami T, Hino T, Saito F, Otsuka Y (1994) Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension 23:450–455PubMedGoogle Scholar
  142. Trost BN, Weidmann P (1988) Metabolic effects of calcium antagonists in humans, with emphasis on carbohydrate, lipid, potassium, and uric acid homeostases. J Cardiovasc Pharmacol 12 Suppl 6:S86–S92PubMedCrossRefGoogle Scholar
  143. Ura N, Higashiura K, Shimamoto K (1999) The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor. Immunopharmacology 44:153–159PubMedGoogle Scholar
  144. Velasco M, Silva H, Feldstein E, Pellicer R, Morillo J, Urbina-Quintana A, Hernandez-Pieretti O (1985) Effects of prazosin and alphamethyldopa on blood lipids and lipoproteins in hypertensive patients. Eur J Clin Pharmacol 28:513–516PubMedGoogle Scholar
  145. Velliquette RA, Ernsberger P (2003a) Contrasting metabolic effects of antihypertensive agents. J Pharmacol Exp Ther 307:1104–1111PubMedGoogle Scholar
  146. Velliquette RA, Ernsberger P (2003b) The role of I(1)-imidazoline and alpha(2)-adrenergic receptors in the modulation of glucose metabolism in the spontaneously hypertensive obese rat model of metabolic syndrome X. J Pharmacol Exp Ther 306:646–657PubMedGoogle Scholar
  147. Velliquette RA, Kossover R, Previs SF, Ernsberger P (2006) Lipid-lowering actions of imidazoline antihypertensive agents in metabolic syndrome X. Naunyn-Schmiedeberg’s Arch Pharmacol 372:300–312Google Scholar
  148. Verma S, Bhanot S, Hicke A, McNeill JH (1997) Chronic T-type Ca2+ channel blockade with mibefradil in hyperinsulinemic, insulin-resistant and hypertensive rats. Cardiovasc Res 34:121–128PubMedGoogle Scholar
  149. Webster WB Jr, McConnaughey MM (1982) Clonidine and glucose intolerance. Drug Intell Clin Pharm 16:325–328PubMedGoogle Scholar
  150. Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, Leenen FH, Louis GT, Margolis KL, Mathis DE, Moloo J, Nwachuku C, Panebianco D, Parish DC, Pressel S, Simmons DL, Thadani U (2005) Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 165:1401–1409PubMedGoogle Scholar
  151. Williams PT, Haskell WL, Vranizan KM, Krauss RM (1995) The associations of high-density lipoprotein subclasses with insulin and glucose levels, physical activity, resting heart rate, and regional adiposity in men with coronary artery disease: The Stanford Coronary Risk Intervention Project Baseline Survey. Metabolism 44:106–114PubMedGoogle Scholar
  152. Yakubu-Madus FE, Johnson WT, Zimmerman KM, Dananberg J, Steinberg MI (1999) Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat model of type 2 diabetes. Diabetes 48:1093–1100PubMedGoogle Scholar
  153. Yamauchi T, Iwai M, Kobayashi N, Shimazu T (1998) Noradrenaline and ATP decrease the secretion of triglyceride and apoprotein B from perfused rat liver. Pflugers Arch 435:368–374PubMedGoogle Scholar
  154. Yenicesu M, Yilmaz MI, Caglar K, Sonmez A, Eyileten T, Acikel C, Kilic S, Bingol N, Bingol S, Vural A (2005) Blockade of the renin-angiotensin system increases plasma adiponectin levels in type-2 diabetic patients with proteinuria. Nephron Clin Pract 99:c115–c121PubMedGoogle Scholar
  155. Yorek MA, Rufo GA Jr, Ray PD (1980) Gluconeogenesis in rabbit liver. III. The influences of glucagon, epinephrine, alpha- and beta-adrenergic agents on gluconeogenesis in isolated hepatocytes. Biochim Biophys Acta 632:517–526PubMedGoogle Scholar
  156. Yvan-Charvet L, Even P, Bloch-Faure M, Guerre-Millo M, Moustaid-Moussa N, Ferre P, Quignard-Boulange A (2005) Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance. Diabetes 54:991–999PubMedGoogle Scholar
  157. Zaitsev SV, Efanov AM, Efanova IB, Larsson O, Östenson CG, Gold G, Berggren PO, Efendic S (1996) Imidazoline compounds stimulate insulin release by inhibition of KATP channels and interaction with the exocytotic machinery. Diabetes 45:1610–1618PubMedGoogle Scholar
  158. Zhu QM, Lesnick JD, Jasper JR, MacLennan SJ, Dillon MP, Eglen RM, Blue DR Jr (1999) Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice. Br J Pharmacol 126:1522–1530PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of NutritionCase Western Reserve University School of MedicineClevelandUSA

Personalised recommendations