Abstract
AT1-blockade has been shown to induce weight loss in animals or patients. The aim of this study was to investigate whether weight reduction after AT1-blockade is dependent on dose, blood pressure reduction and leptin signalling. Spontaneously hypertensive rats (SHR) and lean and obese Zucker rats were treated for 4 weeks with candesartan (0, 2, 6 or 16 mg/kg/day). Body weight, food intake and hypothalamic mRNA levels of (an)orexigenic peptides were determined. Obese Zucker rats served as a model of primary leptin resistance. In SHR, body mass index and food intake were decreased selectively by 16 mg/kg/day candesartan but not after using normal (2 mg/kg/day) or supranormal (6 mg/kg/day) doses. Correlation analysis between blood pressure and body weight indicated no relationship of hypotensive potency on weight loss. The hypothalamic mRNA levels of the orexigenic peptide MCH (melanin-concentrating hormone) were diminished in parallel. Consistent to the results in SHRs, 16 mg/kg/day candesartan revealed a decrease of body weight, food intake and hypothalamic MCH mRNA levels in lean Zucker rats. In obese Zucker rats, none of these parameters were reduced by candesartan. Loss of body weight and hypophagia are not general features of AT1-blockers, since neither was seen after normal or moderately supranormal doses, but they were, after the highest doses. These actions of AT1-blockers occur independently of their ability to lower blood pressure. They do depend on an intact leptin signalling, since they were absent in obese Zucker rats that feature a genetic mutation of the leptin receptor.
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References
Enalapril in Hypertension Study Group (UK) (1984) Enalapril in essential hypertension: a comparative study with propranolol. Br J Clin Pharmacol 18:51–56
Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA, Kurtz TW (2004) Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 43:993–1002
Bustin SA (2002) Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): trends and problems. J Mol Endocrinol 29:23–39
Cabassi A, Coghi P, Govoni P, Barouhiel E, Speroni E, Cavazzini S, Cantoni AM, Scandroglio R, Fiaccadori E (2005) Sympathetic modulation by carvedilol and losartan reduces angiotensin II-mediated lipolysis in subcutaneous and visceral fat. J Clin Endocrinol Metab 90:2888–2897
Campbell DJ, Duncan AM, Kladis A, Harrap SB (1995) Converting enzyme inhibition and its withdrawal in spontaneously hypertensive rats. J Cardiovasc Pharmacol 26:426–436
Carter CS, Cesari M, Ambrosius WT, Hu N, Diz D, Oden S, Sonntag WE, Pahor M (2004) Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J Gerontol A Biol Sci Med Sci 59:416–423
Cassis LA, Marshall DE, Fettinger MJ, Rosenbluth B, Lodder RA (1998) Mechanisms contributing to angiotensin II regulation of body weight. Am J Physiol 274:E867–E876
Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL (1996a) Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271:994–996
Chua SC Jr, White DW, Wu-Peng XS, Liu SM, Okada N, Kershaw EE, Chung WK, Power-Kehoe L, Chua M, Tartaglia LA, Leibel RL (1996b) Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). Diabetes 45:1141–1143
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 46:137–143
Cole BK, Keller SR, Wu R, Carter JD, Nadler JL, Nunemaker CS (2010) Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat diet in mice. Hypertension 55:715–721
Culman J, von Heyer C, Piepenburg B, Rascher W, Unger T (1999) Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. Eur J Pharmacol 367:255–265
de Kloet AD, Krause EG, Woods SC (2010) The renin angiotensin system and the metabolic syndrome. Physiol Behav 100:525–534
de las Heras N, Ruiz-Ortega M, Ruperez M, Sanz-Rosa D, Miana M, Aragoncillo P, Mezzano S, Lahera V, Egido J, Cachofeiro V (2006) Role of connective tissue growth factor in vascular and renal damage associated with hypertension in rats. Interactions with angiotensin II. J Renin Angiotensin Aldosterone Syst 7:192–200
de Souza CJ, Eckhardt M, Gagen K, Dong M, Chen W, Laurent D, Burkey BF (2001) Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. Diabetes 50:1863–1871
Elliott WJ, Meyer PM (2007) Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 369:201–207
Engeli S, Negrel R, Sharma AM (2000) Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 35:1270–1277
Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM (2005) Weight loss and the renin-angiotensin-aldosterone system. Hypertension 45:356–362
Fogari R, Derosa G, Zoppi A, Rinaldi A, Lazzari P, Fogari E, Mugellini A, Preti P (2005) Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients. Hypertens Res 28:209–214
He H, Yang D, Ma L, Luo Z, Ma S, Feng X, Cao T, Yan Z, Liu D, Tepel M, Zhu Z (2010) Telmisartan Prevents Weight Gain and Obesity Through Activation of Peroxisome Proliferator-Activated Receptor-{delta}-Dependent Pathways. Hypertension
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141
Igarashi M, Hirata A, Yamaguchi H, Tsuchiya H, Ohnuma H, Tominaga M, Daimon M, Kato T (2001) Candesartan inhibits carotid intimal thickening and ameliorates insulin resistance in balloon-injured diabetic rats. Hypertension 38:1255–1259
Jöhren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P (2001) Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology 142:3324–3331
Kansui Y, Fujii K, Nakamura K, Goto K, Oniki H, Abe I, Shibata Y, Iida M (2004) Angiotensin II receptor blockade corrects altered expression of gap junctions in vascular endothelial cells from hypertensive rats. Am J Physiol Heart Circ Physiol 287:H216–H224
Kett MM, Alcorn D, Bertram JF, Anderson WP (1996) Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism. J Hypertens 14:107–113
Kim S, Whelan J, Claycombe K, Reath DB, Moustaid-Moussa N (2002) Angiotensin II increases leptin secretion by 3 T3-L1 and human adipocytes via a prostaglandin-independent mechanism. J Nutr 132:1135–1140
Kintscher U, Unger T (2005) Vascular protection in diabetes: a pharmacological view of angiotensin II type 1 receptor blockers. Acta Diabetol 42(Suppl 1):S26–S32
Kintscher U, Foryst-Ludwig A, Unger T (2008) Inhibiting angiotensin type 1 receptors as a target for diabetes. Expert Opin Ther Targets 12:1257–1263
Kohya T, Yokoshiki H, Tohse N, Kanno M, Nakaya H, Saito H, Kitabatake A (1995) Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias. Beneficial effect of angiotensin II blockade. Circ Res 76:892–899
Larsen TM, Toubro S, Astrup A (2003) PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy? Int J Obes Relat Metab Disord 27:147–161
Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C (1997) Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. Front Neuroendocrinol 18:383–439
Lin Y, Tsuchihashi T, Kagiyama S, Matsumura K, Abe I (2001) The influence of chronic antihypertensive treatment on the central pressor response in SHR. Hypertens Res 24:173–178
Lu Q, Zhu YZ, Wong PT (2005) Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. NeuroReport 16:1963–1967
Madala HV, Tiwari S, Riazi S, Hu X, Ecelbarger CM (2008) Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat. Am J Physiol Renal Physiol 294:F1222–F1231
McGrath BP, Matthews PG, Louis W, Howes L, Whitworth JA, Kincaid-Smith PS, Fraser I, Scheinkestel C, MacDonald G, Rallings M (1990) Double-blind study of dilevalol and captopril, both in combination with hydrochlorothiazide, in patients with moderate to severe hypertension. J Cardiovasc Pharmacol 16:831–838
Miesel A, Müller H, Thermann M, Heidbreder M, Dominiak P, Raasch W (2010) Overfeeding-induced obesity in spontaneously hypertensive rats: an animal model of the human metabolic syndrome. Ann Nutr Metab 56:127–142
Mukawa H, Toki Y, Miyazaki Y, Matsui H, Okumura K, Ito T (2003) Angiotensin II type 2 receptor blockade partially negates antihypertrophic effects of type 1 receptor blockade on pressure-overload rat cardiac hypertrophy. Hypertens Res 26:89–95
Nahon JL (2006) The melanocortins and melanin-concentrating hormone in the central regulation of feeding behavior and energy homeostasis. C R Biol 329:623–638
Naruse M, Tanabe A, Sato A, Takagi S, Tsuchiya K, Imaki T, Takano K (2002) Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 40:28–33
Nussdorfer GG, Mazzocchi G, Malendowicz LK (1986) Acute effects of alpha-MSH on the rat zona glomerulosa in vivo. Biochem Biophys Res Commun 141:1279–1284
Paull JR, Widdop RE (2001) Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats. J Hypertens 19:1393–1402
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, San Diego
Prasad A, Quyyumi AA (2004) Renin-angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Circulation 110:1507–1512
Raasch W, Wittmershaus C, Dendorfer A, Voges I, Pahlke F, Dodt C, Dominiak P, Jöhren O (2006) Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in SHR. Endocrinology in press:
Sata N, Tanaka Y, Suzuki S, Kamimura R, Mifune H, Nakamura K, Miyahara K, Arima T (2003) Effectiveness of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on atrial natriuretic peptide. Circ J 67:1053–1058
Schupp M, Janke J, Clasen R, Unger T, Kintscher U (2004) Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 109:2054–2057
Schupp M, Clemenz M, Gineste R, Witt H, Janke J, Helleboid S, Hennuyer N, Ruiz P, Unger T, Staels B, Kintscher U (2005) Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes 54:3442–3452
Schupp M, Lee LD, Frost N, Umbreen S, Schmidt B, Unger T, Kintscher U (2006) Regulation of peroxisome proliferator-activated receptor gamma activity by losartan metabolites. Hypertension 47:586–589
Schwartz MW, Gelling RW (2002) Rats lighten up with MCH antagonist. Nat Med 8:779–781
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671
Sebekova K, Lill M, Boor P, Heidland A, Amann K (2009) Functional and partial morphological regression of established renal injury in the obese zucker rat by blockade of the renin-angiotensin system. Am J Nephrol 29:164–170
Seltzer A, Bregonzio C, Armando I, Baiardi G, Saavedra JM (2004) Oral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats. Brain Res 1028:9–18
Skurk T, Van HV, Blum WF, Hauner H (2005) Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway. Obes Res 13:969–973
Tanabe A, Naruse M, Hara Y, Sato A, Tsuchiya K, Nishikawa T, Imaki T, Takano K (2004) Aldosterone antagonist facilitates the cardioprotective effects of angiotensin receptor blockers in hypertensive rats. J Hypertens 22:1017–1023
Welch WJ, Baumgartl H, Lubbers D, Wilcox CS (2003) Renal oxygenation defects in the spontaneously hypertensive rat: role of AT1 receptors. Kidney Int 63:202–208
Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J, Saavedra JM (2006) Long-term angiotensin II AT(1) receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. Eur J Pharmacol 552:112–122
Zucker TF, Zucker LM (1962) Hereditary obesity in the rat associated with high serum fat and cholesterol. Proc Soc Exp Biol Med 110:165–171
Zucker TF, Zucker LM (1963) Fat accretion and growth in the rat. J Nutr 80:6–19
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This study was supported by a grant (N11-2004) of the Dean of the Medical Faculty of the University of Lübeck.
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Müller-Fielitz, H., Markert, A., Wittmershaus, C. et al. Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure. Naunyn-Schmied Arch Pharmacol 383, 373–384 (2011). https://doi.org/10.1007/s00210-011-0602-5
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DOI: https://doi.org/10.1007/s00210-011-0602-5