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Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats

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Abstract

Adiponectin exerts vasodilatory effects. Irbesartan, an angiotensin receptor blocker, possesses partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activity and increases circulating adiponectin. This study explored the effect of irbesartan alone and in combination with adiponectin on blood pressure, renal hemodynamic excretory function, and vasoactive responses to angiotensin II and adrenergic agonists in spontaneously hypertensive rat (SHR). Irbesartan was given orally (30 mg/kg/day) for 28 days and adiponectin intraperitoneally (2.5 μg/kg/day) for last 7 days. Groups of SHR received either irbesartan or adiponectin or in combination. A group of Wistar Kyoto rats (WKY) served as controls. Metabolic data and plasma samples were taken on days 0, 21, and 28. In acute studies, the renal vasoconstrictor actions of angiotensin II (ANGII), noradrenaline (NA), phenylephrine (PE), and methoxamine (ME) were determined. SHR control rats had a higher mean blood pressure than the WKY (132 ± 7 vs. 98 ± 2 mmHg), lower plasma and urinary adiponectin, creatinine clearance, urine flow rate and sodium excretion, and oxidative stress markers compared to WKY (all P < 0.05) which were progressively normalized by the individual drug treatments and to a greater extent by combined treatment. Responses to intrarenal administration of NA, PE, ME, and ANGII were larger in SHR (P < 0.05) than WKY by 20–25 %. Irbesartan enhanced (P < 0.05) responses to NA and PE, while adiponectin blunted responses to all vasoconstrictors (all P < 0.05). Combined treatment in SHR further decreased the renal vascular responses to ANGII. These findings suggest that an interactive relationship may exist between PPAR-γ, alpha adrenoceptors, and ANGII in the renal vasculature of the SHR.

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References

  1. Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Abdallah HH, Johns EJ (2009) Chronic treatment with losartan and carvedilol differentially modulates renal vascular responses to sympathomimetics compared to treatment with individual agents in normal Wistar Kyoto and spontaneously hypertensive rats. Eur J Pharmacol 612:69–74

    Article  CAS  PubMed  Google Scholar 

  2. Abdulla MH, Sattar MA, Khan MA, Abdullah NA, Johns EJ (2009) Influence of sympathetic and AT-receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive rats. Acta Physiol 195:397–404

    Article  CAS  Google Scholar 

  3. Alexander WD, Branch RA, Levine DF, Hartog M (1977) The urinary sodium: potassium ratio and response to diuretics in resistant oedema. Postgrad Med J 53:117–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Armando I, Carranza A, Nishimura Y, Hoe KL, Barontini M, Terron JA et al (2001) Peripheral administration of an angiotensin II AT[1] receptor antagonist decreases the hypothalamic-pituitary-adrenal response to isolation stress. J Endocrinol 142:3880–3889

    Article  CAS  Google Scholar 

  5. Beierwaltes WH, Arendshorst WJ, Klemmer PJ (1982) Electrolyte and water balance in young spontaneously hypertensive rats. Hypertension 4:908–915

    Article  CAS  PubMed  Google Scholar 

  6. Bolterman RJ, Manriquez MC, Ortiz Ruiz MC, Juncos LA, Romero JC (2005) Effects of captopril on the renin angiotensin system, oxidative stress, and endothelin in normal and hypertensive rats. Hypertension 46:943–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chabrashvili T, Kitiyakara C, Blau J, Karber A, Aslam S, Welch WJ et al (2003) Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression. Am J Physiol Regul Integr Comp Physiol 285:117–124

    Article  Google Scholar 

  8. Chen H, Montagnani M, Funahashi T, Shimomura I, Quon MJ (2003) Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278:45021–45026

    Article  CAS  PubMed  Google Scholar 

  9. Christou GA, Kiortsis DN (2014) The role of adiponectin in renal physiology and development of albuminuria. J Endocrinol 221:13–0578

    Article  CAS  Google Scholar 

  10. Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M et al (2005) PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension 46:137–143

    Article  CAS  PubMed  Google Scholar 

  11. Cowley AW Jr, Roman RJ (1996) The role of the kidney in hypertension. JAMA 275:1581–1589

    Article  PubMed  Google Scholar 

  12. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472

    PubMed  Google Scholar 

  13. Fruebis J, Tsao T-S, Javorschi S, Ebbets-Reed D, Erickson MRS, Yen FT et al (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005–2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fu M, Zhou J, Qian J, Jin X, Zhu H, Zhong C et al (2012) Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction—an experimental study. Lipids Health Dis 11:106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gardiner SM, Kemp PA, March JE, Bennett T (1993) Regional haemodynamic effects of angiotensin II [3–8] in conscious rats. Br J Pharmacol 110:159–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iwai M, Kanno H, Senba I, Nakaoka H, Moritani T, Horiuchi M (2011) Irbesartan increased PPARgamma activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction. Biochem Biophys Res Commun 406:123–126

    Article  CAS  PubMed  Google Scholar 

  17. Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M et al (2003) Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52:1655–1663

    Article  CAS  PubMed  Google Scholar 

  18. Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K et al (2004) Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 43:1318–1323

    Article  CAS  PubMed  Google Scholar 

  19. Jiang X, Song D, Ye B, Wang X, Song G, Yang S et al (2011) Effect of intermittent administration of adiponectin on bone regeneration following mandibular osteodistraction in rabbits. J Orthop Res 29:1081–1085

    Article  CAS  PubMed  Google Scholar 

  20. Kusminski C, McTernan PG, Schraw T, Kos K, O’Hare JP, Ahima R et al (2007) Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum. Diabetologia 50:634–642

    Article  CAS  PubMed  Google Scholar 

  21. Liu M, Zhou L, Xu A, Lam KS, Wetzel MD, Xiang R et al (2008) A disulfide-bond A oxidoreductase-like protein [DsbA-L] regulates adiponectin multimerization. Proc Natl Acad Sci U S A. doi:10.1073/0806341105

    Google Scholar 

  22. Pinho MJ, Serrao MP, Soares-da-Silva P (2007) High-salt intake and the renal expression of amino acid transporters in spontaneously hypertensive rats. Am J Physiol Renal Physiol 292:1452–1463

    Article  CAS  Google Scholar 

  23. Ran J, Hirano T, Fukui T, Saito K, Kageyama H, Okada K et al (2006) Angiotensin II infusion decreases plasma adiponectin level via its type 1 receptor in rats: an implication for hypertension-related insulin resistance. Metabolism 55:478–488

    Article  CAS  PubMed  Google Scholar 

  24. Ravera M, Ratto E, Vettoretti S, Parodi D, Deferrari G (2005) Prevention and treatment of diabetic nephropathy: the program for irbesartan mortality and morbidity evaluation. J Am Soc Nephrol 16:48–52

    Article  CAS  Google Scholar 

  25. Sarafidis PA, Lasaridis AN (2006) Actions of peroxisome proliferator-activated receptors-γ agonists explaining blood pressure lowering effect. Am J Hypertens 19:646–653

    Article  CAS  PubMed  Google Scholar 

  26. Schupp M, Janke J, Clasen R, Unger T, Kintscher U (2004) Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-γ activity. Circulation 109:2054–2057

    Article  CAS  PubMed  Google Scholar 

  27. Sica DA, Bakris GL (2002) Type 2 diabetes: RENAAL and IDNT—the emergence of new treatment options. J Clin Hypertens 4:52–57

    Article  Google Scholar 

  28. Sugawara A, Uruno A, Kudo M, Matsuda K, Yang CW, Ito S (2011) PPARγ agonist beyond glucose lowering effect. Korean J Intern Med 26:19–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tanida M, Shen J, Horii Y, Matsuda M, Kihara S, Funahashi T et al (2007) Effects of adiponectin on the renal sympathetic nerve activity and blood pressure in rats. Exp Biol Med [Maywood] 232:390–397

    CAS  Google Scholar 

  30. Vaishya R, Singh J, Lal H (2008) Effect of irbesartan on streptozotocin induced diabetic nephropathy: an interventionary study. Indian J Clin Biochem 23:195–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vittorio TJ, Lang CC, Katz SD, Packer M, Mancini DM, Jorde UP (2003) Vasopressor response to angiotensin II infusion in patients with chronic heart failure receiving β-blockers. Circulation 107:290–293

    Article  CAS  PubMed  Google Scholar 

  32. Wu L, Wang R, De Champlain J, Wilson TW (2004) Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats. Am J Hypertens 17:749–756

    Article  CAS  PubMed  Google Scholar 

  33. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S et al (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295

    Article  CAS  PubMed  Google Scholar 

  34. Yilmaz MI, Sonmez A, Caglar K, Celik T, Yenicesu M, Eyileten T et al (2007) Effect of antihypertensive agents on plasma adiponectin levels in hypertensive patients with metabolic syndrome. Nephrology 12:147–153

    Article  CAS  PubMed  Google Scholar 

  35. Zorad S, J-t D, Benicky J, Hutanu D, Tybitanclova K, Zhou J et al (2006) Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARγ. Eur J Pharmacol 552:112–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors fully acknowledge the Universiti Sains Malaysia, Research grant no. 1001/PFARMASI/815078, provided by Universiti Sains Malaysia for this work.

Sheryar Afzal is a recipient of USM Fellowship from the Institute of Post-Graduate Studies (IPS), Universiti Sains Malaysia (USM), Penang, Malaysia, and this support is gratefully acknowledged.

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Authors and Affiliations

  1. Cardiovascular and Renal Physiology Lab, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, 11800, Malaysia

    S. Afzal, M. A. Sattar, Safia Akhtar & Fayyaz Hashmi

  2. Department of Physiology, University College Cork, Cork, Ireland

    Edward J. Johns & Mohammed H. Abdulla

  3. Department of Pharmacology, Universiti Malaya, Kuala Lumpur, 50603, Malaysia

    Nor Azizan Abdullah

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  1. S. Afzal
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  2. M. A. Sattar
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  3. Edward J. Johns
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  4. Mohammed H. Abdulla
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  5. Safia Akhtar
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  6. Fayyaz Hashmi
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  7. Nor Azizan Abdullah
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Correspondence to S. Afzal.

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The present experiment was conducted in Cardiovascular and Renal Physiology Lab, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, 11800, Malaysia

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Afzal, S., Sattar, M.A., Johns, E.J. et al. Interaction between irbesartan, peroxisome proliferator-activated receptor (PPAR-γ), and adiponectin in the regulation of blood pressure and renal function in spontaneously hypertensive rats. J Physiol Biochem 72, 593–604 (2016). https://doi.org/10.1007/s13105-016-0497-1

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  • DOI: https://doi.org/10.1007/s13105-016-0497-1

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