OJEMD  Vol.4 No.7 , July 2014
Can Sitaglipten Attenuate Hypertension, Myocardial Changes and Vascular Reactivity Induced by Long Term Blockade of Nitric Oxide Synthesis in the Rat?
Abstract: Background: Glucagon-like peptide-1 (GLP-1) is an incretin hormone with insulinotropic properties that regulates glucose metabolism. GLP-1 receptors are the most extensively key modulators of lipid and glucose homeostasis. They are predominantly expressed in adipose tissues, some non adipose tissues including heart, kidney, spleen, and all relevant cells of the vasculature: endothelial cells, smooth muscle cells, and macrophages. The vascular distribution suggests their involvement in the control of cardiovascular function. Objective: The present experiment was designed to study the effect of sitaglipten alone or in combination with captopril on blood pressure, antioxidant enzymes, vascular reactivity and cardiac hypertrophy in NG-nitro-L-arginine methylester (L-NAME) induced hypertension in rats. Methods: One hundred male albino rats weighing from 150 - 200 g were included in this study. Rats were divided into two main groups. Group I, (20 rats) served as a control group for group II, and received 1 ml of physiological saline (0.9%), orally for seven weeks. Group II: hypertensive group, (80 rats) was given daily L-NAME in a dose of 40 mg/kg orally for seven weeks. Rats were further subdivided into A, B, C, and D, each of 20 rats. Group-A, received 1 ml of distilled water daily orally for six weeks, starting one week after L-NAME administration. Groups B, C and D were treated with daily sitaglipten (10 mg/kg b.wt. orally) and captopril (100 mg/kg b.wt. orally), alone or together for six weeks. Blood pressure, serum tumor necrosis factor-α (TNF-α), body weight (BW) and heart weight (HW) were measured. Malondialdehyde (MDA) and reduced glutathione (GSH) were estimated in cardiac tissues. Thoracic aorta was isolated and the aortic rings were allowed to achieve maximal tension by cumulative addition of phenylephrine (PE) (10-9-10-5 M) to the bath solution. Results: Sitaglipten and captopril, alone or together produced significant decreases in blood pressure and TNF-α. Higher oxidative stress accompanying hypertension was significantly reduced by sitaglipten and captopril treatment. The results showed that both drugs significantly attenuated the augmented contractile response to PE in hypertensive rats. In addition, they inhibited the cardiac hypertrophy (reduction in HW/BW ratio). Conclusion: These data suggest that DPP4 inhibitor (sitaglipten) “is away from being insulinotropic and regulates glucose metabolism”, contributes to normal regulation of blood pressure and exerts protective effects in hypertension via many mechanisms, as inhibition of generation of free radicals.
Cite this paper: Mohamed, M. (2014) Can Sitaglipten Attenuate Hypertension, Myocardial Changes and Vascular Reactivity Induced by Long Term Blockade of Nitric Oxide Synthesis in the Rat?. Open Journal of Endocrine and Metabolic Diseases, 4, 197-210. doi: 10.4236/ojemd.2014.47019.

[1]   Verma, A. and Solomon, S.D. (2009) Diastolic Dysfunction as a Link between Hypertension and Heart Failure. Medical Clinics of North America, 93, 647-664.

[2]   Sciarretta, S., Paneni, F., Palano, F., Chin, D., Tocci, G., Rubattu, S. and Volpe, M. (2009) Role of the Renin-Angiotensin-Aldosterone System and Inflammatory Processes in the Development and Progression of Diastolic Dysfunction. Clinical Science, 116, 467-477.

[3]   Reboldi, G., Gentile, G., Angeli, F. and Verdecchia, P. (2009) Choice of ACE Inhibitor Combinations in Hypertensive Patients with Type 2 Diabetes: Update after Recent Clinical Trials. Vascular Health and Risk Management, 5, 411-427.

[4]   Van Heerebeek, L., Somsen, A. and Paulus, W.J. (2009) The Failing Diabetic Heart: Focus on Diastolic Left Ventricular Dysfunction. Current Diabetes Reports, 9, 79-86.

[5]   Drucker, D.J. (2007) The Role of Gut Hormones in Glucose Homeostasis. Journal of Clinical Investigation, 117, 24-32.

[6]   Nikolaidis, L.A., Sunil Mankad, S., Sokos, G.G., Miske, G., Shah, A., Elahi, D. and Shannon, R.P. (2004) Effects of Glucagon-Like Peptide-1 in Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction after Successful Reperfusion. Circulation, 109, 962-965.

[7]   Yu, M., Moreno, C., Hoagland, K.M., Dahly, A., Ditter, K., Mistry, M. and Roman, R.J. (2003) Antihypertensive Effects of Glucagon-Like Peptide-1 in Dahl Salt-Sensitive rats. Journal of Hypertension, 21, 1125-1135.

[8]   Garber, A.J. (2012) Novel GLP-1 Receptor Agonists for Diabetes. Expert Opinion on Investigational Drugs, 21, 45-57.

[9]   Chang, G., Zhang, P., Ye, L., Lu, K., Wang, Y., Duan, Q., et al. (2013) Protective Effects of Sitagliptin on Myocardial Injury and Cardiac Function in an Ischemia/Reperfusion Rat Model. European Journal of Pharmacology, 718, 105-113.

[10]   Henrion, D., Dechaux, E., Dowell, F.J., Maclouf, J., Samuel, J., Levy, B.I. and Michel, J.B. (1997) Alteration of Flow-Induced Dilatation in Mesenteric Resistance Arteries of L-NAME Treated Rats and Its Partial Association with Induction of Cyclo-Oxygenase-2. British Journal of Pharmacology, 121, 83-90.

[11]   Khan, B.V., Harrison, D.G., Olbrych, M.T., Alexander, R.W. and Medford, R.M. (1996) Nitric Oxide Regulates Vascular Cell Adhesion Molecule 1 Gene Expression and Redox-Sensitive Transcriptional Events in Human Vascular Endothelial Cells. Proceedings of the National Academy of Sciences, 93, 9114-9119.

[12]   Bernatova, I., Pechanova, O. and Simko, F. (1994) Effect of Captopril in L-NAME-Induced Hypertension on the Rat Myocardium, Aorta, Brain and Kidney. Experimental Physiology, 84, 1095-1105.

[13]   Bose, A.K., Mocanu, M.M., Carr, R.D. and Yellon, D.M. (2005) Glucagon Like Peptide-1 Is Protective against Myocardial Ischemia/Reperfusion Injury When Given Either as a Preconditioning Mimetic or at Reperfusion in an Isolated Rat Heart Model. Cardiovascular Drugs and Therapy, 19, 9-11.

[14]   Freslon, J.L. and Giudicelli, J.F. (1983) Compared Myocardial and Vascular Effects of Captopril and Dihydralazine during Hypertension Development in Spontaneously Hypertensive Rats. British Journal of Pharmacology, 80, 533-543.

[15]   Riley, V. (1960) Adaptation of Orbital Bleeding Technique to Rapid Serial Blood Studies. Experimental Biology and Medicine, 104, 751-755.

[16]   Mattson, D.L. (1998) Long-Term Measurement of Arterial Blood Pressure in Conscious Mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 274, R564-R570.

[17]   Aukrust, P., Libak, N.B., Muller, F., Lien, E., Espevik, T. and Froland, S.S. (1994) Serum Levels of Tumor Necrosis Factor-α (TNF-α) and Soluble TNF Receptors in Human Immunodeficiency Virus Type 1 Infection, Correlations to Clinical Immunologic and Virologic Parameters. Journal of Infectious Diseases, 169, 420-424.

[18]   Ohkawa, H., Ohishi, M. and Yagi, K. (1979) Assay for Lipid Peroxides in Animal Tissues by Thiobarbituric Acid Reaction. Analytical Biochemistry, 95, 351-358.

[19]   Ellman, G.I. (1959) Tissue Sulfhydryl Groups. Archives of Biochemistry and Biophysics, 82, 70-77.

[20]   Satoh, H. and Satoh, S. (1984) Prostaglandine E2 and I2 Production in Isolated Renal Arteries in Absence or Presence of Vascular Endothelial Cells. Biochemical and Biophysical Research Communications, 188, 873-876.

[21]   Brooks, W.W., Bing, O.H.L., Robinson, K.G., Slawsky, M.T., Chaletsky, D.M. and Conard, C.H. (1997) Effect of Angiotensin-Converting Enzyme Inhibition on Myocardial Fibrosis and Function in Hypertrophied and Failing Myocardium from the Spontaneously Hypertensive Rat. Circulation, 96, 4002-4010.

[22]   Hill, B.A. (1971) Principles of Medical Statistics. 9th Edition, Lancet Limited Publications, London, 147, 383.

[23]   Lorber, D. (2012) GLP-1 Receptor Agonists: Effects on Cardiovascular Risk Reduction. Cardiovascular Therapeutics, 31, 238-249.

[24]   Wong, W.T., Wong, S.L., Tian, X.Y. and Huang, Y. (2010) Endothelial Dysfunction: The Common Consequence in Diabetes and Hypertension. Journal of Cardiovascular Pharmacology, 55, 300-307.

[25]   Stratton, I.M., Cull, C.A., Adler, A.I., Matthews, D.R., Neil, H.A. and Holman, R.R. (2006) Additive Effects of Glycaemia and Blood Pressure Exposure on Risk of Complications in Type 2 Diabetes: A Prospective Observational Study (UKPDS 75). Diabetologia, 49, 1761-1769.

[26]   Chinda, K., Palee, S., Surinkaew, S., Phornphutkul, M., Chattipakorn, S. and Chattipakorn, N. (2013) Cardioprotective Effect of Dipeptidyl Peptidase-4 Inhibitor during Ischemia-Reperfusion Injury. International Journal of Cardiology, 167, 451-457.

[27]   Huisamen, B., Genis, A., Marais, E. and Lochner, A. (2011) Pre-Treatment with a DPP-4 Inhibitor Is Infarct Sparing in Hearts from Obese, Pre-Diabetic Rats. Cardiovascular Drugs and Therapy, 25, 13-20.

[28]   Schwartz, E.A., Koska, J., Mullin, M.P., Syoufi, I., Schwenke, D.C. and Reaven, P.D. (2010) Exenatide Suppresses Postprandial Elevations in Lipids and Lipoproteins in Individuals with Impaired Glucose Tolerance and Recent Onset Type 2 Diabetes Mellitus. Atherosclerosis, 212, 217-222.

[29]   Grieve, D.J., Cassidy, R.S. and Green, B.D. (2009) Emerging Cardiovascular Actions of the Incretin Hormone Glucagon-Like Peptide-1: Potential Therapeutic Benefits beyond Glycaemic Control? British Journal of Pharmacology, 157, 1340-1351.

[30]   Ku, H.C., Chen, W.P. and Su, M.J. (2010) GLP-1 Signaling Preserves Cardiac Function in Endotoxemic Fischer 344 and DPP4-Deficient Rats. Naunyn-Schmiedeberg’s Archives of Pharmacology, 382, 463-474.

[31]   Mundil, D., Cameron-Vendrig, A. and Husain, M. (2012) GLP-1 Receptor Agonists: A Clinical Perspective on Cardiovascular Effects. Diabetes and Vascular Disease Research, 9, 95-108.

[32]   Gill, A., Hoogwerf, B.J., Burger, J., Bruce, S., Macconell, L., Yan, P., Braun, D., Giaconia, J. and Malone, J. (2010) Effect of Exenatide on Heart Rate and Blood Pressure in Subjects with Type 2 Diabetes Mellitus: A Double-Blind, Placebo Controlled, Randomized Pilot Study. Cardiovascular Diabetology, 9, 16.

[33]   Scheen, A.J. (2012) Cardiovascular Effects of Gliptins. Nature Reviews. Cardiology, 10, 73-84.

[34]   Kim, M., Platt, M.J., Shibasaki, T., Quaggin, S.E., Backx, P.H., Seino, S., Simpson, J.A. and Drucker, D.J. (2013) GLP-1 Receptor Activation and Epac2 Link Atrial Natriuretic Peptide Secretion to Control of Blood Pressure. Nature Medicine, 19, 567-575.

[35]   Read, P.A., Hoole, S.P., White, P.A., Khan, F.Z., O’Sullivan, M., West, N.E. and Dutka, D.P. (2011) A Pilot Study to Assess Whether Glucagon-Like Peptide-1 Protects the Heart from Ischemic Dysfunction and Attenuates Stunning after Coronary Balloon Occlusion in Humans. Circulation: Cardiovascular Interventions, 4, 266-272.

[36]   Liu, L., Liu, J., Wong, W.T., Tian, X.Y., Lau, C.W., Wang, Y.X., et al. (2012) Dipeptidyl Peptidase 4 Inhibitor Sitagliptin Protects Endothelial Function in Hypertension through a Glucagon-Like Peptide 1-Dependent Mechanism. Hypertension, 60, 833-841.

[37]   Pacheco, B.P., Crajoinas, R.O., Couto, G.K., Davel, A.P., Lessa, L.M., Rossoni, L.V. and Girardi, A.C. (2011) Dipeptidyl Peptidase IV Inhibition Attenuates Blood Pressure Rising in Young Spontaneously Hypertensive Rats. Journal of Hypertension, 29, 520-528.

[38]   Ceriello, A., Esposito, K., Testa, R., Bonfigli, A.R., Marra, M. and Giugliano, D. (2011) The Possible Protective Role of Glucagon-Like Peptide 1 on Endothelium During the Meal and Evidence for an “Endothelial Resistance” to Glucagon-Like Peptide 1 in Diabetes. Diabetes Care, 34, 697-702.

[39]   Koska, J., Schwartz, E.A., Mullin, M.P., Schwenke, D.C. and Reaven, P.D. (2010) Improvement of Postprandial Endothelial Function after a Single Dose of Exenatide in Individuals with Impaired Glucose Tolerance and Recent-Onset Type 2 Diabetes. Diabetes Care, 33, 1028-30.

[40]   Arakawa, M., Mita, T., Azuma, K., Ebato, C., Goto, H., Nomiyama, T., Fujitani, Y., Hirose, T., Kawamori, R. and Watada, H. (2010) Inhibition of Monocyte Adhesion to Endothelial Cells and Attenuation of Atherosclerotic Lesion by a Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4. Diabetes, 59, 1030-1037.

[41]   Liu, H., Hu, Y., Simpson, R.W. and Dear, A.E. (2008) Glucagon-Like Peptide-1 Attenuates Tumour Necrosis Factor-Alpha-Mediated Induction of Plasmogen Activator Inhibitor-1 Expression. Journal of Endocrinology, 196, 57-65.

[42]   Ferreira, L., Teixeira-De-Lemos, E., Pinto, F., Parada, B., Mega, C., Vala, H., et al. (2010) Effects of Sitagliptin Treatment on Dysmetabolism, Inflammation, and Oxidative Stress in an Animal Model of Type 2 Diabetes (ZDF Rat). Mediators of Inflammation, 2010, Article ID: 592760.

[43]   Matsui, T., Nishino, Y., Takeuchi, M. and Yamagishi, S.I. (2011) Vildagliptin Blocks Vascular Injury in Thoracic Aorta of Diabetic Rats by Suppressing Advanced Glycation End Product-Receptor Axis. Pharmacological Research, 63, 383-388.

[44]   Zhang, X., Wang, Z., Huang, Y. and Wang, J. (2011) Effects of Chronic Administration of Alogliptin on the Development of Diabetes and β-Cell Function in High Fat Diet/Streptozotocin Diabetic Mice. Diabetes, Obesity and Metabolism, 13, 337-347.

[45]   Liu, Q., Anderson, C., Broyde, A., Polizzi, C., Fernandez, R., Baron, A. and Parkes, D.G. (2010) Glucagon-Like Peptide-1 and the Exenatide Analogue AC3174 Improve Cardiac Function, Cardiac Remodeling, and Survival in Rats with Chronic Heart Failure. Cardiovascular Diabetology, 9, 76.

[46]   Ossum, A., van Deurs, U., Engstrom, T., Jensen, J.S. and Treiman, M. (2009) The Cardioprotective and Inotropic Components of the Postconditioning Effects of GLP-1 and GLP-1(9-36)a in an Isolated Rat Heart. Pharmacological Research, 60, 411-417.

[47]   Best, J.H., Hoogwerf, B.J., Herman, W.H., Pelletier, E.M., Smith, D.B., Wenten, M. and Hussein, M.A. (2011) Risk of Cardiovascular Disease Events in Patients with Type 2 Diabetes Prescribed the Glucagon-Like Peptide 1 (GLP-1) Receptor Agonist Exenatide Twice Daily or Other Glucose-Lowering Therapies: A Retrospective Analysis of the Life Link Database. Diabetes Care, 34, 90-95.

[48]   Pfisterer, M., Buser, P., Rickli, H., Gutmann, M., Erne, P., et al. (2009) BNP-Guided vs Symptom-Guided Heart Failure Therapy: The Trial of Intensified vs Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIMECHF) Randomized Trial. JAMA, 301, 383-392.

[49]   Yan, X., Sano, M., Lu, L., Wang, W., Zhang, Q., Zhang, R.Y., Wang, L.J., Chen, Q.J., Fukuda, K. and Shen, W.F. (2010) Plasma Concentrations of Osteopontin, but Not Thrombin-Cleaved Osteopontin, Are Associated with the Presence and Severity of Nephropathy and Coronary Artery Disease in Patients with Type 2 Diabetes Mellitus. Cardiovascular Diabetology, 9, 70.

[50]   Susana, R., Amaia, Z. and Diez, J. (2012) GLP-1 and Cardioprotection: From Bench to Bedside. Cardiovascular Research, 94, 1-8.

[51]   Guleria, R.S., Choudhary, R., Tanaka, T., Baker, K.M. and Pan, J. (2011) Retinoic Acid Receptor-Mediated Signaling Protects Cardiomyocytes from Hyperglycemia Induced Apoptosis: Role of the Rennin Angiotensin System. Journal of Cellular Physiology, 226, 1292-1307.

[52]   Kumar, R., Yong, Q.C., Thomas, C.M. and Baker, K.M. (2012) Intracardiac Intracellular Angiotensin System in Diabetes. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 302, R510-R517.

[53]   Kurdi, M. and Booz, G.W. (2011) New Take on the Role of Angiotensin II in Cardiac Hypertrophy and Fibrosis. Hypertension, 57, 1034-1038.