Skip to main content
Top
Published in: Journal of Endocrinological Investigation 4/2015

01-04-2015 | Original Article

Pentoxifylline alleviates hypertension in metabolic syndrome: effect on low-grade inflammation and angiotensin system

Authors: A. Azhar, H. M. El-Bassossy

Published in: Journal of Endocrinological Investigation | Issue 4/2015

Login to get access

Abstract

Introduction and objective

Pentoxifylline is a well-tolerated drug used in treatment of vascular insufficiency. We previously showed that pentoxifylline protects from impairment in vascular reactivity in cases of metabolic syndrome. The aim of this study was to investigate the protective effect of pentoxifylline against hypertension in metabolic syndrome rats.

Methods

Metabolic syndrome was induced by feeding rats a high-fructose, high-fat and high-salt diet for 12 weeks. Pentoxifylline was administered daily (30 mg kg−1) during the last 4 weeks of the study, before blood pressure parameters were assessed at the end of study. In addition, serum levels of glucose, fructosamine, insulin, tumor necrosis factor alpha, adiponectin, and lipid profile parameters were determined. Aortic protein levels of angiotensin II and angiotensin receptor 1 were assessed by immunofluorescence.

Results

Pentoxifylline administration prevented excessive weight gain but did not affect hyperinsulinemia or hypertriglyceridemia seen in metabolic syndrome animals. In addition, pentoxifylline prevented the elevations in mean blood pressure associated with metabolic syndrome. Particularly, pentoxifylline prevented elevations in systolic, diastolic, and notch blood pressure; however, elevation in pulse blood pressure was not affected. Further, pentoxifylline alleviated the low-grade inflammation associated with metabolic syndrome, as reflected by the significantly lower serum tumor necrosis factor α and higher serum adiponectin levels metabolic syndrome animals treated with pentoxifylline. Also, pentoxifylline inhibited elevated expression of angiotensin receptor 1 in aortic tissue of metabolic syndrome animals.

Conclusion

Pentoxifylline directly alleviated hypertension in metabolic syndrome rats, at least in part, via amelioration of low-grade inflammation and inhibition of angiotensin system.
Literature
2.
go back to reference Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7CrossRefPubMed Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7CrossRefPubMed
3.
go back to reference Navab M, Gharavi N, Watson AD (2008) Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 11:459–464CrossRefPubMed Navab M, Gharavi N, Watson AD (2008) Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 11:459–464CrossRefPubMed
4.
go back to reference Frigolet ME, Torres N, Tovar AR (2013) The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 24:2003–2015CrossRefPubMed Frigolet ME, Torres N, Tovar AR (2013) The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 24:2003–2015CrossRefPubMed
5.
go back to reference Reilly DT, Quinton DN, Barrie WW (1987) A controlled trial of pentoxifylline (Trental 400) in intermittent claudication: clinical, haemostatic and rheological effects. N Z Med J 100:445–447PubMed Reilly DT, Quinton DN, Barrie WW (1987) A controlled trial of pentoxifylline (Trental 400) in intermittent claudication: clinical, haemostatic and rheological effects. N Z Med J 100:445–447PubMed
6.
go back to reference Zabel P, Schade FU, Schlaak M (1993) Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 187:447–463CrossRefPubMed Zabel P, Schade FU, Schlaak M (1993) Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 187:447–463CrossRefPubMed
7.
go back to reference El-Bassossy HM, El-Moselhy MA, Mahmoud MF (2011) Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition. Naunyn Schmiedebergs Arch Pharmacol 384:277–285CrossRefPubMed El-Bassossy HM, El-Moselhy MA, Mahmoud MF (2011) Pentoxifylline alleviates vascular impairment in insulin resistance via TNF-α inhibition. Naunyn Schmiedebergs Arch Pharmacol 384:277–285CrossRefPubMed
8.
go back to reference Azhar A, El-Bassossy HM (2014) Pentoxifylline alleviates cardiac ischemia and dysfunction following experimental angina in insulin resistance. PLoS One 9:e98281CrossRefPubMedCentralPubMed Azhar A, El-Bassossy HM (2014) Pentoxifylline alleviates cardiac ischemia and dysfunction following experimental angina in insulin resistance. PLoS One 9:e98281CrossRefPubMedCentralPubMed
9.
go back to reference Huang ZS, Lee TK (1991) Comparison of in vitro platelet aggregation and its inhibition by three antithrombotic drugs between human and guinea pig. Proc Natl Sci Counc Repub China B 15:8–14PubMed Huang ZS, Lee TK (1991) Comparison of in vitro platelet aggregation and its inhibition by three antithrombotic drugs between human and guinea pig. Proc Natl Sci Counc Repub China B 15:8–14PubMed
10.
go back to reference Weithmann KU, Just M, Schlotte V, Seiffge D (1989) Stimulatory effects of vascular prostaglandins on the antiaggregatory activities of pentoxifylline acetylsalicylic acid combinations in vitro. Vasa 18:273–276PubMed Weithmann KU, Just M, Schlotte V, Seiffge D (1989) Stimulatory effects of vascular prostaglandins on the antiaggregatory activities of pentoxifylline acetylsalicylic acid combinations in vitro. Vasa 18:273–276PubMed
11.
go back to reference Lenoble G (1989) New aspects of the pharmacology of pentoxifylline. J Mal Vasc 14 (Suppl A):35–41 Lenoble G (1989) New aspects of the pharmacology of pentoxifylline. J Mal Vasc 14 (Suppl A):35–41
12.
go back to reference Herskovits E, Famulari A, Tamaroff L, Gonzalez AM, Vazquez A, Dominguez R, Fraiman H, Vila J (1985) Preventive treatment of cerebral transient ischemia: comparative randomized trial of pentoxifylline versus conventional antiaggregants. Eur Neurol 24:73–81CrossRefPubMed Herskovits E, Famulari A, Tamaroff L, Gonzalez AM, Vazquez A, Dominguez R, Fraiman H, Vila J (1985) Preventive treatment of cerebral transient ischemia: comparative randomized trial of pentoxifylline versus conventional antiaggregants. Eur Neurol 24:73–81CrossRefPubMed
13.
go back to reference Seiffge D, Kremer E (1984) Antithrombotic effects of pentoxifylline on laser-induced thrombi in rat mesenteric arteries. IRCS Med Sci 12:91–92 Seiffge D, Kremer E (1984) Antithrombotic effects of pentoxifylline on laser-induced thrombi in rat mesenteric arteries. IRCS Med Sci 12:91–92
14.
go back to reference Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (2006) A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:F625–F631CrossRefPubMed Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (2006) A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:F625–F631CrossRefPubMed
15.
go back to reference El-Bassossy H, Dsokey N, Fahmy A (2014) Characterization of vascular complications in experimental model of fructose induced metabolic syndrome. Toxicol Mech Methods, pp 1–8. doi: 10.3109/15376516.2014.945109 El-Bassossy H, Dsokey N, Fahmy A (2014) Characterization of vascular complications in experimental model of fructose induced metabolic syndrome. Toxicol Mech Methods, pp 1–8. doi: 10.​3109/​15376516.​2014.​945109
16.
go back to reference Field KJ, White WJ, Lang CM (1993) Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats. Lab Anim 27:258–269CrossRefPubMed Field KJ, White WJ, Lang CM (1993) Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats. Lab Anim 27:258–269CrossRefPubMed
17.
go back to reference Radovits T, Bomicke T, Kokeny G, Arif R, Loganathan S, Kecsan K, Korkmaz S, Barnucz E, Sandner P, Karck M, Szabo G (2009) The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br J Pharmacol 156:909–919CrossRefPubMedCentralPubMed Radovits T, Bomicke T, Kokeny G, Arif R, Loganathan S, Kecsan K, Korkmaz S, Barnucz E, Sandner P, Karck M, Szabo G (2009) The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus. Br J Pharmacol 156:909–919CrossRefPubMedCentralPubMed
18.
go back to reference Hassan N, El-Bassossy HM, Zakaria MNM (2013) Heme oxygenase-1 induction protects against hypertension associated with diabetes: effect on exaggerated vascular contractility. Naunyn Schmiedebergs Arch Pharmacol 386:217–226CrossRefPubMed Hassan N, El-Bassossy HM, Zakaria MNM (2013) Heme oxygenase-1 induction protects against hypertension associated with diabetes: effect on exaggerated vascular contractility. Naunyn Schmiedebergs Arch Pharmacol 386:217–226CrossRefPubMed
19.
go back to reference Hassan NA, El-Bassossy HM, Mahmoud MF, Fahmy A (2014) Caffeic acid phenethyl ester, a 5-lipoxygenase enzyme inhibitor, alleviates diabetic atherosclerotic manifestations: effect on vascular reactivity and stiffness. Chem Biol Interact 213:28–36CrossRefPubMed Hassan NA, El-Bassossy HM, Mahmoud MF, Fahmy A (2014) Caffeic acid phenethyl ester, a 5-lipoxygenase enzyme inhibitor, alleviates diabetic atherosclerotic manifestations: effect on vascular reactivity and stiffness. Chem Biol Interact 213:28–36CrossRefPubMed
20.
go back to reference Mahmoud MF, Hassan NA, El Bassossy HM, Fahmy A (2013) Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLoS One 8:1–11 Mahmoud MF, Hassan NA, El Bassossy HM, Fahmy A (2013) Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLoS One 8:1–11
21.
go back to reference El-Bassossy HM, Fahmy A, Badawy D (2011) Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem Toxicol 49:3007–3012CrossRefPubMed El-Bassossy HM, Fahmy A, Badawy D (2011) Cinnamaldehyde protects from the hypertension associated with diabetes. Food Chem Toxicol 49:3007–3012CrossRefPubMed
22.
go back to reference El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML (2013) Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol 169:693–703CrossRefPubMedCentralPubMed El-Bassossy HM, El-Fawal R, Fahmy A, Watson ML (2013) Arginase inhibition alleviates hypertension in the metabolic syndrome. Br J Pharmacol 169:693–703CrossRefPubMedCentralPubMed
23.
go back to reference Rowell LB (1993) Human cardiovascular control. Oxford University Press, New YorkCrossRef Rowell LB (1993) Human cardiovascular control. Oxford University Press, New YorkCrossRef
24.
go back to reference Hulin I, Kinova S, Paulis L, Slavkovsky P, Duris I, Mravec B (2010) Diastolic blood pressure as a major determinant of tissue perfusion: potential clinical consequences. Bratislavsk_Ñ lek_Érske listy 111: 54–56 Hulin I, Kinova S, Paulis L, Slavkovsky P, Duris I, Mravec B (2010) Diastolic blood pressure as a major determinant of tissue perfusion: potential clinical consequences. Bratislavsk_Ñ lek_Érske listy 111: 54–56
25.
go back to reference Strandberg TE, Pitkala K (2003) What is the most important component of blood pressure: systolic, diastolic or pulse pressure? Curr Opin Nephrol Hypertens 12:293–297CrossRefPubMed Strandberg TE, Pitkala K (2003) What is the most important component of blood pressure: systolic, diastolic or pulse pressure? Curr Opin Nephrol Hypertens 12:293–297CrossRefPubMed
26.
go back to reference Raptis S, Mitrakou A, Hadjidakis D, Diamantopoulos E, Anastasiou C, Fountas A, Muller R (1987) 24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas. Acta Diabetol Lat 24:181–192CrossRefPubMed Raptis S, Mitrakou A, Hadjidakis D, Diamantopoulos E, Anastasiou C, Fountas A, Muller R (1987) 24-h blood glucose pattern in type I and type II diabetics after oral treatment with pentoxifylline as assessed by artificial endocrine pancreas. Acta Diabetol Lat 24:181–192CrossRefPubMed
27.
go back to reference Flint H, Cotter MA, Cameron NE (2000) Pentoxifylline effects on nerve conduction velocity and blood flow in diabetic rats. Int J Exp Diabetes Res 1:49–58CrossRefPubMedCentralPubMed Flint H, Cotter MA, Cameron NE (2000) Pentoxifylline effects on nerve conduction velocity and blood flow in diabetic rats. Int J Exp Diabetes Res 1:49–58CrossRefPubMedCentralPubMed
28.
go back to reference Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823CrossRefPubMed Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823CrossRefPubMed
29.
go back to reference Mahmoud MF, El-Nagar M, El-Bassossy HM (2012) Anti-inflammatory effect of atorvastatin on vascular reactivity and insulin resistance in fructose fed rats. Arch Pharm Res 35:155–162CrossRefPubMed Mahmoud MF, El-Nagar M, El-Bassossy HM (2012) Anti-inflammatory effect of atorvastatin on vascular reactivity and insulin resistance in fructose fed rats. Arch Pharm Res 35:155–162CrossRefPubMed
30.
go back to reference Brito G, Dourado M, Polari L, Celestino D, Carvalho LP, Queiroz A, Carvalho EM, Machado PRL, Passos S (2014) Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline. Am J Trop Med Hyg 90:617–620CrossRefPubMed Brito G, Dourado M, Polari L, Celestino D, Carvalho LP, Queiroz A, Carvalho EM, Machado PRL, Passos S (2014) Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline. Am J Trop Med Hyg 90:617–620CrossRefPubMed
31.
go back to reference Goicoechea M, Garcia de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, Panizo N, Verde E, Munoz MA, Luno J (2012) Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol 25:969–975CrossRefPubMed Goicoechea M, Garcia de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, Panizo N, Verde E, Munoz MA, Luno J (2012) Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol 25:969–975CrossRefPubMed
32.
go back to reference Gonzalez-Espinoza L, Rojas-Campos E, Medina-Perez M, Pena-Quintero P, Gomez-Navarro B, Cueto-Manzano AM (2012) Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial. Nephrol Dial Transpl 27:2023–2028CrossRef Gonzalez-Espinoza L, Rojas-Campos E, Medina-Perez M, Pena-Quintero P, Gomez-Navarro B, Cueto-Manzano AM (2012) Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial. Nephrol Dial Transpl 27:2023–2028CrossRef
33.
go back to reference Maiti R, Agrawal NK, Dash D, Pandey BL (2007) Effect of pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients. Vasc Pharmacol 47:118–124CrossRef Maiti R, Agrawal NK, Dash D, Pandey BL (2007) Effect of pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients. Vasc Pharmacol 47:118–124CrossRef
34.
go back to reference Fernandes JL, de Oliveira RT, Mamoni RL, Coelho OR, Nicolau JC, Blotta MH, Serrano CV (2008) Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease—a randomized placebo-controlled study. Atherosclerosis 196:434–442CrossRefPubMed Fernandes JL, de Oliveira RT, Mamoni RL, Coelho OR, Nicolau JC, Blotta MH, Serrano CV (2008) Pentoxifylline reduces pro-inflammatory and increases anti-inflammatory activity in patients with coronary artery disease—a randomized placebo-controlled study. Atherosclerosis 196:434–442CrossRefPubMed
35.
go back to reference Ghorbani A, Omidvar B, Beladi-Mousavi SS, Lak E, Vaziri S (2012) The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: a double blind and randomized clinical trial. Nefrologia 32:790–796PubMed Ghorbani A, Omidvar B, Beladi-Mousavi SS, Lak E, Vaziri S (2012) The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: a double blind and randomized clinical trial. Nefrologia 32:790–796PubMed
36.
go back to reference Kang YM, Wang Y, Yang LM, Elks C, Cardinale J, Yu XJ, Zhao XF, Zhang J, Zhang LH, Yang ZM, Francis J (2010) TNF-α in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters. Tohoku J Exp Med 222:251–263CrossRefPubMed Kang YM, Wang Y, Yang LM, Elks C, Cardinale J, Yu XJ, Zhao XF, Zhang J, Zhang LH, Yang ZM, Francis J (2010) TNF-α in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters. Tohoku J Exp Med 222:251–263CrossRefPubMed
37.
go back to reference Guggilam A, Patel KP, Haque M, Ebenezer PJ, Kapusta DR, Francis J (2008) Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail 10:625–634CrossRefPubMedCentralPubMed Guggilam A, Patel KP, Haque M, Ebenezer PJ, Kapusta DR, Francis J (2008) Cytokine blockade attenuates sympathoexcitation in heart failure: cross-talk between nNOS, AT-1R and cytokines in the hypothalamic paraventricular nucleus. Eur J Heart Fail 10:625–634CrossRefPubMedCentralPubMed
38.
go back to reference Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Chahin J, Mendez ML, Gallego E, Macia M, del Castillo N, Rivero A, Getino MA, Garcia P, Jarque A, Garcia J (2014) Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol ASN [Epub ahead of print] Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Chahin J, Mendez ML, Gallego E, Macia M, del Castillo N, Rivero A, Getino MA, Garcia P, Jarque A, Garcia J (2014) Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN trial. J Am Soc Nephrol ASN [Epub ahead of print]
39.
go back to reference Kabbesh N, Gogny M, Chatagnon G, Noireaud J, Thorin C, Desfontis JC, Mallem MY (2012) Vasodilatory effect of pentoxifylline in isolated equine digital veins. Vet J 192:368–373CrossRefPubMed Kabbesh N, Gogny M, Chatagnon G, Noireaud J, Thorin C, Desfontis JC, Mallem MY (2012) Vasodilatory effect of pentoxifylline in isolated equine digital veins. Vet J 192:368–373CrossRefPubMed
40.
go back to reference Greenberg A, Piraino BH, Kroboth PD, Weiss J (1984) Severe theophylline toxicity. Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion. Am J Med 76:854–860CrossRefPubMed Greenberg A, Piraino BH, Kroboth PD, Weiss J (1984) Severe theophylline toxicity. Role of conservative measures, antiarrhythmic agents, and charcoal hemoperfusion. Am J Med 76:854–860CrossRefPubMed
Metadata
Title
Pentoxifylline alleviates hypertension in metabolic syndrome: effect on low-grade inflammation and angiotensin system
Authors
A. Azhar
H. M. El-Bassossy
Publication date
01-04-2015
Publisher
Springer International Publishing
Published in
Journal of Endocrinological Investigation / Issue 4/2015
Electronic ISSN: 1720-8386
DOI
https://doi.org/10.1007/s40618-014-0209-z

Other articles of this Issue 4/2015

Journal of Endocrinological Investigation 4/2015 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine