Skip to main content
NCBI home page
Current Therapeutic Research, Clinical and Experimental logoLink to Current Therapeutic Research, Clinical and Experimental
. 2007 Sep;68(5):338–348. doi: 10.1016/j.curtheres.2007.10.008

Effects of Valsartan on Inflammatory and Oxidative Stress Markers in Hypertensive, Hyperglycemic Patients: An Open-Label, Prospective Study

Koji Kuboki 1, Kaoru Iso 1, Eiichi Murakami 2, Seiko Abe 3, Emi Araki 3, Hajime Ueshiba 1, Gen Yoshino 1,a
PMCID: PMC3969933  PMID: 24692765

Abstract

Background: Diabetes mellitus and hypertension are aggravated by activation of the renin-angiotensin system caused by increased oxygen stress and local inflammatory responses. Several studies have suggested that angiotensin II type 1 receptors can reduce inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, IL-18, soluble vascular cell adhesion molecule [VCAM]-I, and l-selectin) and oxidative stress markers (urinary 8-hydroxy-7,8-dihydro-2'-deoxyguanosine [8-OHdG] and 8-epi-prostaglandin F2α [8-isoprostane]) in hypertensive patients.

Objective: The aim of this study was to assess the effects of valsartan, an angiotensin II receptor blocker, on inflammatory and oxidative stress markers in hypertensive patients with mild diabetes or impaired glucose tolerance.

Methods: In this open-label, prospective study, hypertensive patients aged >20 years with mild diabetes (requiring treatment by diet alone or an oral hypoglycemic), seen on an outpatient basis at the Division of Diabetes, Metabolism, and Endocrinology, Omori Hospital, Toyko, Japan, who were receiving a therapeutic dietary regimen for ≥1 month in the treatment of diabetes or hypertension, were eligible for enrollment. Blood pressure, inflammatory markers (hs-CRP, IL-6, IL-18, VCAM-1, and L-selectin), and oxidative stress markers (urinary 8-OHdG and 8-isoprostane) were monitored before treatment commencement with valsartan (40-80 mg/d) and after 3 months of treatment.

Results: A total of 26 patients (18 men, 8 women; mean [SD] age, 57.7 [11.3] years; mean [SD] weight, 65.3 [13.1] kg) were enrolled in the study. After 3 months of treatment, patients' mean (SD) blood pressure had significantly decreased from 153.1 (11.2)/88.3 (11.4) to 143.7 (13.7)/85.2 (9.0) mm Hg (P < 0.05). Among the inflammatory and oxidative stress markers, hs-CRP, VCAM-1, and urinary 8-OHdG concentrations decreased significantly from 0.231 (0.199) to 0.134 (0.111) mg/dL (P = 0.043), 471.1 (193.9) to 403.2 (135.2) ng/mL (P = 0.012), and 12.12 (5.99) to 8.07 (3.36) ng/mg · creatinine (P = 0.001), respectively. The reductions in these markers were observed in patients regardless of whether or not their glycosylated hemoglobin (HbA1c) concentration improved (defined as a decrease of ≥1% in HbA1c).

Conclusion: This small, open-label, prospective study found that a 3-month treatment with valsartan was associated with a significant reduction of hs-CRP, VCAM-1, and urinary 8-OHdG concentrations independent of improvement in HbA1c concentration in these hypertensive patients with hyperglycemia.

Key words: valsartan, hypertension, diabetes, inflammatory marker, oxidative stress marker

Full Text

The Full Text of this article is available as a PDF (646.5 KB).

References

  • 1.Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–2038. doi: 10.1001/jama.241.19.2035. [DOI] [PubMed] [Google Scholar]
  • 2.National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–3421. [PubMed] [Google Scholar]
  • 3.Definition and the diagnostic standard for metabolic syndrome—Committee to Evaluate Diagnostic Standards for Metabolic Syndrome. Nippon Naika Gakkai Zasshi. 2005;94:794–809. [in Japanese] [PubMed] [Google Scholar]
  • 4.Turnbull F, for the Blood Pressure Lowering Treatment Trialists' Collaboration Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527–1535. doi: 10.1016/s0140-6736(03)14739-3. [DOI] [PubMed] [Google Scholar]
  • 5.Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: A quantitative overview updated until 1 March 2003. J Hypertens. 2003;21:1055–1076. doi: 10.1097/00004872-200306000-00002. [DOI] [PubMed] [Google Scholar]
  • 6.Rakugi H, Ogihara T. Guidelines for treatment of hypertension: JSH2004. Nippon Ronen Igakkai Zasshi. 2006;43:569–573. doi: 10.3143/geriatrics.43.569. [DOI] [PubMed] [Google Scholar]
  • 7.Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation. 1988;77:I4–I13. [PubMed] [Google Scholar]
  • 8.Shiuchi T, Iwai M, Li HS. Angiotensin II type-1 receptor blocker valsartan enhances insulin sensitivity in skeletal muscles of diabetic mice. Hypertension. 2004;43:1003–1010. doi: 10.1161/01.HYP.0000125142.41703.64. [DOI] [PubMed] [Google Scholar]
  • 9.Chan P, Wong KL, Liu IM. Antihyperglycemic action of angiotensin II recep- tor antagonist, valsartan, in streptozotocin-induced diabetic rats. J Hypertens. 2003;21:761–769. doi: 10.1097/00004872-200304000-00020. [DOI] [PubMed] [Google Scholar]
  • 10.Dzau VJ. Theodore Cooper Lecture: Tissue angiotensin and pathobiology of vascular disease: A unifying hypothesis. Hypertension. 2001;37:1047–1052. doi: 10.1161/01.hyp.37.4.1047. [DOI] [PubMed] [Google Scholar]
  • 11.Cheng ZJ, Vapaatalo H, Mervaala E. Angiotensin II and vascular inflammation. Med Sci Monit. 2005;11:RA194–RA205. [PubMed] [Google Scholar]
  • 12.Ridker PM, Danielson E, Rifai N. Valsartan, blood pressure reduction, and C-reactive protein: Primary report of the Val-MARC trial. Hypertension. 2006;48:73–79. doi: 10.1161/01.HYP.0000226046.58883.32. for the Val-MARC Investigators. [DOI] [PubMed] [Google Scholar]
  • 13.Saisho Y, Komiya N, Hirose H. Effect of valsartan, an angiotensin II receptor blocker, on markers of oxidation and glycation in Japanese type 2 diabetic subjects: Blood pressure-independent effect of valsartan. Diabetes Res Clin Pract. 2006;74:201–203. doi: 10.1016/j.diabres.2006.04.015. [DOI] [PubMed] [Google Scholar]
  • 14.Ogawa S, Mori T, Nako K. Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy. Hypertens. 2006;47:699–705. doi: 10.1161/01.HYP.0000203826.15076.4b. [DOI] [PubMed] [Google Scholar]
  • 15.Ledue TB, Weiner DL, Sipe JD. Analytical evaluation of particle-enhanced immunonephelometric assays for C-reactive protein, serum amyloid A and mannose-binding protein in human serum. Ann Clin Biochem. 1998;35:745–753. doi: 10.1177/000456329803500607. [DOI] [PubMed] [Google Scholar]
  • 16.Proudfoot J, Barden A, Mori TA. Measurement of urinary F(2)-isoprostanes as markers of in vivo lipid peroxidation—a comparison of enzyme immunoassay with gas chromatography/mass spectrometry. Anal Biochem. 1999;272:209–215. doi: 10.1006/abio.1999.4187. [DOI] [PubMed] [Google Scholar]
  • 17.Erhola M, Toyokuni S, Okada K. Biomarker evidence of DNA oxidation in lung cancer patients: Association of urinary 8-hydroxy-2Ldeoxyguanosine excretion with radiotherapy, chemotherapy, and response to treatment. FEBS Lett. 1997;409:287–291. doi: 10.1016/s0014-5793(97)00523-1. [DOI] [PubMed] [Google Scholar]
  • 18.Sesso HD, Buring JE, Rifai N. C-reactive protein and the risk of developing hypertension. JAMA. 2003;290:2945–2951. doi: 10.1001/jama.290.22.2945. [DOI] [PubMed] [Google Scholar]
  • 19.Niskanen L, Laaksonen DE, Nyyssonen K. Inflammation, abdominal obesity, and smoking as predictors of hypertension. Hypertension. 2004;44:859–865. doi: 10.1161/01.HYP.0000146691.51307.84. [DOI] [PubMed] [Google Scholar]
  • 20.Rahman ST, Lauten WB, Khan QA. Effects of eprosartan versus hydrochloro-thiazide on markers of vascular oxidation and inflammation and blood pressure (renin-angiotensin system antagonists, oxidation, and inflammation) Am J Cardiol. 2002;89:686–690. doi: 10.1016/s0002-9149(01)02340-2. [DOI] [PubMed] [Google Scholar]
  • 21.Fliser D, Buchholz K, Hailer H, for the EUropean Trial on Olmesartan and Pravastatin in Inflammation and Atherosclerosis (EUTOPIA) Investigators Antiinflammatory effects of angiotensin II subtype 1 receptor blockade in hypertensive patients with microinflammation. Circulation. 2004;110:1103–1107. doi: 10.1161/01.CIR.0000140265.21608.8E. [DOI] [PubMed] [Google Scholar]
  • 22.Schieffer B, Bunte C, Witte J. Comparative effects of ATl-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease. J Am Coll Cardiol. 2004;44:362–368. doi: 10.1016/j.jacc.2004.03.065. [DOI] [PubMed] [Google Scholar]
  • 23.Brasier AR, Recinos A, III, Eledrisi MS. Vascular inflammation and the reninangiotensin system. Arterioscler Thromb Vasc Biol. 2002;22:1257–1266. doi: 10.1161/01.atv.0000021412.56621.a2. [DOI] [PubMed] [Google Scholar]
  • 24.Wang CH, Li SH, Weisel RD. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation. 2003;107:1783–1790. doi: 10.1161/01.CIR.0000061916.95736.E5. [DOI] [PubMed] [Google Scholar]
  • 25.Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148. doi: 10.1161/01.res.74.6.1141. [DOI] [PubMed] [Google Scholar]
  • 26.Verma S, Li SH, Badiwala MV. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002;105:1890–1896. doi: 10.1161/01.cir.0000015126.83143.b4. [DOI] [PubMed] [Google Scholar]
  • 27.Julius S, Kjeldsen SE, Weber M, for the VALUE Trial Group Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial. Lancet. 2004;363:2022–2031. doi: 10.1016/S0140-6736(04)16451-9. [DOI] [PubMed] [Google Scholar]
  • 28.Mochizuki S, Shimizu M, Taniguchi I, for the JIKEI HEART Study Group JIKEI HEART Study—a morbi-mortality and remodeling study with valsartan in Japanese patients with hypertension and cardiovascular disease. Cardiovasc Drugs Ther. 2004;18:305–309. doi: 10.1023/B:CARD.0000041250.00079.84. [DOI] [PubMed] [Google Scholar]
  • 29.Ogihara T, Saruta T, Matsuoka H. Valsartan in elderly isolated systolic hypertension (VALISH) study: Rationale and design. Hypertens Res. 2004;27:657–661. doi: 10.1291/hypres.27.657. [DOI] [PubMed] [Google Scholar]

Articles from Current Therapeutic Research, Clinical and Experimental are provided here courtesy of Elsevier

RESOURCES