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Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats

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Abstract

Our previous studies identified potent antioxidant effects and improvement of vascular function by telmisartan therapy in experimental diabetes and nitrate tolerance. The present study compared the beneficial effects of single telmisartan or amlodipine versus telmisartan/amlodipine combination therapy (T+A) in streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were injected once with STZ (60 mg/kg, i.v.) and 1 week later the drugs (telmisartan, amlodipine, or T+A) were administrated orally by a special diet (2.5–5 mg kg−1 day−1) for another 7 weeks. We only observed a marginal beneficial on-top effect of T+A therapy over the single drug regimen that was most evident in the improvement of endothelial function (acetylcholine response) and less pronounced in the reduction of whole blood, vascular and cardiac oxidative stress (blood leukocyte oxidative burst, aortic dihydroethidine and 3-nitrotyrosine staining, as well as cardiac NADPH oxidase activity and uncoupling of endothelial nitric oxide synthase) in diabetic rats. These effects on oxidative stress parameters were paralleled by those on the expression pattern of NADPH oxidase and nitric oxide synthase isoforms. In addition, development of mild hypotension in the T+A-treated rats was observed. Reasons for this moderate synergistic effect of T+A therapy may be related to the potent beneficial effects of telmisartan alone and the fact that amlodipine and telmisartan share similar pathways to improve endothelial function. Moreover, hypotension in the T+A-treated rats could partially antagonize the beneficial additive effects by counter-regulatory mechanisms (e.g., activation of the renin–angiotensin–aldosterone system).

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Acknowledgments

We thank Jörg Schreiner, Angelica Karpi, Nicole Glas, and Anja Conrad for their expert technical assistance. The present work was supported by generous financial support by the Johannes Gutenberg University and Medical Center Mainz (MAIFOR and Forschungsfonds grants to M.K. and A.D.) and a vascular biology grant from Boehringer Ingelheim Pharma GmbH & Co. KG (to A.D. and T.M.). M.K. holds a stipend from the “Stiftung Mainzer Herz”. This paper contains results that are part of the doctoral thesis of Elena Zinßius.

Conflict of interest

A.D. and T.M. received research grant support from Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. C.T. is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. C. F. is an employee of Boehringer Ingelheim Pharmaceuticals, Pipeline Product Scientific Support, Ridgefield, CT, USA.

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  1. 2nd Medical Clinic, Department of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Hanke Mollnau, Matthias Oelze, Elena Zinßius, Michael Hausding, Maike Knorr, Jasmin Ghaemi Kerahrodi, Swenja Kröller-Schön, Thomas Jansen, Philip Wenzel, Eberhard Schulz, Thomas Münzel & Andreas Daiber

  2. Department of Pharmacology, Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Zhixiong Wu & Huige Li

  3. Center of Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany

    Maike Knorr & Philip Wenzel

  4. Boehringer Ingelheim Pharmaceuticals, Pipeline Product Scientific Support, Ridgefield, CT, USA

    Christine Teutsch & Carolyn Foster

  5. Universitätsmedizin der Johannes Gutenberg-Universität Mainz, II. Medizinische Klinik–Molekulare Kadiologie, Geb 605/3.OG, Langenbeckstr. 1, 55131, Mainz, Germany

    Thomas Münzel & Andreas Daiber

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  1. Hanke Mollnau
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Correspondence to Thomas Münzel or Andreas Daiber.

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H.M. and M.O. contributed equally to this study and should therefore both be considered as first authors.

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Mollnau, H., Oelze, M., Zinßius, E. et al. Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats. Naunyn-Schmiedeberg's Arch Pharmacol 386, 405–419 (2013). https://doi.org/10.1007/s00210-013-0842-7

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  • DOI: https://doi.org/10.1007/s00210-013-0842-7

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