POSTER PRESENTATION Open Access Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone Markus Alter1,2,3, Ina Ott1, Karoline von Websky1,2, Oleg Tsuprykov1,2, Yuliya Sharkovska2, Katharina Krause-Relle2,3, Jens Raila3, Andrea Henze3, Axel Kretschmer4, Johannes-Peter Stasch4,5, Berthold Hocher2,3* From 5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Halle, Germany. 24-26 June 2011 Background Riociguat is the first of a new class of drugs, the soluble guanylate cyclase (sGC) stimulators. Riociguat has a dual mode of action: it sensitizes sGC to the body’s own NO and can also increase sGC activity in the absence of NO. The NO-sGC-pathway is impaired in many cardiovascular diseases such as heart failure, pulmonary hypertension and diabetic nephropathy (DN). DN leads to high cardiovascu- lar morbidity and mortality. There is still a high unmet medical need. The urinary albumin excretion rate is a pre- dictive biomarker for these clinical events. Therefore, we investigated the effect of riociguat, alone and in combina- tion with the angiotensin II receptor antagonist (ARB) tel- misartan on the progression of DN in diabetic eNOS knock out mice, a new model closely resembling human pathology. Methods Seventy-six male eNOS knockout C57BL/6J mice were divided into 4 groups after receiving intraperitoneal high-dose streptozotocin: telmisartan (1 mg/kg), rioci- guat (3 mg/kg), riociguat+telmisartan (3 and 1 mg/kg), and vehicle. Fourteen mice were used as non-diabetic controls. After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose con- centrations were highly increased and similar in all diabetic groups. Results Riociguat, alone (105.2 ± 2.5 mmHg; mean±SEM; n = 14) and in combination with telmisartan (105.0 ± 3.2 mmHg; n = 12), significantly reduced blood pressure versus dia- betic controls (117.1 ± 2.2 mmHg; n = 14; p = 0.002 and p = 0.004, respectively), whereas telmisartan alone (111.2 ± 2.6 mmHg) showed a modest blood pressure lowering trend (p = 0.071; n = 14). The effects of single treatment with either riociguat (97.1 ± 15.7 µg/d; n = 13) or telmisartan (97.8 ± 26.4 µg/d; n = 14) did not signifi- cantly lower albumin excretion on its own (p = 0.067 and p = 0.101, respectively). However, the combined treat- ment led to significantly lower urinary albumin excretion (47.3 ± 9.6 µg/d; n = 12) compared to diabetic controls (170.8 ± 34.2 µg/d; n = 13; p = 0.004), and reached levels similar to non-diabetic controls (31.4 ± 10.1 µg/d, n = 12). Conclusion Riociguat significantly reduced urinary albumin excretion in diabetic eNOS knock out mice that were refractory to treatment with ARB’s alone. Patients with diabetic nephropathy refractory to treatment with ARB’s have the worst prognosis among all patients with diabetic nephro- pathy. Our data indicate that additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for patients with diabetic nephropathy resistant to ARB treatment. Author details 1Department of Nephrology, Charité, Campus Benjamin Franklin, Berlin, Germany. 2Center for Cardiovascular Research, Charité, Campus Mitte, Berlin, * Correspondence: berthold.hocher@charite.de 2Center for Cardiovascular Research, Charité, Campus Mitte, Berlin, Germany Full list of author information is available at the end of the article Alter et al. BMC Pharmacology 2011, 11(Suppl 1):P1 http://www.biomedcentral.com/1471-2210/11/S1/P1 © 2011 Alter et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. mailto:berthold.hocher@charite.de http://creativecommons.org/licenses/by/2.0 Germany. 3Institute for Nutritional Science, University of Potsdam, Germany. 4Bayer HealthCare AG, Cardiovascular Research, Wuppertal, Germany. 5Institute of Pharmacy, Martin-Luther-University of Halle, Germany. Published: 1 August 2011 doi:10.1186/1471-2210-11-S1-P1 Cite this article as: Alter et al.: Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone. BMC Pharmacology 2011 11(Suppl 1):P1. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Alter et al. BMC Pharmacology 2011, 11(Suppl 1):P1 http://www.biomedcentral.com/1471-2210/11/S1/P1 Page 2 of 2 Background Methods Results Conclusion Author details