@article{SharkovskaKalkLawrenzetal.2010,
  author    = {Sharkovska, Yuliya and Kalk, Philipp and Lawrenz, Bettina and Godes, Michael and Hoffmann, Linda Sarah and Wellkisch, Kathrin and Geschka, Sandra and Relle, Katharina and Hocher, Berthold and Stasch, Johannes-Peter},
  title     = {Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models},
  issn      = {0263-6352},
  doi       = {10.1097/Hjh.0b013e32833b558c},
  year      = {2010},
  abstract  = {Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams \& Wilkins.},
  language  = {en}
}
@article{GeschkaKretschmerSharkovskaetal.2011,
  author    = {Geschka, Sandra and Kretschmer, Axel and Sharkovska, Yuliya and Evgenov, Oleg V. and Lawrenz, Bettina and Hucke, Andreas and Hocher, Berthold and Stasch, Johannes-Peter},
  title     = {Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats},
  series = {PLoS one},
  volume    = {6},
  journal   = {PLoS one},
  number    = {7},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0021853},
  pages     = {10},
  year      = {2011},
  abstract  = {Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33\% to 85\%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.},
  language  = {en}
}
@inproceedings{GeschkaKretschmerSharkovskaetal.2011,
  author    = {Geschka, Sandra and Kretschmer, A. and Sharkovska, J. and Evgenov, O. V. and Lawrenz, Bettina and Stasch, Johannes-Peter and Hocher, Berthold},
  title     = {Soluble guanylate cyclase stimulation prevents fibrotic tissue Remodelling and improves survival in salt-sensitive dahl rats},
  series = {Journal of vascular research},
  volume    = {48},
  booktitle = {Journal of vascular research},
  number    = {4},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1018-1172},
  pages     = {171 -- 171},
  year      = {2011},
  language  = {en}
}