Document Detail


Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models.
MedLine Citation:
PMID:  20613628     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yuliya Sharkovska; Philipp Kalk; Bettina Lawrenz; Michael Godes; Linda Sarah Hoffmann; Kathrin Wellkisch; Sandra Geschka; Katharina Relle; Berthold Hocher; Johannes-Peter Stasch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of hypertension     Volume:  28     ISSN:  1473-5598     ISO Abbreviation:  J. Hypertens.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-21     Completed Date:  2010-11-12     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8306882     Medline TA:  J Hypertens     Country:  England    
Other Details:
Languages:  eng     Pagination:  1666-75     Citation Subset:  IM    
Affiliation:
Institute for Nutritional Science, University of Potsdam, Center for Cardiovascular Research, Charité, Berlin, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Genetically Modified
Antihypertensive Agents / pharmacology
Disease Models, Animal
Disease Progression
Dose-Response Relationship, Drug
Guanylate Cyclase / antagonists & inhibitors,  metabolism*
Heart / drug effects*
Hypertension / chemically induced,  enzymology,  prevention & control*
Kidney / drug effects*,  pathology
Longevity / drug effects
Male
Muscle Contraction / drug effects
Muscle, Smooth, Vascular / drug effects
Myocardium / pathology
NG-Nitroarginine Methyl Ester / toxicity
Nephrectomy
Nephritis, Interstitial / chemically induced,  pathology,  prevention & control
Nitric Oxide / metabolism*
Pyrazoles / pharmacology
Pyrimidines / pharmacology
Rabbits
Rats
Rats, Wistar
Renin / drug effects,  physiology*
Signal Transduction
Chemical
Reg. No./Substance:
0/Antihypertensive Agents; 0/Pyrazoles; 0/Pyrimidines; 10102-43-9/Nitric Oxide; 50903-99-6/NG-Nitroarginine Methyl Ester; 625115-55-1/riociguat; EC 3.4.23.15/Renin; EC 4.6.1.2/Guanylate Cyclase

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