Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models.
OBJECTIVE
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.


CONCLUSIONS
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.
Sharkovska
Yuliya
Y
Institute for Nutritional Science, University of Potsdam, Center for Cardiovascular Research, Charité, Berlin, Germany.
Kalk
Philipp
P
Lawrenz
Bettina
B
Godes
Michael
M
Hoffmann
Linda Sarah
LS
Wellkisch
Kathrin
K
Geschka
Sandra
S
Relle
Katharina
K
Hocher
Berthold
B
Stasch
Johannes-Peter
JP
D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
D000959:Antihypertensive Agents; D011720:Pyrazoles; D011743:Pyrimidines; D009569:Nitric Oxide; D012083:Renin; D006162:Guanylate Cyclase; C542595:riociguat; D019331:NG-Nitroarginine Methyl Ester