The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats.
BACKGROUND
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.


RESULTS
Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55 ± 0.02, p<0.05), increased cardiac output (60.8 ± .8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03 ± 0.3 mmHg min(-1) ml(-1) 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05).


CONCLUSIONS
Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil.
University of Giessen and Marburg Lung Center, Giessen, Germany.
Michaela
M
Lang
Baktybek
B
Kojonazarov
Xia
X
Tian
Anuar
A
Kalymbetov
Norbert
N
Weissmann
Friedrich
F
Grimminger
Axel
A
Kretschmer
Johannes-Peter
JP
Stasch
Werner
W
Seeger
Hossein Ardeschir
HA
Ghofrani
Ralph Theo
RT
Schermuly
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications; D007150:Immunohistochemistry; D007211:Indoles / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000068677:Sildenafil Citrate; D000071756:Soluble Guanylyl Cyclase; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
D007211:Indoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; C116890:Semaxinib; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C542595:riociguat