Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling.
BACKGROUND
Severe pulmonary hypertension is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. Using wild-type and homozygous endothelial nitric oxide synthase (NOS3(-/-)) knockout mice with pulmonary hypertension induced by chronic hypoxia and rats with monocrotaline-induced pulmonary hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse pulmonary vascular remodeling.


RESULTS
Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3(+/+)) or NOS3(-/-) mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral pulmonary arteries. Treatment of wild-type mice with the activator of sGC, Bay58-2667 (10 mg/kg per day), or the stimulator of sGC, Bay41-2272 (10 mg/kg per day), after full establishment of pulmonary hypertension from day 21 to day 35 significantly reduced pulmonary hypertension, right ventricular hypertrophy, and structural remodeling of the lung vasculature. In contrast, only minor efficacy of chronic sGC activator therapies was noted in NOS3(-/-) mice. In monocrotaline-injected rats with established severe pulmonary hypertension, both compounds significantly reversed hemodynamic and structural changes.


CONCLUSIONS
Activation of sGC reverses hemodynamic and structural changes associated with monocrotaline- and chronic hypoxia-induced experimental pulmonary hypertension. This effect is partially dependent on endogenous nitric oxide generated by NOS3.
Dumitrascu
Rio
R
Medical Clinic II/V, University Hospital, Giessen, Germany.
Weissmann
Norbert
N
Ghofrani
Hossein Ardeschir
HA
Dony
Eva
E
Beuerlein
Knut
K
Schmidt
Harald
H
Stasch
Johannes-Peter
JP
Gnoth
Mark Jean
MJ
Seeger
Werner
W
Grimminger
Friedrich
F
Schermuly
Ralph Theo
RT
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D006332:Cardiomegaly / Q000201:enzymology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology; D000860:Hypoxia / Q000150:complications; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency; D052250:Nitric Oxide Synthase Type III; D011652:Pulmonary Circulation; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D001565:Benzoates; D011720:Pyrazoles; D011725:Pyridines; C480588:BAY 58-2667; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006162:Guanylate Cyclase