The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice.
Severe pulmonary hypertension (PH) is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. In mice with PH induced by chronic hypoxia, we examined the acute and chronic effects of the soluble guanylate cyclase (sGC) activator HMR1766 on hemodynamics and pulmonary vascular remodeling. In isolated perfused mouse lungs from control animals, HMR1766 dose-dependently inhibited the pressor response of acute hypoxia. This dose-response curve was shifted leftward when the effects of HMR1766 were investigated in isolated lungs from chronic hypoxic animals for 21 days at 10% oxygen. Mice exposed for 21 or 35 days to chronic hypoxia developed PH, right heart hypertrophy, and pulmonary vascular remodeling. Treatment with HMR1766 (10 mg x kg(-1) x day(-1)), after full establishment of PH from day 21 to day 35, significantly reduced PH, as measured continuously by telemetry. In addition, right ventricular (RV) hypertrophy and structural remodeling of the lung vasculature were reduced. Pharmacological activation of oxidized sGC partially reverses hemodynamic and structural changes in chronic hypoxia-induced experimental PH.
Weissmann
Norbert
N
Univ. of Giessen Lung Center Medical Clinic II/V, Klinikstr. 36, 35392 Giessen, Germany.
Hackemack
Sascha
S
Dahal
Bhola Kumar
BK
Pullamsetti
Soni Savai
SS
Savai
Rajkumar
R
Mittal
Manish
M
Fuchs
Beate
B
Medebach
Thomas
T
Dumitrascu
Rio
R
Eickels
Martin van
Mv
Ghofrani
Hossein Ardeschir
HA
Seeger
Werner
W
Grimminger
Friedrich
F
Schermuly
Ralph Theo
RT
D000818:Animals; D006332:Cardiomegaly; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000517:prevention & control*; D000860:Hypoxia / Q000517:prevention & control*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013449:Sulfonamides / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D013481:Superoxides; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; C515616:5-chloro-2-(5-chlorothiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)phenyl)benzamide