Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular Remodeling

Abstract

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 Ϫ/Ϫ ) knockout mice with pulmonary hypertension induced by chronic hypoxia and rats with monocrotalineinduced pulmonary hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse pulmonary vascular remodeling. Methods and 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 ϩ/ϩ ) or NOS3 Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

“…Therefore, pharmacological stimulation of sGC is an appealing strategy to treat PAH and discovery of pharmacological tools, such as sGC stimulators, is of high interest. Recently, the sGC stimulator BAY 41-2272 was shown to be a systemic and pulmonary vasodilator [11] and to improve PAH in experimental models of PAH [12]. The aim of the present study was to investigate the expression of sGC in IPAH and experimental models of PAH.…”

Advances in the Management of Pediatric Pulmonary Hypertension

“…137 In animal models of PH, sGC expression was similarly upregulated, and direct sGC activation improved hemodynamics and vascular remodeling. [137][138][139] A proof-of-concept study was conducted that included 19 adult patients with PH (either PAH or chronic thromboembolic PH) who received the new drug riociguat (BAY 63-251). 140,141 That study suggested that riociguat was safe and found that pulmonary hemodynamics and cardiac output improved in a dose-dependent fashion.…”

Inhalative and intravenous stimulation of soluble guanylate cyclase reduces pulmonary vascular resistance and increases cardiac output in experimental septic shock

“…These pulmonary vasodilators have been investigated in experimental models of pulmonary arterial hypertension (PAH) (3), pressure and hypoxia induced myocardial injury, ischemia-reperfusion injury of the lung (4), and in patients with PAH (5,6) or decompensated heart failure (7). Pulmonary vasodilators have been shown to reduce pulmonary vascular resistance (PVR) and improve remodelling following myocardial injury (8,9).…”