Cinaciguat Prevents Postnatal Closure of Ductus Arteriosus by Vasodilation and Anti-remodeling in Neonatal Rats

Abstract

Closure of the ductus arteriosus (DA) involves vasoconstriction and vascular remodeling. Cinaciguat, a soluble guanylyl cyclase (sGC) activator, was reported with vasodilatory and anti-remodeling effects on pulmonary hypertensive vessels. However, its effects on DA are not understood. Therefore, we investigated whether cinaciguat regulated DA patency and examined its underlying mechanisms. In vivo, we found that cinaciguat (10 mg/kg, i.p. at birth) prevented DA closure at 2 h after birth with luminal patency and attenuated intimal thickening. These anti-remodeling effects were associated with enhanced expression of cyclic guanosine monophosphate (cGMP) in DA. Ex vivo, cinaciguat dilated oxygen-induced DA constriction dose-dependently. Such vasodilatory effect was blunted by KT-5823, a PKG inhibitor. In DA smooth muscle cells (DASMCs), we further showed that cinaciguat inhibited angiotensin II (Ang II)-induced proliferation and migration of DASMCs. In addition, cinaciguat inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production. Finally, Ang II-activated MAPKs and Akt were also inhibited by cinaciguat. In conclusion, cinaciguat prevents postnatal DA closure by vasodilation and anti-remodeling through the cGMP/PKG pathway. The mechanisms underlying anti-remodeling effects include anti-proliferation and anti-migration, with attenuation of mitochondrial ROS production, MAPKs, and Akt signaling. Thus, this study implicates that sGC activation may be a promising novel strategy to regulate DA patency.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino

“…We placed a Swan-Ganz in the pulmonary artery of neonatal lambs on postnatal day 3 and gave a lower daily dose of (35 μg/kg x day, i.v. for 7 days: 245 μg/kg total) from postnatal day 4–10 Cinaciguat than that used by Hung et al, 2021 in newborn rats. Cinaciguat treatment induced an acute decrease in pulmonary arterial pressure for 45 min, which then leveled off until the next dose of Cinaciguat the following day.…”

“…Control newborns infused with vehicle did not display changes in any of the variables studied (data not shown). Recently, Hung et al, 2021 , reported that administration in term newborn rats (10 mg/kg, i.p. at birth) prevented the closure Cinaciguat of the ductus arteriosus, which normally occurs around 2 h after birth in rats.…”

“…Cinaciguat also decrease ROS production via PKG-induced antioxidant gene expression in bone osteoblasts from diabetic mice ( Kalyanaraman et al, 2018 ). Similarly, Cinaciguat inhibits mitochondrial ROS elicited by Ang II in ductus arteriosus smooth muscle cells ( Hung et al, 2021 ). We found increased HO-1 protein expression in the lung tissue of lambs treated with Cinaciguat.…”

“…sGC α1 and sGC β1 expression in the lung was the same in both groups of neonates; therefore, the greater vasodilatation response to SNP in the myographic experiment supports an increase in sGC function. Cinaciguat reduces oxidative stress ( Kalyanaraman et al, 2018 ; Hung et al, 2021 ) by increasing iron reduction to Fe 2+ in sGC and sGC activity. Concurrently, Ebensperger, 2011 , found that treating chronically hypoxic and high altitude pulmonary hypertensive animals with hemin increased HO-1 protein expression and SNO induced relaxation compared to Controls.…”

Scutellarin Reduces Cerebral Ischemia Reperfusion Injury Involving in Vascular Endothelium Protection and PKG Signal

“…NO may cause endothelium-dependent and independent relaxations. When NO is generated from L-arginine due to NO Synthase (NOS) action, it activates guanylate cyclase (GC) and produces guanine nuclear glucoside 3',5'-cyclic phosphate (cGMP) which further leads to cGMP-dependent protein kinase (PKG)-mediated vasodilation [ 16 – 18 ]. In particular, the endothelium-derived NOS (eNOS) mediating eNOS-GC-cGMP-PKG pathway plays a key role in maintaining endothelium dependent vascular tone [ 19 , 20 ].…”