Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth

Abstract

Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats

“…Newborn rats were randomized on postnatal day 1 (P1) into two groups to receive RA or hyperoxia, 85% O 2 as previously described 21 , 22 . On P14, pups were anesthetized, blood samples were collected by right ventricular puncture, and plasmas were obtained.…”

Targeting soluble guanylate cyclase with Riociguat has potency to alleviate testicular ischaemia reperfusion injury via regulating various cellular pathways

“…In literature review, we found that Riociguat possess anti‐inflammatory activity in various diseases (Toxvig et al, 2019). Riociguat was reported to contribute on anti‐inflammatory process via inhibiting the formation of NLRP‐1 inflammasome/IL‐1β cascade (Donda et al, 2018). When we compare these literatures and our current experiment, we observe consistent results.…”

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review

“…Researchers partially explained these findings by indication that NO needs oxygen for its formation and sildenafil only inhibits degradation of NO-induced cGMP, in contrast, riociguat directly stimulates guanylate cyclase and cGMP production [57] . Donda et al show that riociguat reduces inflammation and vascular remodelling, therefore protects lungs in rat model of hyperoxia-induced lung injury [58] . However, this study has similar construction as these regarding sildenafil and shows only effects of riociguat in prevention of lung injury, not in treatment of disease-changed lungs.…”

“… Under hypoxic conditions riociguat was approximately 3-fold more potent than under physiological oxygen levels. Donda et al [58] Sprague-Dawley rats: Normoxia + placebo (6) Normoxia + riociguat (6) Hyperoxia + placebo (6) Hyperoxia + riociguat (6) Hemodynamical and histological analysis of rat pulmonary arteries. Riociguat significantly reduces inflammation and vascular remodelling in compare to placebo group, therefore it protects lungs in rat model of hyperoxia-induced lung injury.…”