Phase 3 Anticancer Agent, RRx-001, Ameliorates Hypoxia-Induced Pulmonary Hypertension

Abstract

Background: The hallmark features of pulmonary artery hypertension (PAH), for which hypoxia triggers, are vascular remodeling, elevated pulmonary blood pressure, oxidative stress, and right ventricular hypertrophy. RRx-001 is a minimally toxic Phase 3 anticancer agent with anti-oxidative, anti-inflammatory, nitric oxide-donating, and anti-proliferative properties. This study aimed to investigate the effect of RRx-001 on intermittent hypoxia-induced PAH in rats. Methods: Male Wistar rats (180-220 g) were divided into four groups (n=6 per group): normoxic control, hypoxic with vehicle treatment (2 weeks breathing an atmosphere containing 10% oxygen), hypoxic treated with oral endothelin-1 receptor inhibitor, bosentan, 50 mg/kg per day for 2 weeks during hypoxia and one intravenous dose of 5mg/kg RRx-001 given the day before the start of the hypoxia. After sacrifice, hearts and lungs were removed and harvested for analysis. Results: Both RRx-001 and bosentan treated animals, separately and to a similar degree, significantly attenuated hypoxia-induced increases in right ventricular systolic pressure and right ventricular hypertrophy compared to control animals. RRx-001 and bosentan, separately and to a similar degree, also significantly decreased pulmonary artery media thickness. RRx-001 treatment reduced vasocostriction of pulmonary arterioles and the wall thickness/external diameter ratio of the pulmonary arteries compared to vehicle treated animals. Conclusions: RRx-001 reduces right ventricular systolic pressure and pulmonary vascular remodeling in a rat model of PAH, potentially making it a new therapeutic option for this disease. The combination of bosentan and RRx-001 will be attempted as a next step. Commercial and private foundation grants This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.