Effect of Digoxin on Hypoxic Pulmonary Hypertension (HPH)

Many lung diseases induce HPH, leading to increased mortality. HPH, caused by vascular contraction and remodeling, is associated with increased intracellular pH (pH i ) and calcium concentration ([Ca 2+ ] i ) in pulmonary arterial smooth muscle cells (PASMCs). Hypoxia‐inducible factor 1 (HIF‐1), a transcription factor, plays a critical role in the development of HPH. Recently, digoxin (Dig) was found to inhibit HIF‐1. We hypothesized that Dig could attenuate the development of HPH. Mice were weighed and injected daily with saline or Dig (low = 0.2 mg/kg or high = 1.0 mg/kg; i.p.) and kept in hypoxia (10% O 2 ) or room air. After 21 days, right ventricular (RV) pressures were measured via closed‐chest puncture. Hypoxia increased RV pressures in mice receiving saline. Low Dig reduced, and high Dig normalized, RV pressure in hypoxic mice. RV hypertrophy (RVH) increased in hypoxic mice treated with saline or low Dig, but was reduced in hypoxic mice receiving high Dig. Hypoxia increased hematocrit in mice treated with saline or low Dig, whereas high Dig reduced the hypoxia‐induced increase in hematocrit. Both pH i and [Ca 2+ ] i increased in PASMCs from saline‐treated hypoxic mice, and treatment with low or high Dig prevented these changes in ion homeostasis. From these results, we conclude that digoxin attenuates pulmonary vascular responses to chronic hypoxia and may be a possible candidate for treatment of HPH. HL67191, GM008074