Therapeutic Role of Ambrisentan for the Treatment of Hypoxic Pulmonary Vasoconstriction: Impact of Intrapulmonary Delivery

Abstract

Hypoxic pulmonary vasoconstriction (HPV) results in robust increases in pulmonary artery pressures (PAP), which underlie the development of pulmonary hypertension (PH), and potentially edema, in those that travel to or work at altitude. Endothelin‐1 receptor (ET‐1) antagonists are currently given orally to treat PH, however intrapulmonary delivery of this therapeutic may provide acute relief of the HPV response at a lower dose and thus could ameliorate the functional impairments caused by PH whilst minimizing the amount of drug required. Despite this potential, the efficacy of intrapulmonary ET‐1 antagonist therapy to treat hypoxia induced PH has yet to be determined. We tested the hypothesis that intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan would attenuate an HPV mediated increase in PAP when compared to a saline control. Adult male Sprague‐Dawley rats were randomized into three groups to receive aerosolized saline (Saline, n=8), a low dose (ALD, 1 mg/kg, n=8) or high dose (AHD, 5 mg/kg, n=8) of Ambrisentan (administered via a microinhaler) following the induction of HPV (via 13% inspired O2, simulating ~4000m). PAP were monitored continuously throughout the procedure via indwelling catheters. Pre‐hypoxia PAP values were not different between groups (Saline: 18 ± 1, ALD 19 ± 1, AHD: 17 ± 1 mmHg, P>0.05). Following an initial hypoxia induced increase in PAP (Saline: 37 ± 1, ALD: 30 ± 2, AHD: 33 ± 2 mmHg, P<0.05 vs. pre‐hypoxia for all) intrapulmonary Ambrisentan reduced significantly PAP when compared to Saline (Saline: 34 ± 1, ALD: 23 ± 1, AHD, 23 ±1 mmHg, P<0.05) with no significant differences between ALD and AHD (P>0.05). Intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan reduced significantly the increase in PAP following exposure to hypoxia with no significant differences between low and high doses. These results suggest that intrapulmonary delivery of Ambrisentan, at a dose approximating 1/5th of that given orally, may be an effective therapeutic for the treatment of hypoxia induced PH. Given the life threatening complications and impaired work capacity associated with PH and high altitude pulmonary edema (HAPE), individuals traveling to or working at altitude (i.e. military and mining personnel, mountain athletes) as well as those suffering from pathologically induced PH may benefit from acute intrapulmonary delivery of Ambrisentan.Support or Funding InformationONR# N00014‐14‐1‐0699DARPA # N66001‐10‐C‐2134