Hypoxia-inducible factors activator, roxadustat, increases pulmonary vascular resistance in rats

Abstract

Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.

Fig. 1

(A) Example pressure recording (Rox2w group) illustrating the lung perfusion protocol. P/Q, pressure-flow curve measurement; A-II, inflow injection of 0.15 μg angiotensin II; 0 % O₂, hypoxic challenge; DIZE, 0.1 mM diminazene aceturate added to the perfusate. (B–E) Perfusion pressure-flow curves are shifted to higher pressures by diminazene aceturate (DIZE) in untreated (B, n=5), roxadustat-treated (for 2 weeks, Rox2w, n=7; panel D) and chronically hypoxic (CH, n=6; E), but not control (C, n=7, panel C) and roxadustat-treated (once before the measurement, Rox2d, n=7, not shown) groups. Flow was a significant source of variation in all groups (P<0.0001, two-way repeated measures ANOVA). * P=0.0453 effect of group (values after DIZE are higher than values before DIZE even when flow is not considered). ** P=0.0064 effect of group (pre vs. post DIZE). ^† P≤0.0055 effect of group (pre vs. post DIZE) × flow interaction (values after DIZE are getting more different from the values before DIZE as flow increases).