Eucapnic intermittent hypoxia increases Rho kinase‐independent myofilament Ca2+ sensitization in small pulmonary arteries

Abstract

Intermittent hypoxia (IH) associated with sleep apnea increases circulating concentrations of the vasoconstrictor peptide, endothelin‐1 (ET‐1), and elicits pulmonary hypertension. We hypothesized that, similar to chronic sustained hypoxia, eucapnic IH (E‐IH) enhances pulmonary vasoconstrictor reactivity to ET‐1 through Rho kinase (ROK)‐mediated vascular smooth muscle (VSM) Ca2+ sensitization. To test this hypothesis, we assessed vasoconstrictor responses to ET‐1 (10−11–10−7 M) in the presence or absence of the ROK inhibitor fasudil (10 μM) in endothelium‐disrupted, pressurized pulmonary arteries (158 ± 10 μ m inner diameter) from E‐IH rats (3 min cycles of 5% O2, 5% CO2/air flush, 7 hr/day, 4 wk) or air controls (air/air cycling for equal duration). VSM was loaded with fura‐2 AM to assess changes in VSM intracellular Ca2+ ([Ca2+]i) associated with ET‐1‐induced vasoconstrictor responses. Consistent with our hypothesis, E‐IH augmented ET‐1‐induced vasoconstrictor reactivity (10−9–10−7.5 M) without changing VSM [Ca2+]i responses. Surprisingly, ROK inhibition did not alter vasoconstriction or VSM [Ca2+]i responses in either group. We conclude that E‐IH enhances ET‐1‐induced Ca2+ sensitization in pulmonary VSM through a ROK‐independent mechanism.(Supported by NIH grants HL‐07736, HL‐77876, HL‐58124 and HL‐63207)