Intermittent hypoxia increases Rho kinase‐mediated myofilament Ca2+ sensitization in small pulmonary arteries

Abstract

Chronic 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, 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 (10−10–10−7 M) in the presence or absence of the ROK inhibitor Y-27632 (10 μM) in endothelium-denuded, pressurized pulmonary arteries (141 ± 16 μm inner diameter) from IH rats (3 min cycles to 5% O2/air flush, 7 hr/day for 4 wk) or air controls (air/air cycling for equal duration). Arteries were permeabilized to Ca2+ with ionomycin (3 μM) and superfused with a 300 nM Ca2+solution. VSM was loaded with fura-2 AM to verify that the intracellular free Ca2+ concentration was maintained constant during ET-1-induced vasoconstriction. Consistent with our hypothesis, IH augmented ET-1-induced vasoconstriction (10−10–10−9 M). Furthermore, ROK inhibition attenuated ET-1-mediated constriction in both control (10−8 M) and CH (10−10–10−7 M) arteries and normalized responses between groups. We conclude that IH enhances ET-1-induced, ROK-dependent Ca2+ sensitization in pulmonary VSM. (Supported by NIH grants HL-07736, HL-77876, HL-58124 and HL-63207) Figure 1Open in figure viewerPowerPoint Pulmonary Vascular Responses to Acute Aypoxia