title: Effects of acute Rho kinase inhibition on chronic hypoxia-induced changes in proximal and distal pulmonary arterial structure and function.
abstract: Hypoxic pulmonary hypertension (HPH) is initially a disease of the small pulmonary arteries. Its severity is usually quantified by pulmonary vascular resistance (PVR). Acute Rho kinase inhibition has been found to reduce PVR toward control values in animal models, suggesting that persistent pulmonary vasoconstriction is the dominant mechanism for increased PVR. However, HPH may also cause proximal arterial changes, which are relevant to right ventricular (RV) afterload. RV afterload can be quantified by pulmonary vascular impedance, which is obtained via spectral analysis of pulsatile pressure-flow relationships. To determine the effects of HPH independent of persistent pulmonary vasoconstriction in proximal and distal arteries, we quantified pulsatile pressure-flow relationships before and after acute Rho kinase inhibition and measured pulmonary arterial structure with microcomputed tomography. In control lungs, Rho kinase inhibition decreased 0 Hz impedance (Z₀), which is equivalent to PVR, from 2.1 ± 0.4 to 1.5 ± 0.2 mmHg·min·ml⁻¹ (P < 0.05) and tended to increase characteristic impedance (Z(C)) from 0.21 ± 0.01 to 0.22 ± 0.01 mmHg·min·ml⁻¹. In HPH lungs, Rho kinase inhibition decreased Z₀ (P < 0.05) without affecting Z(C). Microcomputed tomography measurements performed on lungs after acute Rho kinase inhibition demonstrated that HPH significantly decreased the unstressed diameter of the main pulmonary artery (760 ± 60 vs. 650 ± 80 μm; P < 0.05), decreased right pulmonary artery compliance, and reduced the frequency of arteries of diameter 50-100 μm (both P < 0.05). These results demonstrate that acute Rho kinase inhibition reverses many but not all HPH-induced changes in distal pulmonary arteries but does not affect HPH-induced changes in the conduit arteries that impact RV afterload.
authors.affiliation: Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, USA.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.forename: Ah Ram
authors.initials: AR
authors.lastname: Kim
authors.forename: Robert
authors.initials: R
authors.lastname: Molthen
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Chesler
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D055119:Elastic Modulus; D006976:Hypertension, Pulmonary / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000503:physiopathology*; D011859:Radiography; D014661:Vasoconstriction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D054460:rho-Associated Kinases