Effects of acute Rho kinase inhibition on chronic hypoxia-induced changes in proximal and distal pulmonary arterial structure and function

Vanderpool, Rebecca; Kim, Ah Ram; Molthen, Robert C.; Chesler, Naomi C.

doi:10.1152/japplphysiol.00533.2010

Cited by 42 publications

(74 citation statements)

References 57 publications

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“…Characteristic impedance, Z C , is frequently interpreted as a measure of arterial stiffness. Indeed, in the absence of viscous effects, such as in the artery wall and at the blood-artery interact, Z C can be approximated as ͱ *E*h 2* 2 *r 5 where E is arterial elastic modulus, h is arterial wall thickness, and r is arterial inner radius (37). However, it is important to note that Z C can be calculated as the square root of the blood inertance divided by the compliance of the proximal segments of the arterial network (23).…”

Section: Discussionmentioning

confidence: 99%

Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia

Schreier

Hacker²,

Hunter

et al. 2014

Journal of Applied Physiology

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Chesler N. Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia. J Appl Physiol 117: 833-839, 2014. First published August 28, 2014 doi:10.1152/japplphysiol.00059.2014.-Chronic hypoxia causes chronic mountain sickness through hypoxiainduced pulmonary hypertension (HPH) and increased hematocrit. Here, we investigated the impact of increased hematocrit and HPH on right ventricular (RV) afterload via pulmonary vascular impedance. Mice were exposed to chronic normobaric hypoxia (10% oxygen) for 10 (10H) or 21 days (21H). After baseline hemodynamic measurements, ϳ500 l of blood were extracted and replaced with an equal volume of hydroxyethylstarch to normalize hematocrit and all hemodynamic measurements were repeated. In addition, ϳ500 l of blood were extracted and replaced in control mice with an equal volume of 90% hematocrit blood. Chronic hypoxia increased input resistance (Z 0 increased 82% in 10H and 138% in 21H vs. CTL; P Ͻ 0.05) and characteristic impedance (Z C increased 76% in 10H and 109% in 21H vs. CTL; P Ͻ 0.05). Hematocrit normalization did not decrease mean pulmonary artery pressure but did increase cardiac output such that both Z 0 and ZC decreased toward control levels. Increased hematocrit in control mice did not increase pressure but did decrease cardiac output such that Z 0 increased. The paradoxical decrease in ZC with an acute drop in hematocrit and no change in pressure are likely due to inertial effects secondary to the increase in cardiac output. A novel finding of this study is that an increase in hematocrit affects the pulsatile RV afterload in addition to the steady RV afterload (Z 0). Furthermore, our results highlight that the conventional interpretation of Z C as a measure of proximal artery stiffness is not valid in all physiological and pathological states. cardiopulmonary hemodynamics; chronic hypoxia; characteristic impedance; blood viscosity; pulmonary vascular impedance CHRONIC MOUNTAIN SICKNESS (CMS), also known as Monge's disease, occurs after chronic exposure to hypoxia at high altitudes and is characterized by increased pulmonary artery pressures and pulmonary vascular resistance (29) as well as increased hematocrit (19). Chronic hypoxia also contributes to worse outcomes in lung diseases such as chronic obstructive pulmonary disease, sleep apnea, and pulmonary fibrosis (1,10,15). In preclinical animal models of pulmonary arterial hypertension (PAH), chronic hypoxia is often used to generate hypoxia-induced pulmonary hypertension (HPH). PAH is a debilitating disease with a low median survival of 2.8 yr (6,17) and is characterized by remodeling throughout the pulmonary vasculature, including distal arterial narrowing and proximal and distal pulmonary artery stiffening, leading to right ventricular (RV) dysfunction that progresses to RV failure as the cause of death (28). HPH in rodents recapitulates the pulmonary vascular remodeling and RV hypertrophy that occur in patients with PAH but also increases hematocrit. Indeed, the increase in ...

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Section: Discussionmentioning

confidence: 99%

Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia

Schreier

Hacker²,

Hunter

et al. 2014

Journal of Applied Physiology

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“…In some forms of severe PAH, increased medial muscularity is coupled with the development of occlusive lesions, involving PASMCs, ECs and possibly cells of nonvascular origin (597,637). Reductions in arteriolar caliber, whether from vasoconstriction or occlusion, clearly exert the greatest influence on PVR; however, decreased compliance (i.e., increased stiffness) in the elastic proximal pulmonary arteries may also increase right ventricular afterload (199,394,596,647).…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

“…Indeed, the ROCK signaling pathway plays a central role in mediating vasoconstriction in all PH models [reviewed in (466,671)] and is implicated in the remodeling process (167,465). ROCK activation is necessary for PASMC migration and proliferation (212,366,465), and while acute administration of ROCK inhibitors markedly reduces right ventricular systolic pressure in most preclinical models (448,449,647), prolonged inhibition of ROCK reduces vascular remodeling in CH mice (160,286). At least part of the mechanism by which ROCK modulates PASMC function occurs via cytoskeletal rearrangement in PASMCs and ECs, with RhoB contributing to hypoxia-induced migration and proliferation in both cell types (702).…”

Section: Rho Kinasementioning

confidence: 99%

Lung Circulation

Suresh

Shimoda

2016

Comprehensive Physiology

104

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The circulation of the lung is unique both in volume and function. For example, it is the only organ with two circulations: the pulmonary circulation, the main function of which is gas exchange, and the bronchial circulation, a systemic vascular supply that provides oxygenated blood to the walls of the conducting airways, pulmonary arteries and veins. The pulmonary circulation accommodates the entire cardiac output, maintaining high blood flow at low intravascular arterial pressure. As compared with the systemic circulation, pulmonary arteries have thinner walls with much less vascular smooth muscle and a relative lack of basal tone. Factors controlling pulmonary blood flow include vascular structure, gravity, mechanical effects of breathing, and the influence of neural and humoral factors. Pulmonary vascular tone is also altered by hypoxia, which causes pulmonary vasoconstriction. If the hypoxic stimulus persists for a prolonged period, contraction is accompanied by remodeling of the vasculature, resulting in pulmonary hypertension. In addition, genetic and environmental factors can also confer susceptibility to development of pulmonary hypertension. Under normal conditions, the endothelium forms a tight barrier, actively regulating interstitial fluid homeostasis. Infection and inflammation compromise normal barrier homeostasis, resulting in increased permeability and edema formation. This article focuses on reviewing the basics of the lung circulation (pulmonary and bronchial), normal development and transition at birth and vasoregulation. Mechanisms contributing to pathological conditions in the pulmonary circulation, in particular when barrier function is disrupted and during development of pulmonary hypertension, will also be discussed.

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“…Using the isolated, ventilated, perfused mouse lung preparation, we have been able to show that smooth muscle cell de-activation by acute rho-kinase inhibition has no direct effect on the compliance of the large, conduit arteries that significantly impact RV afterload 7 . The clinical importance of proximal artery compliance has been increasingly recognized [9][10][11] .…”

Section: Significancementioning

confidence: 96%

“…It also was used to investigate the effects of vasoactive agents in the pulmonary circulation 6 and to quantify the proximal and distal pulmonary vascular effects of acute rho kinase inhibition 7 . This technique can be used to quantify pulmonary vascular physiology in inbred or outbred strains of mice or genetically engineered mice 8 .…”

Section: Applicationsmentioning

confidence: 99%

Characterization of the Isolated, Ventilated, and Instrumented Mouse Lung Perfused with Pulsatile Flow

Vanderpool

Chesler

2011

JoVE

Self Cite

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The isolated, ventilated and instrumented mouse lung preparation allows steady and pulsatile pulmonary vascular pressure-flow relationships to be measured with independent control over pulmonary arterial flow rate, flow rate waveform, airway pressure and left atrial pressure. Pulmonary vascular resistance is calculated based on multi-point, steady pressure-flow curves; pulmonary vascular impedance is calculated from pulsatile pressure-flow curves obtained at a range of frequencies. As now recognized clinically, impedance is a superior measure of right ventricular afterload than resistance because it includes the effects of vascular compliance, which are not negligible, especially in the pulmonary circulation. Three important metrics of impedance -the zero hertz impedance Z0, the characteristic impedance ZC, and the index of wave reflection RWprovide insight into distal arterial cross-sectional area available for flow, proximal arterial stiffness and the upstream-downstream impedance mismatch, respectively. All results obtained in isolated, ventilated and perfused lungs are independent of sympathetic nervous system tone, volume status and the effects of anesthesia. We have used this technique to quantify the impact of pulmonary emboli and chronic hypoxia on resistance and impedance, and to differentiate between sites of action (i.e., proximal vs. distal) of vasoactive agents and disease using the pressure dependency of ZC. Furthermore, when these techniques are used with the lungs of genetically engineered strains of mice, the effects of molecular-level defects on pulmonary vascular structure and function can be determined. ProtocolIn this protocol we demonstrate an isolated, ventilated, perfused mouse lung preparation that has previously been used to quantify the impact of pulmonary emboli and chronic hypoxia on pulsatile pulmonary vascular pressure-flow relationships (Tuchscherer, Webster, & Chesler, 2006;Tuchscherer et al., 2007). In brief, the mouse lungs are surgically isolated from surrounding tissues, placed in a heated chamber (IL-1; Harvard Apparatus, Holliston, MA) and ventilated (Ventilatory Control Module (VCM)-R with timer counter module (TCM); Harvard Apparatus). The lung vasculature is perfused with heated RPMI 1640 cell culture medium with 3.5% Ficoll using a syringe pump (Cole-Parmer, Vernon Hills, IL) to generate the steady flow waveforms or a high-frequency oscillatory pump (Bose -Electro Force, Eden Prairie, MN) in parallel with the syringe pump to create pulsatile pulmonary vascular flow waveforms. Pressure transducers (P75, Harvard Apparatus) measure the instantaneous pulmonary artery pressure (PAP) and left atrial pressure (LAP). Instantaneous flow rate (Q) is measured with an in-line flow meter (Transonic Systems, Inc., Ithaca, NY). Pulsatile pressure-flow relationships are derived from these measurements, which provide insight into pulmonary vascular physiology and pathology and right ventricular afterload. 1. Distilled water heated to 37°C by the heating bath is circulated into t...

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Effects of acute Rho kinase inhibition on chronic hypoxia-induced changes in proximal and distal pulmonary arterial structure and function

Cited by 42 publications

References 57 publications

Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia

Impact of increased hematocrit on right ventricular afterload in response to chronic hypoxia

Lung Circulation

Characterization of the Isolated, Ventilated, and Instrumented Mouse Lung Perfused with Pulsatile Flow

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