Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: Alveolar hypoxia in diseases such as COPD, high altitude, or obstructive sleep apnea leads to a pulmonary artery constrictive response, the severity of which varies substantially among individuals with similar physiologic or mechanical disease. To better study these differences and help determine genetic factors, we propose an intact in-vivo rodent model for describing and quantifying a pulmonary artery pressure (PAP) stimulus response to brief episodic hypoxia.
METHODS: Measurements of mean systemic and pulmonary arterial pressures, inspired oxygen, oxygen saturation and heart rate (Mouse Ox®) were continuously measured in closed chest and mechanically ventilated Wistar Kyoto (WKY) rats. Urethane anaesthesia and vecuronium paralysis was used to maintain constant ventilation and decrease chest excursions thus eliminating ventilatory responses and isolating the vascular response. Initial experiments were designed to determine feasibility and optimal duration of hypoxic measurements (n=3). The dose response curve to variable hypoxic exposures was then determined in 6 rats. In 2 additional rats the chest was opened and measurements were repeated along with continuous cardiac output using a flow probe placed around the ascending aorta.
RESULTS: Thirty second hypoxic episodes provided a consistent increase in pulmonary artery pressure, measurable oxygen desaturation, and less pronounced systemic hypotension. This hypoxic interval allowed determining an in vivo pulmonary artery stimulus response relating inspired oxygen (and oxygen saturation) to % change in PAP and was quantified using a 4 parametric logistic equation. The WKY rats exhibited a sigmoidal (r=.96) dose response relationship defined by a minimum PAP response of -0.8±1.4mmHg; maximal PAP response of 30.9±1.6mmHg; inflection point at 7.6±0.5% FiO2; and slope of -2.6±0.5mmHg/%FiO2. Ascending aortic flow measurements showed incrementally decreasing flow with worsening hypoxia ascertaining an increase in the pulmonary artery resistance.
CONCLUSIONS: This approach and metric demonstrates the feasibility of quantifying a hypoxic pulmonary artery stimulus response curve in rats. The availability of rodent genetic models allows applying this metric for the in vivo study of differences in response to hypoxia and the pre-clinical animal testing of drugs that may affect pulmonary vascular tone and remodeling in response to hypoxia, injury or genetic predisposition relevant to human disease.