New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

Abstract

PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8&#xa0;&#xb1;&#xa0;1.8&#xa0;mmHg. Hypoxia caused a reliable increase in mean PAP (+&#x2009;12.2&#xa0;&#xb1;&#xa0;3.2&#xa0;mmHg, p&#x2009;<&#x2009;0.0001). Both, sildenafil (- 6.8&#xa0;&#xb1;&#xa0;4.4&#xa0;mmHg) and ANP (- 6.4&#xa0;&#xb1;&#xa0;3.8&#xa0;mmHg) significantly (p&#x2009;<&#x2009;0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.