Comparison of 3 Methods to Induce Acute Pulmonary Hypertension in Pigs

Large animal models for acute pulmonary hypertension (PHT) show distinct differences between species and underlying mechanisms. Two embolic procedures and continuous infusion of a stable thromboxane A₂ analogue (U46619) were explored for their ability to induce PHT and their effects on right ventricular function and pulmonary and systemic circulation in 9 pigs. Injection of small (100 to 200 µm) or large (355 to 425 µm) polystyrene beads and incremental dosage (0.2 to 0.8 µg kg⁻¹ min⁻¹) of U46619 all induced PHT. However, infusion of U46619 resulted in stable PHT, whereas that after bead injection demonstrated a gradual continuous decline in pressure. This instability was most pronounced with small beads, due to right ventricular failure and consecutive circulatory collapse. Furthermore, cardiac output decreased during U46619 infusion but increased after embolization with no relevant differences in systemic pressure. This result was likely due to the more pronounced effect of U46619 on pulmonary resistance and impedance in combination with limited effects on pulmonary gas exchange. Coronary autoregulation and adaption of contractility to afterload increase was not impaired by U46619. All parameters returned to baseline values after infusion was discontinued. Continuous infusion of a thromboxane A2 analogue is an excellent method for induction of stable, acute PHT in large animal hemodynamic studies.Abbreviations: PHT, pulmonary hypertensionSystematic investigation of the pathophysiology of acute pulmonary hypertension (PHT), especially adaption of the right ventricular function in response to increased afterload, requires valid animal models with conclusions that are transferable to humans. In addition, the availability of such models would promote the evaluation of treatment options for pulmonary vasodilatation and inotropic support of the right ventricle. The various models reported in the literature can be classified by animal size, developmental period, and techniques. Due to cardiac dimensions and basic regulatory principles, sophisticated and transferable hemodynamic measurements require large animals such as dogs, pigs, and goats, and differences in vasoconstrictory responsiveness and adaption to hypoxia between these species and humans must be taken into account.^9,16,21 Chronic models of PHT in large animals are used less frequently than acute models and typically are induced through injection of monocrotaline pyrrole,⁶ surgical creation of an aortopulmonary shunt,²² or pulmonary banding.⁵ Techniques for the induction of acute PHT can be weighed in light of their underlying mechanisms, side effects, stability, and reversibility. Exposure to hypoxia ⁶ and repeated embolism^{9,17, 23} are used more frequently than are constriction of the pulmonary artery or infusion of the stable thromboxane A₂ analogue U46619.⁵ Whereas hypoxia mediates vasoconstriction by means of endothelin 1, serotonin, and the inhibition of voltage-gated potassium channels in smooth muscle cells,⁷ embolic procedures reduce the vascular cross-sectional area and increase concentrations of thromboxane A2.¹⁹ The size of injected particles positively correlates with the degree of hypoxia⁹ and inversely correlates with induction of thromboxane A2 production, thereby resulting in PHT and circulatory collapse.¹⁹ These mechanisms influence the stability of PHT, cardiac function, and sympathetic tone as a consequence of hypoxia. A leading advantage of transient occlusion, constriction of the pulmonary artery, and infusion of U46619 is that the resulting PHT is reversible. Compared with embolic procedures, proximal occlusion of the pulmonary artery induced different grade of afterload increase for the right ventricle, whereas U46619 may have systemic and coronary vasoconstrictory effects, thus causing negative inotropy.¹¹ The design of a study involving a PHT model therefore is influenced not only by the animal and technique selected but also by the underlying mechanisms of the technique and the sensitivity of the resulting PHT to drug intervention.To study the effects of volatile anesthetics on right ventricular function during acute PHT, we aimed to develop a large animal model with stable increased afterload over several hours and minimal direct effects on cardiac function. We tested embolization techniques with different sizes of microbeads and the infusion of U46619. We favored pigs over dogs and goats because of the thickness of the arteriolar vascular muscle layer and the degree of collateral ventilation, which thus make the sensitivity of the pulmonary vasculature of swine more representative of that in humans.