Development of an anesthetized rat model of exercise hyperpnoea: An integrative model of respiratory control using an equilibrium diagram

New Findings

• What is the central question of this study?

  The lack of useful small animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states.

• What is the main finding and its importance?

  We developed an anesthetized rat model for studying exercise hyperpnoea, using respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models.

Abstract

Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of the respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiologic basis in various disease models, the lack of integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anesthetized rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data, and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO₂ pressure (P_ETCO2) and minute ventilation (V_E), and the plant by the hyperbolic relationship between V_E and P_ETCO2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen output. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (V_E and P_ETCO2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anesthetized rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models.

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