A Murine Model of the Exercise Pressor Reflex

Abstract

The exercise pressor reflex (EPR) is an involuntary response to exercise. It is defined by a rise in mean arterial pressure (MAP) and heart rate (HR) in response to muscle contraction and is necessary for providing adequate blood flow to the exercising muscle to match metabolic demand and prevent premature fatigue. Proper function of this reflexive response is essential to healthy cardiovascular responses to exercise. Animal models available to test the EPR such as cat, dog, and rabbit have been utilized extensively to gain physiological information across species but generating disease or translating observations to humans has been challenging in these models. While this reflex can be tested rapidly and non‐invasively in humans, an elucidation of the mechanisms that regulate this reflex at the cellular and molecular level limit the utility of such studies. To test the EPR in the setting of heart failure, we previously developed a reliable and reproducible decerebrate rat model that allowed us to study the EPR in cardiomyopathic animals. We observed that this model yielded similar responses to exercise to those observed in humans. Here, we have developed a novel murine model of the EPR to allow for unlimited exploration of physiological and pathological cellular and molecular mechanisms in a variety of transgenic and genetically modified mouse lines. Like the rat model, we observed that ventral root stimulation (VRS; to evoke contraction of skeletal muscle) in an anesthetized mouse causes a depressor response and a reduction in HR. In contrast, the same stimulation in a decerebrate mouse causes a rise in MAP and HR. The responses observed in the decerebrate murine preparation are abolished by disruption of afferent innervation of the muscle via dorsal rhizotomy or by neuromuscular blockade. Moreover, we demonstrate that TRPV1 antagonism in wild type (WT) mice and Trpv1 null mice display a reduced MAP response to VRS while the response to mechanosensitive stimulation (passive stretch) remains intact. Additionally, we demonstrate that intra‐arterial infusion of capsaicin (a TRPV1 agonist) results in a dose related rise in MAP and HR that is significantly reduced by a selective and potent TRPV1 antagonist and, further, that these responses are completely abolished in Trpv1 null mice. Lastly, we observe no role of the Piezo2 receptor in mediating the EPR under physiological conditions. These data serve to validate the development of a decerebrate mouse model for the study of cardiovascular responses to exercise and further define the role of the TRPV1 receptor in mediating the EPR. This novel model will allow for extensive study of the EPR in unlimited transgenic and mutant mouse lines, thus allowing for an unprecedented exploration of the molecular mechanisms that control cardiovascular responses to exercise in health and disease.