Histamine and the Exercise Responsome

Histamine, a biogenic amine, commonly associated with the immune and inflammatory response is produced and released within skeletal muscle during exercise. The exact role(s) of histamine in the exercise response is largely unknown and understudied. Histamine’s function in physiological contexts outside of exercise, such as its role in the modulation of tissue blood flow and inflammation, has guided the formation and interpretation of the studies included in this dissertation. Specifically, this research was divided into three separate studies intended to expand upon previous research on endurance capacity, exercise/functional hyperemia, and exercise-induced inflammation. In summary, the results of the studies suggest that skeletal muscle histamine may have a duration and intensity dependent function during exercise. Systemically blocking histamine’s interaction with H1 and H2 receptors had no effect on low- to moderate-intensity exercise, but compromised the ability of individuals to perform exercise of long durations and high intensities. The reduced exercise capacity may relate to histamine’s influence on the microvasculature. In immune and inflammatory responses, histamine dilates arterioles and increases capillary permeability to facilitate blood delivery and nutrient, immune cell, and metabolic byproduct transfer between the tissue and circulation. Blocking histamine H1/H2 receptors did not reduce, but in fact increased leg blood flow during exercise. The increased blood flow may have been a consequence of alterations within the muscle milieu increasing the hydrogen ion concentration, thereby increasing the stimulus for blood flow. The increased blood flow and reduced pH suggest a role of histamine in mediating capillary nutrient transfer during exercise. Finally, blocking histamine H1/H2 receptors did not affect the systemic immune response (circulating leukocytes and cytokines) resulting from muscle-damaging exercise, but this study did not address responses within the skeletal muscle tissue where histamine is released/produced. Future research should focus on specific functions of histamine within the skeletal muscle, as these studies did not detect alterations in systemic function when histaminergic signaling was blocked. The findings of these studies suggest that histamine plays vital roles in many physiological pathways associated with the stress of exercise within the muscle. Future research expanding upon these findings will be important as very little is known about autocrine, paracrine, and endocrine role of histamine as part of the exercise responsome. This dissertation includes previously published co-authored material