The hormonal response (HR) to hemorrhage (H) mediates the restitution of blood volume (BVR) that restores cardiovascular (CV) homeostasis. However, the HR to traumetic injury depends on several factors in addition to hypovolemia that include past history and other stimuli. A hypovolemic episode potentiates the HR to a repeated H. Experiments will examine possible afferent and efferent mechanisms that underlie this potentiation and its biologic significance as well as the interaction of thermal stimulation(nociception) and acousticstartle (anxiety) on the hormonal and hemodynamic responses to H. Failure of BVR with CV decompensation occurs after large H despite an increased HR. Experiments will examine hemodynamic variables, including atrial filling and volume, and the HR and metabolic changes after large H to assess their relationship to the failure of BVR. The possible role of endogenous opiates in this failure will be examined. Other studies will examine the ability of fluid replacement, Trendelenberg position, and the pneumatic antishock garment to promote increased atrial filling and to limit HR after H. The above in vivo studies will use cats, dogs, pigs, and rats. Central neural changes in aminergic activity will be assessed with in vivo voltammetry. Hormones to be measured include ACTH, atrial natriuretic factor, AVP, angiotensin II, Bendorphin, enkephalins, renin(all with RIA), and catecholamines and steroids (with HPLC). Peripheral metabolic measurements include osmolality, electrolytes, protein, glucose, and glucose metabolism. In vitro studies wil test potential humoral mediators of changes in intracellular (IC) Ca++ and in membrane Ca++ Mg++ ATP-ase activity. Such changes may lead to IC damage that promotes the expansion of IC volume after large H and, thus, causes impaired BVR. Humorally-mediated changes in red blood cell (RBC) IC Ca++ will be monitored using spectrofluorimetry with Quinn-II as a chelator and using nuclear magnetic resonance (NMR) with 19F as a chelator. RBC membrane ATP-ase will be assessed by the decrease in IC ATP using NMR to monitor the IC generation of inorganic phosphate from 31P-ATP directly. Thus, we propose to use NMR to characterize the cellular derangement leading to the evolution of shock. Results from these proposed studies will enhance the understanding of the pathophysiology of injury and may lead to improved therapies that reduce the detrimental consequences of injury and the time and cost of its treatment.
