Recent studies have shown that endothelial cells play an active role in the regulation of the microcirculation through production of several vasoactive substances, including vasodilators such as nitric oxide and prostacyclin, and constrictors such as endothelin-1. Altered production of these endothelial-derived factors has been postulated as an initiating event in microcirculatory dysfunction, and may represent an underlying cause of multiple organ injury in a variety of clinical settings. The goal of the proposed studies is to examine the formation and actions of these endothelial-derived factors in the gastric microcirculation under various conditions. The conditions to be studied include: 1) physiological conditions, 2) administration of complement C5a and FMLP (formyl-leucyl-methionyl-phenylalanine) which activate circulating leukocytes, a condition known to occur during sepsis, and 3) ischemia/reperfusion, a consequence of hypotension and shock, which causes endothelial cell injury due to free radical generation. These studies will utilize an ex vivo mechanically-perfused segment of the dog's stomach. Changes in tissue and blood levels of prostacyclin and endothelin-1 will be measured by enzyme immunoassays, and nitric oxide by a microelectrode technique under the above experimental conditions. Gastric microvascular injury will also be assessed by changes in vascular permeability to plasma proteins, vascular resistance, leukocyte adherence, and free radical generation. We postulate that there is a feedback regulation of synthesis of these endothelial-derived factors under normal conditions. These feedback mechanisms protect the gastric microcirculation by attenuating changes in vascular permeability and vascular resistance in response to vasoactive agents. However, this normal feedback mechanism may be impaired following leukocyte- or free radical-dependent endothelial injury, as occurs in clinical settings such as sepsis and shock. The proposed studies of this application will provide new information regarding the role of endothelial-derived factors in the development of gastric microvascular injury, an initiating event in gastric mucosal injury. Since the stomach is one of the organs adversely affected in patients with shock, sepsis, and multiple organ failure, a better understanding of gastric microcirculatory changes should be beneficial to our knowledge regarding other organ dysfunctions.
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