The maintenance of tone underlying circulatory regulation by vascular smooth muscle (VSM) is closly coupled to metabolism. Knowledge of the substrates utilized and control points, two poorly understood aspects central to understanding vascular metabolism, will be addressed by this project. While VSM is primarily an oxidative tissue, the substrate has not been unambiguously identified. The nature of the oxidative tissue, the substrate has not been unambiguously identified. The nature of the oxidative substrate will be assessed using measurement of O2 consumption and CO2 production to establish the respiratory quotient (RQ). The hypothesis that substrate utilization is dependent on metabolic demand will be tested by measuring the RQ as a function of substrate, mode of stimulation and contractility. Utilizing the overall direction set by RQ studies, substrate radioisotopes will be used to completely specify utilization patterns. A second major gap in our understanding of vascular metabolism relates to the observation that under fully oxygenated conditions, most of the glucose entering VSM is catabolized only to lactate. This aerobic glycolysis has often been proposed as an index of vascular myopathy; however, recent evidence from my laboratory indicats that it is related to Na-K transport in normal VSM. The control points for aerobic glycolysis will be determined and the hypothesis that Na-K transport is specifically coupled to glycolysis will be tested. This will include determination, under conditions in which glycolysis is altered by varying Na-K transport, of the role of glucose transport as a rate-limiting step, and from measurements of glycolytic intermediates, the rate-limiting enzymatic steps. To specify carbohydrate catabolism, the role of glycogenolysis will be assessed by direct measurement of glycogen breakdown and its control by measurement of the activation of glycogen phosphorylase. Vessels from both pulmonary and systemic circulations will be studied with the long-term goal of relating specific substrate utilization patterns to normal vascular function so that potentially more sensitive metabolic changes can be used in addition to contractility to detect and characterize vascular myopathy.
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