The purpose of these series of investigations is to define which substrates are preferentially utilized by vascular smooth muscle to support energy metabolism under resting conditions and under conditions in which the smooth muscle is stimulated to contract. The impetus for this proposal comes from recent studies from this laboratory indicating that fatty acids profoundly affect glucose and glycogen metabolism and contractile function of vascular smooth muscle. Fatty acids were also found to significantly affect the activities of key enzymes involved in the regulation of glycogen catabolism and synthesis. Prior to these studies, it had been generally assumed that the energy substrates preferentially utilized by vascular smooth muscle to support contractile function is glycogen. Therefore, with these observations, the relative roles and inter-relationship of carbohydrate with fatty acid in energy metabolism became open to question. To discern which substrate(s) is preferentially utilized by smooth muscle, detailed analytical studies ascertaining the fate of radiolabelled fatty acid and glucose present in the incubation medium will be performed in resting and contracting porcine carotid arteries. The oxidation of these substrates over time and during contractile activation of the muscle is determined by measuring the rate of production of 14/CO2 from 14/C-glucose and 14/C-palmitate (or 14/C- acetate). This is correlated with the oxygen consumption of the tissue under identical substrate conditions. Based on the stoichiometry of the quantity of substrate oxidized/O2 consumed, the substrate serving as primary fuel can be identified. The utilization and metabolism of endogenous vascular smooth muscle glycogen and lipid stores will also be determined by pre-labelling these substrates with labelled fatty acid and glucose and following their metabolism over time. The proposed studies will be the first comprehensive investigation of the metabolism of fatty acid, its integration with carbohydrate metabolism, and the role of fatty acid in the physiological function of vascular smooth muscle. The results of these studies will have important implications to our understanding of vascular biology and to research in vascular disease states such as occurs in diabetes mellitus, atherosclerosis, hypertension, and circulatory shock states.
| Barron, J T; Barany, M; Gu, L et al. (1998) Metabolic fate of glucose in vascular smooth muscle during contraction induced by norepinephrine. J Mol Cell Cardiol 30:709-19 |
