CORONARY MICROVESSEL PERMEABILITY

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Within the heart, exercise training increases coronary permeability- surface area product, an index of exchange capacity, by unknown mechanisms. The current view of the capillary exchange barrier has progressed from one of a static boundary to a dynamic structure involved in moment-to-moment regulation of gas, water, and solute movements between blood and tissue. Since surface area does not account for the observed training-induced increase of exchange capacity, this project focuses on microvessel permeability and applies the specialized techniques of this laboratory to measure microvessel transport. From these measurements the mechanisms responsible for coronary microvessel adaptation to exercise training will be elucidated. The primary hypothesis is that exercise training increases coronary microvessel permeability (Aims 1 & 2). Further, the studies are designed to determine whether training effects are local or systemic (Aim 3), whether exercise training alters the dynamic status of the vascular barrier (Aim 4), and/or whether changes in individual vessels contribute equally to the integrated responses of intact hearts (Aims 5). In resistance arteries and venules isolated from the heart and mesentery of sedentary ad exercise trained pigs, solute flux of fluorescent probes of known size and change, will be measured as a function of perfusion pressure. From these measurements the transport coefficients diffusive solute permeability (Pd) and solvent drag coefficient (Lp(1-sigma)) will be calculated. Permeability responses of the microvessels will be assessed under basal conditions and then following perfusion with endothelium- dependent and -independent vasodilators. Permeability/surface area product will also be measured, first, in whole hearts from sedentary and exercise trained pigs and, second, in resistance arteries and venules isolated from these same hearts. Knowledge of mechanisms that dictate control of permeability in individual microvessels and intact hearts will provide a basis for elucidating observed exercise training-induced increases in coronary exchange capacity. The key to understanding whether exercise training compensates for or reverses dysfunction caused by coronary disease also rests on a mechanistic approach to studying changes observed with training.