The research plan is directed at the definition of a coronary infusate and fluid therapy which can afford optimum metabolic support by redox-balanced fluids for hemodynamic performance of the isolated perfused oxygen-deficient heart. The mechanism by which an exogenous metabolite redox-balance can improve cardiac performance, survival and possibly recovery during and from various states of hypoxia and ischemia shall be studied. A major goal is to measure and analyze the relationships between mechanical performance and key biochemical parameters (redox metabolites, cytosolic phosphate potentials, adenine nucleotide degradation products) during oxygen-deficiency and reoxygenation as influenced by pyruvate, lactate, acetate, octanoate, mannitol. Mild and severe hypoxia as well as ischemia models will be tested. Rates of oxidative pyruvate metabolism will be examined in relation to glycolytic flux, lactate dehydrogenase flux, acetate utilization, and Beta-oxidation of fatty acids. A pump perfused coronary dog heart model in vivo will also be examined. The influence of clinically used cardioactive medicines will be studied, too. Experiments will be conducted using the nonrecirculated perfused working guinea pig heart as the primary model. The hemodynamics will be monitored and measured employing standard techniques. Hypoxia will be induced by reducing the oxygen concentration in the inflow perfusate or by underventilating the open-chest dog with a pump-perfused left coronary circulation. Ischemia will be obtained by reducing coronary perfusion pressure to levels below the threshold for coronary flow autoregulation. In the dog heart model, graded ischemia will be induced by controlled reduction in coronary perfusion rate below normoxia rates. Nucleosides will be measured by an improved HPLC technique. Redox metabolites will be measured by enzymatic-optic tests. Oxidative metabolism will be judged from oxygen uptake (platinum electrode). Pyruvate and lactate metabolism will be evaluated from measurements of pyruvate uptake, lactate release, 14-C0-2-production from [1-14C]pyruvate, sp. activities of released lactate and HC0-3 and the lactate/pyruvate ratio. Glycolytic flux will be estimated from glucose uptake or from the release of tritiated H20 in presence of [3-3-H] D-glucose. Intra- and extracellular spaces will be measured using 3-H-inulin and 14-C-urea as appropriate markers. Cytosolic ATP potentials will be calculated employing the creatine kinase equilibrium and measured tissue pH (C0-2 method). Cytosolic AMP values will be assessed from myokinase equilibrium in comparison to total cardiac AMP.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036067-03
Application #
3350644
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1986-04-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20852