Endothelin-1 myocardial clearance, production, and effect on capillary permeability in vivo

Myocardial metabolism of endothelin-1 (ET-1) and its effect on coronary microcirculatory exchanges were obtained in anesthetized dogs by combining the indicator-dilution technique with immunoreactive ET-1 measurements. The myocardium extracted 17.7 +/- 4.6% of tracer ET-1 (n = 12). Simultaneously measured ET-1 levels in the aorta (0.97 +/- 0.46 pg/ml) and coronary sinus (0.96 +/- 0.53 pg/ml) were not different, supporting a production of ET-1 by the heart that balances the amount extracted. Intracoronary infusion of ET-1 (5 ng.kg-1.min-1) increased coronary sinus ET-1 levels approximately 50-fold, decreased coronary blood flow per unit of interstitial space by approximately 30% (P = 0.006), and increased myocardial microcirculatory transit times (n = 6). Permeability to albumin was unaffected by ET-1, whereas the permeability-surface area product for sucrose decreased following derecruitment of myocardial capillaries. We conclude that there is a normal myocardial metabolic balance of ET-1 and that the heart marginally contributes to circulating ET-1. Pharmacological doses of ET-1 may adversely affect myocardial metabolism by reducing blood flow and the permeability-surface area product for small circulating substances.

Validation of a model for [1-11C]acetate as a tracer of cardiac oxidative metabolism

To develop a compartmental model for estimating myocardial oxygen consumption rate (MVO2) with [1-11C]acetate, the metabolic fate of radiolabeled acetate was determined in normoxic and ischemic conditions in isolated perfused rat hearts. Glutamate composed 63 +/- 1 and 44 +/- 7% of the total tissue radioactivity 2 min postinjection in normoxic and ischemic myocardium, respectively, and radiolabeled glutamate remained the largest fraction throughout 40 min of perfusion. Based on the biochemical pathway of the tracer and the temporal distribution of 14C-labeled metabolites, a six-compartment model was formulated. Studies using [1-11C]acetate and a pair of NaI detectors were then performed in the same perfused heart system to validate the model. Consistency between the model predictions and biochemical measurements of tissue and effluent metabolites supported the validity of the kinetic model in normoxic and ischemic conditions. Model-estimated MVO2 correlated well with experimentally measured MVO2 for normoxic, hypoxic, and ischemic conditions, with a slope of 0.97 (r = 0.95). In addition, the model-estimated rate constant, k42, which corresponded to the oxidative flux, correlated strongly with the myocardial clearance rate (k1 or kmono) determined from the tissue kinetics. These findings provide a mechanistic basis for the use of k1 or kmono as an index of MVO2 in both normoxic and ischemic myocardium studied with [1-11C]acetate and positron emission tomography.

Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography

To test the ability of ketone bodies to inhibit myocardial fatty acid oxidation in vivo, the myocardial clearance kinetics of [1–11C]palmitate was assessed with positron emission tomography in six fasted volunteers and six instrumented dogs, studied repeatedly before and during infusion of 3-hydroxybutyrate (17 mumol.kg-1 x min-1). With the use of multiexponential fitting of tissue time-activity curves, the size, half time (T1/2), and index of the early rapid phase of 11C myocardial clearance, reflecting palmitate oxidation, were calculated. In humans, the relative size (-28%, P < 0.001) and index (-37%, P < 0.01) of the early rapid phase decreased significantly during infusion of 3-hydroxybutyrate, consistent with decreased fatty acid oxidation. Paradoxically, T1/2 decreased from 10.1 +/- 1.6 to 7.4 +/- 1.1 min (P < 0.01). To elucidate possible mechanisms, multiple coronary arteriovenous samples were obtained from the dogs to assess the efflux of oxidized and nonmetabolized tracer. Infusion of 3-hydroxybutyrate resulted in decreased myocardial [11C]CO2 production (-40%, P < 0.05) and reduced palmitate retention (-38%, P < 0.05). In three dogs, the arteriovenous difference in radiolabeled palmitate became negative 10 min after injection, indicating backdiffusion of nonmetabolized tracer from the myocardium. Thus a steady-state infusion of 3-hydroxybutyrate, resulting in physiological plasma levels, alters [1-11C]palmitate kinetics in vivo by decreasing myocardial long-chain fatty acid oxidation and by increasing backdiffusion of nonmetabolized tracer.