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Blood-tissue transport of substrates in the heart: studies by single circulation tracer dilution
1Department of Physiology, King's College, University of London, United Kingdom.
Insights
Carrier-mediated transport, not passive diffusion, governs heart substrate uptake. The single-circulation multiple tracer dilution technique measures transport kinetics and receptor binding in coronary beds for clinical applications like positron emission tomography.
Area of Science:
- Cardiovascular Physiology
- Pharmacokinetics
- Molecular Biology
Background:
- Capillary permeability is typically not rate-limiting for small molecule transport into the heart.
- Carrier-mediated transport and receptor binding are key determinants of substrate uptake in the coronary circulation.
Purpose of the Study:
- To review studies utilizing the single-circulation multiple tracer dilution technique to assess substrate uptake in the heart.
- To investigate the kinetics of transport mechanisms across the sarcolemma and into cardiac cells.
Main Methods:
- Single-circulation multiple tracer dilution technique involving intra-arterial injection of tracers.
- Sequential sampling of venous outflow to analyze tracer kinetics.
- Measurement of capillary permeability-surface product, endothelial transport, interstitial space size, sarcolemmal transport, nerve ending uptake, receptor binding, and metabolic transformations.
Main Results:
- Demonstrated rapid uptake of potassium, ouabain, lactate, amines, glucose, amino acids, acetate, and palmitate in isolated perfused hearts.
- Investigated the kinetics of trans-sarcolemmal influx for lactate and neuronal amine uptake.
- Discussed the role of adenosine uptake and metabolism by the endothelium.
Conclusions:
- The single-circulation multiple tracer dilution technique provides comprehensive data on heart substrate transport mechanisms.
- Understanding these transport kinetics has implications for clinical applications, including positron emission tomography (PET).
Abstract:
Passive capillary permeability is usually not the rate limiting step to movement of small lipid-insoluble molecules from plasma into the heart. At physiological concentrations the rate of carrier-mediated transport and or receptor binding of blood-borne substrates is often measurable in a single circulation through the coronary bed. Here I review some studies on uptake measured by the single-circulation multiple tracer dilution technique. The method consists of a sudden intra-arterial injection of a mixture of tracers followed by sequential rapid sampling of the venous outflow. Generally the tracers include a molecule confined to the intravascular space (e.g. albumin), another confined to the extracellular space and a third test tracer. The data analysis can give information about: a) capillary permeability-surface product (PS), b) endothelial cell membrane transport, c) the size of the interstitial space, d) transport across the sarcolemma, e) uptake by nerve endings, f) binding to receptors, g) rapid metabolic transformations. Studies were performed in the isolated perfused heart (dog and rabbit). Early observations on rapid tissue uptake of potassium and ouabain have recently been extended. Kinetics of unidirectional trans-sarcolemmal influx of lactate, a metabolic substrate for the myocardium and the neuronal uptake of amines, were investigated as well as the myocardium and the neuronal uptake of amines, were investigated as well as the effects of specific inhibitors for these transport mechanisms. Uptake was also measured for glucose, the amino acids L-phenylalanine, L-alanine and taurine; and for acetate and palmitate. Recent literature which proposes an important role for uptake and metabolism of adenosine by the endothelium is discussed. These studies are of interest for clinical applications such as positron emission tomography (PET) which makes use of short-life isotopes.