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Transcapillary adenosine transport and interstitial adenosine concentration in guinea pig hearts
R D Wangler1, M W Gorman, C Y Wang
1Department of Physiology, Michigan State University, East Lansing 48824.
Insights
In guinea pig hearts, adenosine readily enters endothelial cells and is metabolized. Dipyridamole significantly increases interstitial fluid adenosine levels, highlighting its role in adenosine transport.
Area of Science:
- Cardiovascular Physiology
- Microcirculation Research
- Pharmacology
Background:
- Adenosine plays a crucial role in cardiovascular function, but its transport and metabolism in the heart microvasculature are not fully understood.
- Understanding capillary transport mechanisms is vital for drug delivery and understanding physiological regulation in the heart.
Purpose of the Study:
- To investigate the capillary transport and endothelial cell handling of adenosine in isolated guinea pig hearts.
- To quantify interstitial fluid adenosine concentrations under basal conditions and during dipyridamole administration.
Main Methods:
- Utilized the multiple-indicator-dilution technique with radiolabeled albumin, sucrose, and adenosine in Krebs-Henseleit-perfused guinea pig hearts.
- Analyzed coronary inflow and outflow samples using HPLC and radiometric detection.
- Calculated permeability-surface area products for endothelial uptake and metabolism, and interstitial fluid (ISF) adenosine concentrations.
Main Results:
- Endothelial cells avidly uptake and metabolize adenosine; luminal adenosine is twice as likely to enter cells as to permeate clefts.
- Under control conditions, ISF adenosine concentration (6.8 +/- 1.5 nM) was approximately twice the venous concentration (3.6 +/- 0.8 nM).
- Dipyridamole infusion significantly increased venous (44.0 +/- 12.6 nM) and estimated ISF adenosine concentrations (191 +/- 53 nM).
Conclusions:
- In resting guinea pig hearts, interstitial fluid adenosine concentration is significantly higher than venous concentration.
- Dipyridamole administration markedly elevates interstitial fluid adenosine levels, indicating its potent effect on adenosine transport and retention.
- Endothelial cell uptake and metabolism are significant factors in regulating adenosine levels within the cardiac microvasculature.
Abstract:
We used the multiple-indicator-dilution technique to observe the capillary transport of adenosine in isolated Krebs-Henseleit-perfused guinea pig hearts. Tracer concentrations of radiolabeled albumin, sucrose, and adenosine were injected into the coronary inflow; outflow samples were collected for 10-25 s and analyzed by high-performance liquid chromatography (HPLC) and by gamma- and beta-counting. The albumin data define the intravascular transport characteristics; the sucrose data define permeation through interendothelial clefts and dilution in interstitial fluid (ISF). Parameters calculated from adenosine data include permeability-surface area products for endothelial cell uptake at the luminal and abluminal membranes and intraendothelial metabolism. We found that in situ endothelial cells avidly take up and metabolize adenosine. Tracer adenosine in the capillary lumen is twice as likely to enter an endothelial cell as it is to permeate the clefts. There was no adenosine in the arterial perfusate. Under control conditions, the steady-state venous adenosine concentration was 3.6 +/- 0.8 nM, which from the flow and the parameters estimated from the tracer data gave a calculated ISF concentration of 6.8 +/- 1.5 nM. During dipyridamole infusion (10 microM) at constant pressure, the cell permeabilities went essentially to zero, whereas the venous adenosine concentration increased to 44.0 +/- 12.6 nM, giving an estimated ISF concentration of 191 +/- 53 nM. With constant flow perfusion, venous concentration during dipyridamole infusion was 30.9 +/- 6.3 nM, and estimated ISF concentration was 88 +/- 20 mM. We conclude that in this preparation, at rest, the ISF adenosine concentration is about twice the venous concentration and the ISF adenosine concentration increases with dipyridamole administration.