Norepinephrine kinetics in the rat heart: A compartmental analysis

• Main Author: Stylos, Lee
• Format: Dissertation
• Language: English
• Published: Ann Arbor ProQuest Dissertations & Theses 1993
• Subjects: animal physiology

There exists no testable hypothesis of how the subcellular components of sympathetic efferent nervous system of the heart interact due to technical problems in monitoring individual physiological compartments. This difficulty can be partially overcome by developing a multicompartmental mathematical model of heart norepinephrine metabolism based on known physiology and appropriate tracer kinetic data. The multicompartmental mathematical model is a formal testable hypothesis expressed in mathematical terms.
Kinetic data were collected in rat hearts using the Langendorff isolated perfusion procedure. Hearts were perfused with a Krebs-Henseleit bicarbonate buffer at a controlled flow rate of 5 ml$\cdot$min$\sp{-1}$. Hearts were infused with ($\sp3$H) norepinephrine for twenty minutes. Effluent was collected every minute for 150 minutes and ($\sp3$H) norepinephrine and ($\sp3$H) 3,4-dihydroxyphenylglycol were analyzed by high performance liquid chromatography and liquid scintillation spectrometry.
An hypothesis generated from the literature as to connectivity of subcellular components of the sympathetic system was formulated. Two mathematical models were developed using separate modeling approaches.
Based on a priori knowledge of V$\sb{max}$, K$\sb{m}$ and mass of norepinephrine in plasma and heart tissue a compartmental model was created and simulated using the Simulation, Analysis and Modeling (SAAM) software. A six compartment central mammalary structure was modeled. The model was used to simulate data which was then compared to kinetic data from the isolated perfused rat hearts.
A second compartment model based on the data was created using SAAM. A three compartment catanary structure with a delay element was chosen as the best fit based on sum of squares values and parameter identification criteria. The final compartmental structure fit both the ($\sp3$H) norepinephrine and ($\sp3$H-) 3,4-dihydroxyphenylglycol data.
The first model did not provide a sufficient fit to the data due to the lack of information regarding small dense core vesicle uptake and diffusion into and from the plasma compartment. The second model provided a good fit to the kinetic data yet is not a final mathematical representation to the physiological system since kinetic data was only modeled from one physiological space.