Project: Research project

Grant Details


We propose to study the mechanism(s) of organic cation transport in
thearenal proximal tubule. Organic cations (and by extension, organic
bases; OC's) represent a diverse set of physiologically important
compounds, including molecules such as choline, epinephrine, and
N1-methylnicotinamide (NMN). OC's also include a number of drugs, such as
cimetidine, procainamide, and tetraethylammonium(TEA). The processes of
renal tubular secretion and reabsorption are presumed to play an important
role in regulating the plasma concentration of a number of these
compounds. However, comparatively little is known about the mechanism of
tubular transport of OC's. Currently there is conflicting evidence
concerning the nature of the processes responsible for the transepithelial
transport of OC's; some studies suggest that the lumenal membrane of the
proximal tubular cell plays the active role in OC secretion, while the
pertubular membrane play a passive role; other data suggest that the
pertubular membrane is the site of active OC transport, and that the
lumenal membrane is passive. We have preliminary data suggesting that both
the lumenal and peritubular membranes of the rabbit proximal tubule have
active transport processes which serve to facilitate the secretion of
OC's. We propose to extend these studies by examining OC transport using
several different "levels" of cellular organization, each of which offers
unique advantages to the study of transport processes: i) isolated
membranes, which permit both the detailed examination of kinetic mechanisms
under carefully controlled conditions, and the large-scale screening of
many compounds in studies of structural specificity; ii) isolated cells and
tubules, which permit simultaneous examination of the transport
contributions of both lumenal and peritubular membranes, as well as the
study of links between transport and metabolism; and iii) perfused proximal
tubules, which offer the opportunity to study lumenal and peritubular
transport working in series to produce transepithelial fluxes. The
integrated use of these three methodologies will permit us to formulate and
test detailed hypotheses concerning the mechanism of proximal tubular OC
transport. We hope to develop a model for renal tubular OC transport that
will both aid in understanding the role of the kidney in regulation of
plasma levels of these compounds, and increase our general understanding of
epithelial secretory processes.
Effective start/end date1/1/8312/31/89


  • National Institutes of Health


  • Medicine(all)


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