The long term goal of the proposed research is to provide a better understanding of the mechanism by which the endothelium modulates the reactivity of vascular smooth muscle. Although the role played by the vascular endothelium was not appreciated until recently, it is now readily apparent that this cell layer is an essential element in the control of vascular tone. It has recently been proposed that coupling of endothelium to smooth muscle cells may provide for direct electrical signalling between these two cell types. In addition, recent electrophysiologic data support the view that at least two types of ion channels in the endothelium act as transducers of hemodynamic forces to control the release of vasoactive substances. Thus, we propose to elucidate the electrophysiologic properties of endothelial cells to: characterize in greater detail the properties of the different outward and inward currents and the mechanism(s) of their regulation; quantitate the agonist mediated calcium influx through different pathways to establish whether these fluxes are adequate to account for the calcium transient observed; and identify whether differ- ences in properties exist in endothelial cells obtained from different vascular regions, so as to clarify the resulting functional implications. We therefore propose to address the following specific aims: (1) to characterize the different resting ionic currents in endothelial cells, (2) to relate the presence of a particular outward current to both the magnitude and time course of the evoked calcium transient and arachidonic acid released, (3) to characterize the electrophysiologic properties and basis of regulation of the different evoked inward and outward ionic currents in endothelial cells, (4) to ascertain the basis of the evoked calcium transient by measuring the magnitude and time course of the Ca2+ flux through the different pathways into the cytoplasm, (5) to determine if the electrophysiologic properties and response to different agonists are the same in endothelial cells obtained from the resistance vessels and microcirculation as those obtained from large arteries. While the immediate goals of this application are highly focused on examination of the electrophysiologic properties of endothelial cells and the biochemical coupling to vasoactive mediator release, we do not exclude the possibility that ion channels and ion transport systems play a larger role in the regulation of the biology of endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045132-05
Application #
2221933
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Kanai, A J; Strauss, H C; Truskey, G A et al. (1995) Shear stress induces ATP-independent transient nitric oxide release from vascular endothelial cells, measured directly with a porphyrinic microsensor. Circ Res 77:284-93
Rasmusson, R L; Zhang, Y; Campbell, D L et al. (1995) Bi-stable block by 4-aminopyridine of a transient K+ channel (Kv1.4) cloned from ferret ventricle and expressed in Xenopus oocytes. J Physiol 485 ( Pt 1):59-71
Comer, M B; Campbell, D L; Rasmusson, R L et al. (1994) Cloning and characterization of an Ito-like potassium channel from ferret ventricle. Am J Physiol 267:H1383-95
Hamm-Alvarez, S F; Alayof, B E; Himmel, H M et al. (1994) Coordinate depression of bradykinin receptor recycling and microtubule-dependent transport by taxol. Proc Natl Acad Sci U S A 91:7812-6
Qu, Y; Himmel, H M; Campbell, D L et al. (1993) Effects of extracellular ATP on ICa, [Ca2+]i, and contraction in isolated ferret ventricular myocytes. Am J Physiol 264:C702-8
Qu, Y; Campbell, D L; Whorton, A R et al. (1993) Modulation of basal L-type Ca2+ current by adenosine in ferret isolated right ventricular myocytes. J Physiol 471:269-93
Shen, W K; Rasmusson, R L; Liu, Q Y et al. (1993) Voltage and temperature dependence of single K+ channels isolated from canine cardiac sarcoplasmic reticulum. Biophys J 65:747-54
Himmel, H M; Whorton, A R; Strauss, H C (1993) Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. Hypertension 21:112-27
Qu, Y; Campbell, D L; Strauss, H C (1993) Modulation of L-type Ca2+ current by extracellular ATP in ferret isolated right ventricular myocytes. J Physiol 471:295-317
Qu, Y; Campbell, D L; Himmel, H H et al. (1993) Neuromodulation of calcium current by extracellular ATP in isolated ventricular myocytes. Adv Exp Med Biol 346:11-8

Showing the most recent 10 out of 14 publications