Recent studies demonstrate the importance of thrombosis in coronary occlusion and myocardial infarction. However, the mechanism underlying thrombosis and resulting coronary occlusion remain unresolved. The majority of studies on thrombus formation have been conducted in in vitro systems. The primary goal of this study is to determine the role of platelet aggregation and vasoconstriction in coronary artery occlusion in an in vivo model of spontaneous coronary thrombosis. Serotonin release during platelet aggregation will be used as an in vivo index of platelet aggregation. A partial coronary thrombus will be formed in dogs by application of D/C current to the arterial lumen. After the current is stopped, thrombus spontaneously extends to occlude the artery. Platelet aggregation will be assessed by changes in plasma serotonin levels drawn via coronary sinus catheter. Serotonin will be assayed by a sensitive radioenzymatic method. In vivo vascular reactivity (vasomotion) will be measured by microcrystals sewn to the arterial wall. Correlative measurements of myocardial function will be made using Doppler flow probes, length segment crystals (left ventricular contractility), Millar catheters (blood pressure), and epicardial ECGs. Selected agents (aspirin, LY53857, dazoxiben, aminophylline, PGE1, SQ29548, heparin, diltiazem) will be used singly or in combination to inhibit specific mechanisms that lead to platelet aggregation and vasoconstriction. Infusion studies with epinephrine, serotonin or histamine will assess the alteration in local vascular response to autocoids that may be present during thrombus formation. The thrust of these experiments is to better understand the role of platelets and vascular reactivity in occlusive coronary thrombosis, not to the initial events associated the thrombogenesis. Preliminary studies in this laboratory have demonstrated the feasibility of these experiments in an in vivo model that can quantitatively assess platelet aggregation, thrombus formation, and vascular reactivity simultaneously with dynamic measurements of coronary of blood flow and myocardial function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039916-06
Application #
3356891
Study Section
Special Emphasis Panel (SRC (07))
Project Start
1987-09-30
Project End
1993-07-31
Budget Start
1991-08-01
Budget End
1993-07-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Watanabe, T; Pakala, R; Katagiri, T et al. (2001) Angiotensin II and serotonin potentiate endothelin-1-induced vascular smooth muscle cell proliferation. J Hypertens 19:731-9
Watanabe, T; Pakala, R; Katagiri, T et al. (2001) Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation. J Hypertens 19:1065-73
Watanabe, T; Pakala, R; Katagiri, T et al. (2001) Lipid peroxidation product 4-hydroxy-2-nonenal acts synergistically with serotonin in inducing vascular smooth muscle cell proliferation. Atherosclerosis 155:37-44
Watanabe, T; Pakala, R; Katagiri, T et al. (2001) Serotonin potentiates angiotensin II--induced vascular smooth muscle cell proliferation. Atherosclerosis 159:269-79
Watanabe, T; Pakala, R; Koba, S et al. (2001) Lysophosphatidylcholine and reactive oxygen species mediate the synergistic effect of mildly oxidized LDL with serotonin on vascular smooth muscle cell proliferation. Circulation 103:1440-5
Pakala, R; Pakala, R; Sheng, W L et al. (2000) Vascular smooth muscle cells preloaded with eicosapentaenoic acid and docosahexaenoic acid fail to respond to serotonin stimulation. Atherosclerosis 153:47-57
Koba, S; Pakala, R; Katagiri, T et al. (2000) Hyperlipemic-very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein act synergistically with serotonin on vascular smooth muscle cell proliferation. Atherosclerosis 149:61-7
Pakala, R; Pakala, R; Sheng, W L et al. (1999) Eicosapentaenoic acid and docosahexaenoic acid block serotonin-induced smooth muscle cell proliferation. Arterioscler Thromb Vasc Biol 19:2316-22
Pakala, R; Benedict, C (1999) Synergy between thrombin and serotonin in inducing vascular smooth muscle cell proliferation. J Lab Clin Med 134:659-67
Koba, S; Pakala, R; Watanabe, T et al. (1999) Vascular smooth muscle proliferation: synergistic interaction between serotonin and low density lipoproteins. J Am Coll Cardiol 34:1644-51

Showing the most recent 10 out of 20 publications