Much of the recent research interest on myocardial ischemia has been aimed at the preservation of myocardial cellular function and viability, while little attention has been directed toward coronary vascular function and reactivity. It should be apparent, and was indeed confirmed by recent electron microscopic studies, that ischemic damages following transient coronary occlusion occur not only in myocardial cells but also in coronary vasculatures. In particular, coronary endothelium has been shown to be highly sensitive to ischemic injury. The functional significance of these coronary vascular derangements on the maintenance of coronary blood flow during coronary reperfusion is not well understood. Recently, it has been reported that, in addition to its role in the regulation of capillary transport, endothelial cells also possess metabolic and enzymatic activities, such as synthesis and release of prostaglandins and adenine nucleotides, as well as play an obligatory role in the vasodilatation induced by several vasoactive agents. More significantly, in a recent preliminary study, we have reported that thrombin, a naturally occurring blood-borne factor which is readily activated during vascular injury, produced a potent vasodilatation in normal coronary artery with intact endothelium, while it produced a potent, dose-related vasoconstriction in the ischemically injured arteries or in mechanically endothelium-denuded coronary arteries. These findings strongly suggest that coronary intimal endothelium plays a far more important role in the regulation of coronary blood flow than has been thought previously and that an altered response to vasoactive agents in coronary arteries with either ischemically and/or mechanically injured endothelium may contribute to, or be responsible for, the development of coronary vasospasm in ischemic heart disease. Therefore, the primary objective as well as long term goal of the present proposal is to examine the pathophysiological role of intimal endothelial cells in coronary vascular responses to circulating vasoactive factors. Specifically, attempts will be made 1) determine the role of endothelial cells in coronary vascular response to various circulating factors, such as thrombin, acetylcholine and adenine nucleotides, and 2) to determine the mechanism(s) of thrombin-induced coronary vasconstriction and its role in the development of coronary vasospasm. In addition, attempts will also be made to identify conditions and/or pharmacologic agents which may protect the coronary endothelium from ischemic injury and thus minimize the incidences of coronary vasospasm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Modified Research Career Development Award (K04)
Project #
5K04HL001298-04
Application #
3073736
Study Section
Cardiovascular Study Section (CVA)
Project Start
1984-04-01
Project End
1989-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
4
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
School of Medicine & Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Winn, M J; Ku, D D; Nelson, J M (1991) Inhibition of thrombin-induced endothelium-dependent relaxation after coronary ischemia in the dog: possible role of the coagulation cascade. J Cardiovasc Pharmacol 18:68-76
Ku, D D; Ann, H S (1991) Differential effects of magnesium on basal and agonist-induced EDRF relaxation in canine coronary arteries. J Cardiovasc Pharmacol 17:999-1006
Winn, M J; Ku, D D (1990) Investigation of the interrelationship between coagulation and thrombin-induced EDRF-dependent relaxation in dog coronary artery. Thromb Res 60:405-14
Ku, D D (1989) Divalent cation regulation of endothelial-dependent relaxation in coronary blood vessels. Microcirc Endothelium Lymphatics 5:99-120
Ku, D D; Roberts, R B; Sellers, B M et al. (1987) Regression of renal hypertrophy and elevated renal Na+,K+-ATPase activity after insulin treatment in streptozotocin-diabetic rats. Endocrinology 120:2166-73
Ku, D D (1987) Unmasking of thrombin vasoconstriction in isolated perfused dog hearts after intracoronary infusion of air embolus. J Pharmacol Exp Ther 243:571-6
Ku, D D; Ann, H S (1987) Magnesium deficiency produces endothelium-dependent vasorelaxation in canine coronary arteries. J Pharmacol Exp Ther 241:961-6
Ku, D D; Sellers, B M; Meezan, E (1986) Development of renal hypertrophy and increased renal Na,K-ATPase in streptozotocin-diabetic rats. Endocrinology 119:672-9
Ku, D D (1986) Mechanism of thrombin-induced endothelium-dependent coronary vasodilation in dogs: role of its proteolytic enzymatic activity. J Cardiovasc Pharmacol 8:29-36
Ann, H S; Ku, D D (1986) Magnesium inhibits basal release of endothelium-derived relaxing factor in canine coronary arteries. Eur J Pharmacol 130:353-5