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This laboratory is studying the functional nerve-muscle-endothelium relationships in cerebral and peripheral blood vessels, their alterations in pathophysiological conditions, and pharmacological intervention of these changes.
One of our primary research projects is directed towards the understanding of the nature of neuro-vascular transmission and myo-endothelial interaction in health and diseases such as hypertension and stroke. In particular, factors involved in regulating release of nitric oxide (NO) from cerebral perivascular nerves and endothelial cells are the main focus. This information in cerebral vasculature is an essential prerequisite to a description of the neural and endothelial regulation of cerebral blood flow and to the design of a rational therapy for derangements of the cerebral circulation.
Another on going research project is directed towards the understanding of the pathophysiology of sepsis syndrome and pharmacological intervention of this disease. Septic shock is a life-threatening clinical syndrome characterized by a marked reduction in peripheral vascular resistance and hypo-responsiveness to vasoconstrictor agents, leading to death due to circulatory collapse. Endotoxin (lipopolysaccharide, LPS), a toxic component of the gram-negative bacterial outer membrane, has been shown to play a major role in the pathogenesis of this syndrome. The mechanism by which LPS induces marked hypotension has been shown to primarily involve overproduction of NO and other vasodilating substances such as prostaglandins in vascular smooth muscle cells. LPS also can stimulate expression of platelet activating factor receptors and various adhesion molecules, adding to serious complication in clinical management of patients with septic shock. The exact mechanism leading to enhanced production of vasodilating NO and prostaglandins, and treatment of this devastating disease remains unsettled. One of our major efforts therefore is the search of new drugs for preventing overproduction of NO and other vasodilating substances in experimental animal models of sepsis. We have identified a natural product, oroxylin A, a polyphenolic compound isolated from the oriental herbal medicine Huang Qin, is a potent inhibitor of iNOS and COX-2 expression in cell lines. A detailed examination of the beneficial effects of oroxylin A and related natural products in the treatment of sepsis syndrome and related diseases in experimental animals is currently underway.
The multifaceted techniques of in vitro tissue bath, biochemical analysis of vasoactive substances, molecular biology, electrophysiology, and light and ultrastructural immunocytochemistry have been utilized to provide a relatively comprehensive study of the problems.
SELECTED REFERENCES:
Liu J and Lee TJF (1999) Mechanism of Prejunctional Muscarinic Receptor-mediated Inhibition of Neurogenic Vasodilation in Porcine cerebral Arteries.Am J Physiol 276: H194-H204
Ishine T, Yu JG, Asada Y and Lee TJF (1999) Nitric oxide is predominant mediator for neurogenic vasodilation in the porcine pial veins. J Pharmacol Exp Ther 289:398-404
Lee TJF (2000) Nitric oxide and the cerebral vascular function. J Biomed Sci 7: 16-26
Liu J, Evans SM, Brewer GJ and Lee TJFT (2000) N-type Ca2+-channels in cultured rat sphenopalatine ganglion neurons: an immunohistochemical and electrophysiological study. J Cereb Blood Flow Metab 20: 183-191
Chen YC, Yang LL and Lee TJF (2000) Oroxylin A Inhibition of LPS-induced iNOS and COX-2 Gene expressions via suppression of NF-kB activation.Biochem Pharmacol (in press)
Lee, T.J-F, and Mishra R.: Nitrergic neurogenic control of resistance blood vessels. In: Nitric oxide and Free radicals. Ed. S Kalsner. Birkhauser,New York, (in press)
Ishine T, Bouchelet I, Hamel E and Lee TJF (2000) Serotonin 5HT7 receptors mediate relaxation of porcine pial veins. Am J Physiol (in Press) |
