The principal objective of the proposed research is to improve our understanding of relaxation mechanisms in vascular smooth muscle from the lung. Fundamental knowledge of cellular mechanism which regulate vascular smooth muscle tone in the lung is needed for the development of new forms of vasodilator therapy for cor pulmonale, pulnonary hypertension and the persistent fetal circulation syndrome. In spite of the increased use of vasodilaror drugs to reduce pulnonary arterial pressure and pulmonary vascular resistance in the above mentioned disorders, little if anything is known about the mechanisms by which these agents relax vascular smooth muscle from the lung. Studies in our laboratory have shown that four distinctly different types of agents: organic nitrates and nitrites, prostaglandins, beta-adrenergic agonists and calcium channel blocking agents, decrease pulmonary vascular resistance when pulmonary vascular tone has been increased by an active process. In this proposal, relaxation experiments on isolated helical segments and rings of intrapulmonary artery and vein and biochemical studies on these vessels will improve our knowledge of the effects of these four classes of agents on smooth muscle tone and the mechanism by which these agents relax vascular smooth muscle from the lung. These experiments should provide a better understanding of the role of cyclic GMP in smooth muscle relaxation and improve our current understanding of the biological significance of cyclic GMP in mammalian cells. The overall unifying goal of this proposal is to improve our knowledge of vasodilator mechanisms in the lung.
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