The proposed studies are directed to the understanding of the mechanisms underlying heterogeneity of vascular responses, which under normal conditions provides for optimal integration of the functions of the vascular system, whereas in pathological states it can cause vasospasm or hypertensive disorders. We will continue the ongoing studies on isolated arteries and veins taken from different vascular beds. The proposed research will analyze three aspects of endothelium-dependent responsiveness. In a first part, we will attempt to identify the reasons for the heterogeneous behavior of different arteries and large veins under normal conditions. We will determine whether the heterogeneity is due to the endothelium of the smooth muscle. We will examine in particular the possibilities that the endothelial cells generate several vasoactive factors, and that the sensitivity of vascular smooth muscle to endothelium-derived relaxing and contracting factors varies. To examine the role of the endothelium in releasing relaxing and contracting factors, we will compare preparations with and without endothelium, bio-assay the vasoactive properties of solutions exposed to endothelial cells, measure the release of metabolities of arachidonic aid and the production of ammonia. To study responses of vascular smooth muscle, we will measure changes in isometric tension, cell membrane potential and production of cyclic nucleotides. In a second part, we will examine how physiological factors can affect endothelium-dependent responses chronically; the variables to be studied are chronic alterations in blood flow, adrenergic innervation, sex hormones or changes in dietary lipids. In the final part of the proposal, we will study the endothelium- dependent responsiveness of segments of coronary arteries of the pig which have been exposed to a previous injury after which the endothelium has regenerated. The consequences of altered lipid intake on the ability of that endothelium to induce changes in contractility of vascular smooth muscle will be tested also. Among the stimuli causing vascular responses in this model special attention will be paid to aggregating platelets, since these may play a key role in coronary vasospasm.
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