This is a proposal to investigate the effects of cardiac compression on the vasoactive function of the endothelium of coronary arterioles and the mechanisms underlying the endothelial deformation-induced release of NO. The endothelium of intramural coronary arterioles is constantly exposed to rhythmic compression induced by cardiac contraction, which may affect its function. My hypothesis is that endothelial cells of coronary arterioles are sensitive to cellular deformation and in response release NO to restore their original shape by dilating the vessels. This hypothesis will be tested in rats at three subsequent levels: perfused hearts, isolated coronary arterioles and cultured endothelial cells of coronary arterioles.
In Specific Aim 1 in isolated and perfused heart, I aim to examine the relationship between the frequency and magnitude of cardiac compression and coronary flow. I will examine the role of NO in cardiac compression-induced increases in coronary flow and contrast the results with those obtained by flow- or myogenically-induced increases in flow.
In Specific Aim 2, I plan to study the effects of vascular compression on the diameter of isolated coronary arterioles, on the release of NO, and on the myogenic response and flow-induced dilation.
In Specific Aim 3, in cultured endothelial cells, I aim to monitor the changes in [Ca2+]I and the release of NO in response to endothelial deformation induced by compression, and to elucidate the correlation between [Ca2+]I and the increases in Cytosolic NO. Finally, in Specific Aim 4, I plan to investigate the possible signal transduction pathways involved in endothelial deformation-induced release of NO. The specific role of endothelial potassium channels, cytoskeleton and caveolae will be studied. I believe that the findings revealed by these studies will demonstrate a new physiologic control mechanism, namely, that cardiac contractions, by reducing arteriolar diameter and hence changing the shape of endothelial cells enhance the release of NO, which then participates in the regulation of coronary blood flow.
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