Local alterations in the hemodynamic environment regulate endothelial cell function, but the signal-transduction mechanisms involved in this process remain unclear. Because mitogen-activated protein (MAP) kinases have been shown to be activated by physical forces, we measured the phosphorylation and enzyme activity of MAP kinase to identify the signal events involved in the endothelial cell response to fluid shear stress. Flow at physiological shear stress (3.5 to 117 dynes/cm2) activated 42-kD and 44-kD MAP kinases present in cultured bovine aortic endothelial cells, with maximal effect at 12 dynes/cm2. Activation of a G protein was necessary, as demonstrated by complete inhibition by the nonhydrolyzable GDP analog GDP-beta S. Activation of protein kinase C (PKC) was required, as shown by inhibiting PKC with staurosporine or downregulating PKC with phorbol 12,13-dibutyrate. Both Ca(2+)-dependent and -independent PKC activity, measured by translocation and substrate phosphorylation, increased in response to flow. However, MAP kinase activation was not dependent on Ca2+ mobilization, since Ca2+ chelation had no inhibitory effect. On the basis of these findings, it is proposed that flow activates two signal-transduction pathways in endothelial cells. One pathway is Ca2+ dependent and involves activation of phospholipase C and increases in intracellular Ca2+. A new pathway, described in the present study, is Ca2+ independent and involves a G protein and increases in PKC and MAP kinase activity.
Both gamma imaging and positron emission tomography (PET) imaging of cell surface receptors have become possible through the development of agonists and antagonists with high specific radioactivity and high specificity for the receptors. An understanding of the physiology of the cardiac receptor system is essential to comprehending receptor imaging. The complexity of the physiologic information developed over the past decade has been compounded by the concomitant discovery of additional receptor subtypes. The following is a review of a select group of cardiac receptors and their regulation-namely, adrenergic, muscarinic-cholinergic, adenosine, and angiotensin I and II receptors. The role of imaging regional receptor localization and function in providing new insights into cardiac pathology and therapeutic avenues is explored.
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