The series of experiments outlined in this Proposal has been designed to systematically investigate the fundamental mechanisms responsible for laser-induced alterations of vascular tone. Preliminary data resulting from experiments carried out in our Laboratories during the first three years of this Grant, together with data from other Laboratories and established paradigms for physiologic alteration of vascular smooth muscle (VSM) tone have led us to formulate a series of working hypotheses. These hypotheses and the experimental protocols by which they will be tested are organized according to two Specific Aims. The experiments described under Specific Aim 1 have been designed to identify the specific intra-cellular processes which mediate laser-induced relaxation of VSM. Preliminary studies suggest that the heme moiety of cytosolic guanylate cyclase (GC) may serve as a chromophore to promote absorption of laser light, thereby activating GC, resulting in the production of 3',5' cyclic guanosine monophosphate (cGMP) and relaxation of VSM. Accordingly, we will begin by investigating the principal hypothesis that laser-induced photorelaxation of VSM is the result of increased production of cGMP. The experiments described un Specific Aim 2 are designed to identify the specific intracellular processes which mediate laser-induced contraction of VSM. Our approach to this issue will begin with consideration of the hypothesis that laser-induced vasoconstriction results from the breakdown of phosphatidylinositol 4,5-biphosphate (PIP2), releasing inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DG), thereby producing vasoconstriction of VSM. Finally, experiments performed previously in our Laboratory have demonstrated that heat generated under certain circumstances of laser irradiation is a potent stimulus for vasoconstriction of VSM. We will therefore test the hypothesis that intra- cellular processes mediating laser-induced vasoconstriction result in part from heat and/or acoustic transients generated during laser irradiation. Preliminary work currently in progress in our Laboratory suggests that these investigations may yield promising insights into the fundamental basis for laser-induced alterations in vasomotor reactivity, and at the same time suggest meaningful ways that these observations may be incorporated into clinical practice.
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