The overall goal of the proposed research is to understand how conducted vasodilation is involved in the coordination of vascular responses in the terminal arteriolar bed. The hypotheses to be tested in this proposal are based on studies which show that downstream applied L arginine (via micropipette) induces an upstream conducted vasodilation. Further, following the conducted signal, the responsivity of the upstream region is significantly altered, now allowing a dilation to locally-applied L arginine at the upstream location which was not observed before the conducted signal was sent. First, the specificity of both of these responses for L arginine, and for nitric oxide, will be determined (Hypothesis I) by (i) determining whether L arginine and nitric oxide are required for the conducted and subsequent upstream local dilation, and by (ii) determining whether the conducted signal that allows a change in upstream responsivity requires an L arginine linked mediator of conducted dilation, and whether the change in responsivity requires a receptor- mediated vasodilator linked to L arginine. These experiments will provide a mechanistic framework at the cellular transduction level for interpretation of the experiments proposed in the rest of the project. Second, the spatial and temporal extent of the L arginine-induced conducted pathway will be determined by examining the three arteriolar generations immediately upstream from the capillary networks (Hypothesis II) to (i) determine whether the L arginine conducted signal pathway can be stimulated in the capillaries and observed in the terminal arterioles, and stimulated in the feed to the terminal arterioles and observed in the arteriolar generation immediately upstream, and (ii) determine the time course (both magnitude and duration) during which the subsequent local dilation can be generated in the feed to the terminal arterioles following a conducted signal. Using L arginine as a tool to induce these responses, the experiments will define the extent and capacity of this response pathway within the peripheral circulation at the level of control of capillary perfusion. Third, the interaction between both the conducted and subsequent local dilations and the prevailing wall shear stress will be determined (Hypothesis III) by defining the wall shear stress dependence of these responses during baseline conditions and when the wall shear stress is transiently changed. The studies proposed in this application will thus define the extent to which these L arginine-induced responses could coordinate vascular responses in the peripheral circulation, will determine whether each of these responses are modulated by the prevailing wall shear stress, and will provide a mechanistic interpretation of these findings at the cellular transduction level.
