20-HETE is a potent vasoconstrictor produced by the CYP 4A enzyme and has been implicated in the regulation of vascular tone in brain, renal and pulmonary circulation. Patch-clamp studies in our lab have shown that 20-HETE inhibits the KCa channel in VSM causing constriction which is ATP, GTP and tyrosine kinase dependent, however, the exact intracellular signaling mechanism(s) by which 20-HETE acts is unknown. Studies have also suggested that II and endothelin (ET) activate PLA2 causing release of arachidonic acid and inhibition of the KCa channel. Thus it is possible that 20-HETE may be involved in II and ET regulation of the KCa channel. This application will address the hypothesis that AII and ET increase the synthesis of 20-HETE thereby contributing to the renal vasoconstrictor and systemic pressor effects of these agonists by interacting with the c-src, EGF receptor and ras signaling cascade. Activation of this pathway leads to phosphorylation of the KCa channel thus inhibiting its activity, causing membrane depolarization which enhances Ca2+ influx through voltage sensitive channels.
Specific aims : l) To determine the effects of AII and ET on 20- HETE levels, c-src, EGF receptor activity, binding of GTP to ras, and phosphorylation state of the KCa channel in rat renal microvessels. 2) To examine the effects of inhibition of c-src, the EGF receptor or ras on the ability of 20-HETE to inhibit the KCa channel responses in renal microvessels. 3) To examine the effect of inhibition of 20-HETE, c-src, EGF receptor or ras on AII and ET induced vasoconstriction and the inhibition of c-src, EGF receptor or ras on 20-HETE induced vasoconstriction.
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