FUNCTIONAL SIGNIFICANCE: CYTOCHROME P450/HEME OXYGENASE

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This proposal aims at studying the mechanisms and functional significance of the interaction among the vascular heme-heme oxygenase- carbon monoxide system and cytochrome P450-derived eicosanoids in relation to mechanisms regulating vascular tone and blood pressure. Four major hypotheses will be examined. First, the production of 20-HETE by small arterial vessels is subject to inhibitory regulation by carbon monoxide of vascular of origin. Second, the inhibitory of heme oxygenase-derived carbon monoxide on vascular tone and reactivity involves down-regulation of vascular 20-HETE synthesis coupled to activation of Ca2+-activated K+ channels in vascular smooth muscle. Third, chronic alterations in potassium intake brings about reciprocal changes in vascular heme oxygenase expression and 20-HETE production which, in turn, impact on vascular reactivity, e.g., augmentation of potassium intake promotes vascular heme oxygenase expression, decrease 20-HETE production and diminishes vascular reactivity. Fourth, the anti- hypertensive effect accompanying experimentally induced over- expression of heme oxygenase in hypertensive rats is linked to augmentation of carbon monoxide production, leading to down-regulation of 20-HETE synthesis and reduction of vascular reactivity. In testing these hypotheses, the following specific aims will be addressed in rats. AIM 1: To Elucidate the Effect of Interventions That Increase or Decrease the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System on Vascular Synthesis of 20-HETE. AIM 2: To define the Significance of Vascular 20-HETE Synthesis in the Implementation of Vascular Responses to Carbon Monoxide and Interventions That Alter the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System. AIM 3: To Determine the Contribution of Carbon Monoxide 20-HETE Interactions to the Changes in Vascular Reactivity Caused by Chronic Alterations of Potassium Intake in Rats. AIM 4: Determine the Impact of Carbon Monoxide-20-HETE Interactions on the Changes in Blood Pressure Caused by Interventions That Increased Expression of the Heme-Heme Oxygenase-Carbon Monoxide System.