This is a proposal to investigate the participation of vasoconstrictor prostanoids in prohypertensive mechanisms. We propose that activation of vascular TXA2/PGH2 receptors by eicosanoids other that TXA2 participates in the mediation of endothelium-dependent vasoconstriction and in the mechanisms of hypertension. The following aims will be addressed in normotensive rats and in rats with angiotensin dependent and independent forms of hypertension. 1. Characterization of the vasoconstrictor eicosanoids released from vascular tissues via endothelium-dependent mechanisms. Bioassay and HPLC techniques will be used to quantitate and characterize in terms of chromatographic profile, endothelium dependency, requirement of cyclooxygenase and thromboxane synthase for synthesis, and role of TXA2/PGH2 receptors in the implementation of vascular contraction, the contractile material released by arachidonic acid from the perfused aorta and mesenteric vasculature. 2. Investigation of the stimuli for endothelium-dependent release of vasoconstrictor eicosanoids. The release of vasoconstrictor eicosanoids during stimulation with various agents will be examined as in AIM 1. 3. Evaluation of the role of eicosanoid-induced activation of TXA2/PGH2 vascular receptors in the mediation of hormone- induced vasoconstriction. We will contrast the vascular responses to various hormones in isolated vasculatures perfused with and without TXA2/PGH2 vascular receptors in attenuation of EDRF-mediated vascular relaxation. The vasodilatory effect of endothelium-dependent and - independent agents will be studied in the presence and the absence of TXA2/PGH2 antagonists, TXA2 of the role played by eicosanoids that activate TXA2/PGH2 receptors in the development of angiotensin-dependent and - independent forms of hypertension. We will contrast the development of hypertension in rats with and without concurrent treatment with TXA2/PGH2 antagonists, TXA2 synthesis inhibitors, or both treatments combined.
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