LEUKOTRIENES, PROSTACYCLIN, BLOOD VESSELS

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It has been reported that spontaneously hypertensive rats (SHR) have abnormalities of several enzyme systems of eicosanoid metabolism. These abnormalities include: 1) enhanced vascular phospholipase A2 (PLA2) activity; 2) enhanced renal cytochrome P450 enzyme activity; 3) increased output of urinary PGF2alpha; 4) enhanced production of vascular PGI2; 5) increased production of 12-HETE by platelet 12-lipoxygenase. However, the courses and mechanisms involved in these abnormalities in SHR remain unknown. In this proposal we will evaluate the key enzymes responsible for the generation and transformation of these eicosanoids. The following experiments will be performed: 1. Studies on the vascular and renal PLA2 activities of SHR and their relationship to the development of hypertension. 2. Studies of the transformation of 12-HPETE and 15-HPETE by the enzyme "Hydroperoxide Lyase" for the generation of C-12 and C-14 short chain aldehydes and studies of their biological activities. 3. Studies of the activity of 11-ketoreductase in blood vessels and kidney of SHR and the occurance of 9alpha, 11beta- PGF2 instead of PGF2alpha in the urine of SHR. 4. Studies of the vascular "cyclo-oxygenase (PGH-synthase)" and "PGI2-synthase" activities and the enzyme levels in SHR. 5. Studies of the conversion of PGI2 to 5(6)-oxido-PGI2 via the cytochrome P450 epoxygenase system in SHR. 6. Studies of the molecular and cellular biology of "epoxygenase" in SHR. In this particular study, characterization of the renal cytochrome P450 epoxygenase from SHR and WKY and specific antibodies to epoxygenase will be made. Changes in transcription and/or translation of epoxygenase genes will be shown by Northern- and Western dot-blot technique with a renal cDNA clone, which will be prepared in the course of this study. The understanding of the mechanism, enzyme levels and the genetic regulation of these enzyme systems in SHR may lead to the development and treatment for prevention of hypertension.