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This study was conducted to test the hypothesis that the CYP1B1 (cytochrome P450 1B1)-testosterone metabolite 6β-hydroxytestosterone contributes to angiotensin II-induced hypertension by promoting activation of group IV cPLA2 α (cytosolic phospholipase A2 α) and generation of prohypertensive eicosanoids in male mice. Eight-week-old male intact or orchidectomizedcPLA 2 α +/+ /Cyp1b1 +/+ andcPLA 2 α–/– /Cyp1b1 +/+ and intactcPLA 2 α +/+ /Cyp1b1–/– mice were infused with angiotensin II (700 ng/kg/min, subcutaneous) for 2 weeks and injected with 6β-hydroxytestosterone (15 μg/g/every third day, intraperitoneal). Systolic blood pressure was measured by tail-cuff and confirmed by radiotelemetry. Angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production were reduced by disruption of thecPLA 2 α orCyp1b1 genes or by administration of the arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid tocPLA 2 α +/+ /Cyp1b1+/+ mice. 6β-hydroxytestosterone treatment restored these effects of angiotensin II incPLA 2 α +/+ /Cyp1b1–/– mice but not in orchidectomizedcPLA 2 α–/– /Cyp1b1+/+ mice, which were lowered by 5,8,11,14-eicosatetraynoic acid incPLA 2 α +/+ /Cyp1b1–/– mice. Antagonists of prostaglandin E2 -EP1/EP3 receptors and thromboxane A2 -TP receptors decreased the effect of 6β-hydroxytestosterone in restoring the angiotensin II-induced increase in systolic blood pressure, cardiac and renal collagen deposition, and reactive oxygen species production incPLA 2 α +/+ /Cyp1b1–/– mice. These data suggest that 6β-hydroxytestosterone promotes angiotensin II-induced increase in systolic blood pressure and associated pathogenesis via cPLA2 α activation and generation of eicosanoids, most likely prostaglandin E2 and thromboxane A2 that exerts prohypertensive effects by stimulating EP1/EP3 and TP receptors, respectively. Therefore, agents that selectively block these receptors could be useful in treating testosterone exacerbated angiotensin II-induced hypertension and its pathogenesis.

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A 2 α Activity

6β-Hydroxytestosterone Promotes Angiotensin II-Induced Hypertension via Enhanced Cytosolic Phospholipase A ₂ α Activity