Elevated endothelin (ET)-1 has been implicated in cerebrovascular complications following brain trauma characterized by dysregulation of endothelial nitric oxide synthase (eNOS), protein kinase C (PKC), and cerebral function. Recently, vascular expression of PPAR␣ has been observed and suggested to improve vascular dysfunction. We speculate that activation of PPAR␣ in cerebral microvessels can improve cerebral dysfunction following trauma, and we tested the hypothesis that activation of cerebral endothelial peroxisome proliferator-activated receptor (PPAR)␣ will attenuate ET-1 production via a mechanism involving nitric oxide (NO) and PKC. Phorbol 12-myristate 13-acetate (PMA) (1 M), bradykinin (BK, 1 M), angiotensin II (AII, 1 M), or hemoglobin (Hem, 10 ⌴) increased ET-1 levels by 24-, 11.4-, 3.6-, or 1.3-fold increasing ET-1 levels from 0.36 Ϯ 0.08 to 8.6 Ϯ 0. Clofibrate increased PPAR␣ expression, accompanied by increased NO production and eNOS expression. PKC inhibition by calphostin C (10 M) blocked these effects, whereas activation by PMA reduced basal PPAR␣ expression. Thus, PPAR␣ activation attenuated ET-1 production by agents that mediate brain injury through mechanisms that probably result from PPAR␣-induced increase in eNOS expression/NO production and complex PKC signaling pathways. Therefore, PPAR␣ activators can be appropriate therapeutic agents to alleviate cerebrovascular dysfunction following cerebral vasospasm.Pathogenesis of hemorrhage-induced cerebral dysfunction has been reported to result from potent and prolonged cerebral microvascular constriction. Cerebral arterial vasoconstriction following brain trauma has been associated with increased CSF concentration of blood derived vasoactive agents and endothelin (ET)-1 (Findlay et al

These data suggest that cyclosporin A-induced nephrotoxicity can be accounted for by reduced NO production and a consequent increase in 20-HETE. The cyclosporin A-induced nephrotoxicity is thus an ideal model for evaluating NO/CYP450 interactions.

No abstract