CYTOCHROME-P450 METABOLITES OF ARACHIDONIC-ACID AS INTRACELLULAR SIGNALING MOLECULES IN VASCULAR TISSUE

Recent studies from our laboratory have indicated that vascular smooth muscle cells (VSMC) metabolize arachidonic acid via a P4504A-dependen t pathway to 20-hydroxyeicosatetraenoic acid (20-HETE), and that this system serves as a novel signal transduction pathway that plays a cent ral role in the regulation of vascular tone. The major metabolite of a rachidonic acid formed in cerebral and renal arteries is 20-HETE. The mRNA and protein for P4504A enzymes, which produce 20-HETE, have been localized in VSMC. 20-HETE is a potent vasoconstrictor, that acts in p art by inhibition of the opening of the large conductance, calcium-act ivated potassium channel, and depolarizes VSMC membrane. A preliminary study also indicated that 20-HETE activates the L-type calcium curren t in cerebral arterial smooth muscle. Inhibition of the endogenous pro duction of 20-HETE in renal and cerebral arterioles attenuates pressur e-dependent myogenic tone in vitro, as well as autoregulation of renal and cerebral blood flow in vivo. There is also evidence that indicate s that nitric oxide regulates the formation of 20-HETE by binding and inactivating the P450 heme moiety, thus providing a negative feedback control mechanism for this system. The data outlined suggest that 20-H ETE could act as a intracellular second messenger that plays an integr al role in the signal transduction processes underlying the developmen t of pressure-dependent myogenic tone.