ABSTRACT
The endothelium modulates vascular tone by releasing a number of different relaxing factors, including nitric oxide (NO), prostacyclin, epoxyeicosatrienoic acids and other as yet unidentified endothelium-derived hyperpolarizing factors (EDHFs) . The studies summarized in this chapter showed that in contracted rabbit aorta, arachidonic acid and acetylcholine elicited an endothelium-dependent, concentration-related relaxation that was resistant to inhibitors of both N O and cyclooxygenase. Increasing the extracellular potassium (K) concentration from 4 to 20 m M , and pretreatment with inhibitors of lipoxygenases abolished arachidonic acid-and acetylcholine-induced relaxations. In addition, arachidonic acid increased the membrane potential of rabbit aortic smooth muscle cells. Arachidonic acid had no effect on cell membrane potential in rabbit aortas without an intact endothelial layer. Rabbit aortic endothelial cells metabolized ara chidonic acid to a vasodilator 15-lipoxygenase metabolite. Structural analysis of the 15-lipoxygenase products by gas chromatography/mass spectrometry indicated a trihydroxyeicosatrienoic acid ( T H E T A ) structure. Further gas chromatography/mass spectrometry analysis indicated the formation of two peaks that were the regioisomers, 11,12,15-THETA and 11,14,15-THETA. Isolation of the two products using a normal phase high pressure liquid chromatography separation found that only 11,12,15T H E T A relaxed contracted aortas. The relaxation to 11,12,15-THETA was inhibited in the presence of elevated extracellular K concentrations. These studies indicate that arachidonic acid relaxes vascular smooth muscle by opening K channels and hyper polarizing cells. They suggest that these effects are mediated by 11,12,15-THETA.
