Lipoxynoids in the kidney

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There are a variety of non-prostaglandin pathways for conversion of arachidonic acid, including lipoxygenase enzymes and epoxygenase enzymes such as cytochrome P-450. In a manner similar to that in which the cyclooxygenase pathways lead to the prostanoid family, ‘lipoxynoids’ refers to the family of products arising from this alternative group of pathways. Leukotrienes (LT's) are members of the lipoxynoid family arising from the action of 5-lipoxygenase enzymes. In the canine kidney, injections of leukotrienes C 4, D 4 and E 4 into the renal artery produced weak vasodilation at doses of 3–30 ug. Responses to LTC 4 and LTD 4 were similar and greater than responses to LTE 4, and responses were not different in animals which had received ibuprofen to inhibit prostaglandin synthesis. In contrast, these leukotrienes were potent vasoconstrictors of the mesenteric vascular bed in these same animals at doses of 0.01–0.3 ug. The order of potency was LTD 4 LTC 4 LTE 4. Effects of these LT's were not changed in the presence of ibuprofen. Responses to LTC 4 and LTD 4, but not LTE 4 were diminished approximately 50% after administration of FPL-55712 (2 mg/kg). Neither LTB 4 nor 5-HETE produced any change in renal or mesenteric blood flow at doses up to 30 ug. However, indirect evidence has been obtained suggesting that an endogenous lipoxynoid pathway can be activated in the canine kidney which results in the formation of a vasoconstrictor product. Injections of 1–4 mg AA into the renal artery of water-replete dogs leads to vasodilation which can be blocked by inhibitors of cyclooxygenase enzymes. However, when dogs were water deprived for 16–20 hours before the experiment, biphasic changes in renal blood flow were found. Ibuprofen blocked the vasodilator phase of the response but neither ibuprofen or the thromboxane synthesis inhibitor OKY-1581 had any inhibitory effect on the constrictor phase. The constrictor phase was blocked only following administration of ETYA or BW-755C, suggesting that the metabolites responsible for the constriction were lipoxynoids. Since LT's produce renal vasodilation, it appears that the pathway involved is not the 5-lipoxygenase system. These data suggest that other lipoxynoid pathways (e.g. 12-lipoxygenase, 15-lipoxygenase or cytochrome p-450) may play a role in the renal response to water deprivation. At present, however, it may not be possible to distinguish between these possible pathways in vivo .