There is substantial evidence for a role of the epoxygenase products in regulating renal function, although their exact role in the human kidney remains unclear. Both 20-HETE and the EETs are generated in renal tissue. 20-HETE, which potently blocks the smooth muscle cell Ca2+-activated K+ channel and leads to vasoconstriction of the renal arteries, has been implicated in the pathogenesis of hypertension. In contrast, studies support an antihypertensive effect of the EETs because of their vasodilating and natriuretic actions. EETs increase renal blood flow and may protect against inflammatory renal damage by limiting glomerular macrophage infiltration. Inhibitors of soluble epoxide hydrolase, which prolong the biologic activities of the EETs, are being developed as potential new antihypertensive drugs. In vitro studies, and work in animal models, support targeting soluble epoxide hydrolase for blood pressure control, although the potential for pulmonary vasoconstriction and tumor promotion through antiapoptotic actions require careful investigation.
D. Miscellaneous
The effects of these products on the reproductive organs have not been elucidated.
Similarly, actions on the nervous system have been suggested but not confirmed. 12-HETE stimulates the release of aldosterone from the adrenal cortex and mediates a portion of the aldosterone release stimulated by angiotensin II but not that by adrenocorticotropic hormone. Very low concentrations of LTC4 increase and higher concentrations of arachidonate-derived epoxides augment luteinizing hormone (LH) and LH-releasing hormone release from isolated rat anterior pituitary cells.
Corticosteroids block all the known pathways of eicosanoid synthesis, perhaps in part by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A2 activity, probably by interfering with phospholipid binding, thus preventing the release of arachidonic acid.
The NSAIDs (eg, indomethacin, ibuprofen; see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. The more recent, purposefully designed selective COX-2 inhibitors vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which lack nuclei, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition of TXA2 biosynthesis.
EP-receptor agonists and antagonists are under evaluation in the treatment of bone fracture and osteoporosis, whereas TP-receptor antagonists are being investigated for usefulness in the treatment of cardiovascular syndromes. Direct inhibition of PGE2 biosynthesis through selective inhibition of the inducible mPGES-1 isoform is also under examination for potential therapeutic efficacy in pain and inflammation, cardiovascular disease, and chemoprevention of cancer.