Given the overwhelming evidence that the renal and/or vascular production is altered in animal models of hypertension and that mutations in CYP4A11 and 4F2 enzymes are linked to the development of hypertension in human population studies, there is now considerable interest in developing drugs that target the 20-HETE pathway for the treatment of hypertension. A number of selective inhibitors that inhibit the synthesis of 20-HETE have been developed (). These include 17-octadecynoic acid (17-ODYA), N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), dibromododec-11-enoic acid (DDBB), N
-(4-butyl-2methylphenyl)formamidine (HET0016) and N
-hydroxyimido formamide (TS011). More recently, stable analogs 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (6-,15-,20-HEDE) and 20-hydroxyeicosa-6(Z),15(Z)-dienoyl]glycine (6-,15-,20-HEDGE) that block the vasoconstrictor actions of 20-HETE have also been described.172-174
Modulation of the 20-HETE pathway in the control of arterial pressure
In the vasculature, 20-HETE is potent vasoconstrictor that promotes hypertension. The inhibitors of the synthesis of 20-HETE have been shown to reduce arterial pressure in AngII, DOCA-salt and androgen induced models of hypertension as well as the SHR that all are associated with increased vascular production of 20-HETE, oxidative stress and endothelial dysfunction. More recently, HET0016, an inhibitor of the synthesis of 20-HETE, was found to also attenuate the development of hypertension and vascular oxidative stress in DHT infused animals.45
20-HETE inhibitors and antagonists also reduce infarct size following ischemia and reperfusion of the coronary and cerebral circulations.19, 166, 175-176
Thus, the use of inhibitors of the synthesis of 20-HETE (17-ODYA, HET0016 and TS011) or 20-HETE antagonists (6-,15-,20-HEDE and HEDGE) might be prone to be useful to treat hypertension in patients with elevated vascular production of 20-HETE.
At the level of renal tubules, 20-HETE inhibits Na+
transport and deficiencies in the renal formation of 20-HETE have been reported to promote salt-sensitive hypertension in the Dahl S rat47-48, 132, 138
and in patients with inactivating mutations in CYP4A11 and 4F2.140-141, 147, 157
Treatment with the 20-HETE mimetics, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5-,14-,20-HEDE), N
-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5-,14-,20-HEDGE), () and PPAR-α agonists (fibrates) or gene therapy to upregulate the renal formation of 20-HETE would be expected to promote sodium excretion and oppose the development of salt-sensitive hypertension. This therapy may also slow the progression of glomerular disease and renal fibrosis since 20-HETE has a protective effect on the glomerular permeability barrier.130-131
Increasing the renal formation of 20-HETE may also be beneficial for patients following ischemia reperfusion (I/R) injury since recent studies have shown that administration of stable 20-HETE analogues mitigates acute I/R injury via an effect that is likely due to 20-HETE's natriuretic effects.177
Clearly, further studies are needed to better understand the role of the pro- and antihypertensive actions of 20-HETE in various models, but the available evidence support the view that both 20-HETE agonists/mimetics and antagonists/inhibitors may be new and useful therapeutic targets for the treatment of hypertension and associated cardiovascular complications.