Abnormal pressure-natriuresis in hypertension: Role of cytochrome P450 metabolites of arachidonic acid

The pressure-natriuresis relationship is shifted to higher pressures in gen etic and experimental models of hypertension; however, the factors responsi ble for altering kidney function remain to be determined. In spontaneously hypertensive (SHR) and Lyon hypertensive rats, the resetting of pressure-na triuresis results from increased preglomerular renal vascular tone, whereas sodium reabsorption is elevated in the thick ascending loop of Henle (TALH ) of Dahl S rats. Recently, a new route for the renal metabolism of arachid onic acid (AA) has been described, and there is evidence that this pathway contributes to the resetting of renal function in hypertension. In the kidn ey, cytochrome P450 (CYP) enzymes metabolize AA primarily to 20-HETE and EE Ts. 20-METE is a potent constrictor of renal arterioles that has an importa nt role in autoregulation of renal blood flow and tubuloglomerular feedback . 20-METE and EETS also inhibit sodium reabsorption in the proximal tubule and TALH. In the SHR, the renal production of 20-METE is elevated and inhib itors of the formation of 20-HETE decrease arterial pressure. Blockade of 2 0-HETE formation also reduces blood pressure or improves renal function in deoxycorticosterone acetate (DOCA)-salt, angiotensin II-infused, and Lyon h ypertensive rats. In contrast, 20-HETE formation is reduced in the TALH of Dahl S rats and this contributes to elevated sodium reabsorption. Induction of 20-METE synthesis improves pressure-natriuresis and lowers blood pressu re in Dahl S rats, whereas inhibitors of the synthesis of 20-HETE promote t he development of hypertension in Lewis rats. These findings indicate that the renal production of CYP metabolites of AA is altered in genetic and exp erimental models of hypertension and that this system contributes to the re setting of pressure-natriuresis and the development of hypertension in some models. Am J Hypertens 2001;14:90S-97S (C) 2001 American Journal of Hypert ension, Ltd.