Abnormal pressure-natriuresis in hypertension: role of cytochrome P450 metabolites of arachidonic acid.
The pressure-natriuresis relationship is shifted to higher pressures in genetic and experimental models of hypertension; however, the factors responsible for altering kidney function remain to be determined. In spontaneously hypertensive (SHR) and Lyon hypertensive rats, the resetting of pressure-natriuresis 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 arachidonic acid (AA) has been described, and there is evidence that this pathway contributes to the resetting of renal function in hypertension. In the kidney, cytochrome P450 (CYP) enzymes metabolize AA primarily to 20-HETE and EETs. 20-HETE is a potent constrictor of renal arterioles that has an important role in autoregulation of renal blood flow and tubuloglomerular feedback. 20-HETE and EETS also inhibit sodium reabsorption in the proximal tubule and TALH. In the SHR, the renal production of 20-HETE is elevated and inhibitors of the formation of 20-HETE decrease arterial pressure. Blockade of 20-HETE formation also reduces blood pressure or improves renal function in deoxycorticosterone acetate (DOCA)-salt, angiotensin II--infused, and Lyon hypertensive 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-HETE synthesis improves pressure-natriuresis and lowers blood pressure in Dahl S rats, whereas inhibitors of the synthesis of 20-HETE promote the development of hypertension in Lewis rats. These findings indicate that the renal production of CYP metabolites of AA is altered in genetic and experimental models of hypertension and that this system contributes to the resetting of pressure-natriuresis and the development of hypertension in some models.
Moreno
C
C
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Maier
K G
KG
Hoagland
K M
KM
Yu
M
M
Roman
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D009318:Natriuresis
D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System