Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats.

The present study examined whether transfer of overlapping regions of chromosome 5 that include (4A+) or exclude the cytochrome P-450 (CYP) 4A genes from the Lewis rat alters the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) and/or the development of hypertension in congenic strains of Dahl salt-sensitive (S) rats. The expression of CYP4A protein and the production of 20-HETE in the renal outer medulla was greater in the 4A+ congenic strain than the levels seen in S rats or in overlapping control congenic strains that exclude the CYP4A region. Mean arterial pressure (MAP) rose from 122 +/- 2 to 190 +/- 7 mmHg in S rats and from 119 +/- 2 and 123 +/- 2 to 189 +/- 7 and 187 +/- 3 mmHg in the two control congenic strains fed an 8.0% NaCl diet for 3 wk. In contrast, MAP only increased from 112 +/- 2 to 150 +/- 5 mmHg in the 4A+ congenic strain. Chronic blockade of the formation of 20-HETE with N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide (TS-011; 1 mg/kg bid) restored the salt-sensitive phenotype in the 4A+ congenic strain and MAP rose to 181 +/- 6 mmHg after an 8.0% NaCl dietary challenge. TS-011 had no effect on the development of hypertension in S rats or the two control congenic strains. The pressure-natriuretic and diuretic responses were fivefold greater in the 4A+ congenic strain than in S rats. These results indicate that transfer of the region of chromosome 5 between markers D5Rat108 to D5Rat31 from the Lewis rat into the Dahl S genetic background increases the renal production of 20-HETE, improves pressure-natriuresis and opposes the development of salt-induced hypertension.