title: Characterization of blood pressure and renal function in chromosome 5 congenic strains of Dahl S rats.
abstract: 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.
authors.affiliation: Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. rroman@mcw.edu
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Hoagland
authors.forename: Bernardo
authors.initials: B
authors.lastname: Lopez
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garrett
authors.forename: John P
authors.initials: JP
authors.lastname: Rapp
authors.forename: Josef
authors.initials: J
authors.lastname: Lazar
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Albert
authors.initials: A
authors.lastname: Sarkis
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D042926:Cytochrome P-450 CYP4A / Q000235:genetics* / Q000378:metabolism; D006439:Hemodynamics; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D006973:Hypertension / Q000235:genetics; D007668:Kidney / Q000098:blood supply / Q000201:enzymology*; D007679:Kidney Medulla / Q000201:enzymology; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D011917:Rats, Inbred Lew; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D017673:Sodium Chloride, Dietary; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A