Renal cytochrome P4504A activity and salt sensitivity in spontaneously hypertensive rats.
Differences in the renal metabolism of arachidonic acid by cytochrome P450 have been reported in the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rats, but the contribution of this system to the development of hypertension is unclear. The present study compared renal P450 activity and blood pressure in SHR and Brown-Norway rats (BN) under control conditions and in response to an elevation in sodium intake; genetic linkage analysis was performed in an F2 population (n=219) derived from these strains. Basal renal P4504A enzyme activity measured by conversion of [C(14)]arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) was significantly greater in the kidneys of adult SHR (n=7) than of BN (n=8) (82 +/- 7 versus 60 +/- 5 pmol/min per milligram protein). Renal 20-HETE production fell 45 percent in SHR and 22 percent in BN in which salt intake was elevated by drinking of saline instead of water for 2 weeks. Mean arterial pressure averaged 157 +/- 3mm Hg in SHR (n = 9) and 100 +/- 2 mm Hg in BN fed a normal salt diet, and it rose to 170 +/- 7 mm Hg (P<.05) in SHR and fell to 90 +/- 3 mm Hg (P<.05) in BN (n=8) after sodium intake was elevated. A polymorphic marker, D5Rjr1, that spanned a repeated element in the P4504A gene on chromosome 5, where all three P4504A isoforms are located, was used for genotyping of the F2 population. The P4504A genotype did not cosegregate with baseline mean arterial pressure in the F2 population; however, significant linkage was observed with the change in mean arterial pressure after sodium intake of the rats was elevated. The degree of linkage differed in male and female rats, and the highest LOD score (3.6) was observed in male F2 rats with a BN grandfather. These findings suggest that the difference in renal P450 activity in SHR and BN does not contribute to the development of hypertension in this F2 population, but it may play some role in determining the blood pressure response to an elevation in salt intake.
Stec
D E
DE
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Trolliet
M R
MR
Krieger
J E
JE
Jacob
H J
HJ
Roman
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001483:Base Sequence; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008126:Lod Score; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR / Q000378:metabolism*; D011921:Rats, Inbred WKY; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000494:pharmacology*; D013045:Species Specificity
D006893:Hydroxyeicosatetraenoic Acids; D012982:Sodium, Dietary; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A