Effects of chronic cytochrome P-450 inhibition on the course of hypertension and end-organ damage in Ren-2 transgenic rats.
The aim of the present study was to evaluate the effects of inhibition of cytochrome P-450 (CYP) activity by 1-aminobenzotriazole (ABT) and by CoCl(2), first, on the development of hypertension when treatment was started in young male heterozygous Ren-2 transgenic rats (TGR) and, second, on blood pressure (BP) when treatment was started in adult TGR with established hypertension. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. In addition, the renal cortical activities of omega-hydroxylase, the enzyme catalyzing the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), and of epoxygenase, the enzyme responsible for epoxyeicosatrienoic acids (EETs) production, and urinary excretion of 20-HETE and EETs in TGR and HanSD rats were assessed. TGR have higher renal tissue omega-hydroxylase activity and urinary excretion of 20-HETE but have significantly lower renal epoxygenase activity and urinary excretion of EETs than HanSD rats. Treatment of young TGR with ABT and CoCl(2) attenuated the development of hypertension and cardiac hypertrophy and prevented glomerulosclerosis. Administration of ABT and CoCl(2) in adult TGR decreased BP, cardiac hypertrophy, but did not reduce glomerulosclerosis. Our data suggest that altered production and/or action of CYP-derived metabolites play a permissive role in the development and maintenance of hypertension in TGR by enhancing ANG II-induced vasoconstriction.
Chábová
Vera Certíková
VC
Department of Nephrology, 1st Medical Faculty, Charles University, Prague, Czech Republic.
Kramer
Herbert J
HJ
Vanecková
Ivana
I
Vernerová
Zdena
Z
Eis
Václav
V
Tesar
Vladimír
V
Skaroupková
Petra
P
Thumová
Monika
M
Schejbalová
Stanislava
S
Husková
Zuzana
Z
Vanourková
Zdenka
Z
Kolský
Alexander
A
Imig
John D
JD
Cervenka
Ludek
L
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000503:physiopathology; D003035:Cobalt; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005923:Glomerulosclerosis, Focal Segmental / Q000503:physiopathology; D006579:Heterozygote; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D006973:Hypertension / Q000503:physiopathology*; D007672:Kidney Cortex; D008297:Male; D010105:Oxygenases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology*; D014661:Vasoconstriction
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D014230:Triazoles; C033020:1-aminobenzotriazole; D003035:Cobalt; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; D012083:Renin; C018021:cobaltous chloride