Alteration of cytochrome P-450 isozymes by captopril and idrapril in hepatic and renal microsomes of normotensive and spontaneously hypertensive rats.
To examine the effects of angiotensin-converting enzyme (ACE)inhibitors such as captopril and idrapril on the P-450 system, these compounds were administered 100 mg/kg i.p. for 4 days to spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats; thereafter, the principal hepatic and renal microsomal monooxygenase activities were determined. In all the rat strains used, both captopril and idrapril decreased only the P-450 2C11, (as determined by immunoblotting) and its linked activities such as 16alpha-, 2alpha- and 17-testosterone hydroxylases. These changes were accompanied by a significant decrease of blood testosterone levels both in normotensive and, more markedly, in hypertensive rats and by a reduction of systolic blood pressure, but only in SHRs. Only in SHRs as well, the renal immunodetectable P-450 4A content and the P-450 4A-dependent activities, such as the (omega)-lauric acid hydroxylase, diminished after captopril or idrapril treatment. These data suggest that the decrease of increased blood pressure in hypertensive SHRs by the ACE inhibitors may be linked to the downregulation of the circulating testosterone level, the renal P-450 4A expression, and the related formation of the potent vasoconstrictor (omega)-hydroxy arachidonic acid.
Moretti
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Laboratory of Genetics and Biochemical Toxicology, Istituto di Mutagenesi e Differenziamento C.N.R., Pisa, Italy.
Lippi
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Criscuoli
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Subissi
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Gervasi
P G
PG
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002216:Captopril / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006898:Hydroxylamines / Q000494:pharmacology; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D003509:Cyclohexanecarboxylic Acids; D006898:Hydroxylamines; D007527:Isoenzymes; C076966:idrapril; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D002216:Captopril