Effects of idrapril calcium on tissue angiotensin-converting enzyme in rats.
Tissue angiotensin-converting enzyme (ACE) inhibition was measured in rats after single intravenous (i.v.) and oral (p.o.) doses of idrapril calcium, and the correlation between peak inhibition and tissue concentration of the drug was investigated. Five minutes after idrapril calcium (3 mg/kg i.v. as free acid), ACE in the examined tissues (serum, lungs, kidneys, heart, aorta, adrenals, testes, and brain) showed > 50% inhibition, always associated with measurable amounts of idrapril. After 90 min, ACE activity was still inhibited only in serum, lungs, kidneys, and aorta, recovering to basal values by 8 h in all samples but serum. Oral idrapril calcium (30 mg/kg) produced > 50% peak ACE inhibition in serum, lungs, and kidneys, in which measurable levels of the drug were detected, and in the aorta, where idrapril was not detected. Other tissues showed neither marked inhibition nor measurable drug levels. Kinetics of ACE inhibition in affected tissue mirrored those observed after intravenous administration. Idrapril, despite its hydrophilic nature, is able to reach extravascular tissues and to inhibit local ACE. However, in no tissue did the effect on ACE last longer than in serum and the hypothesis of a peculiar role of tissue RAS in determining the hypotensive activity of idrapril calcium is not supported in rats.
Becagli
P
P
Istituto Policattedra di Discipline Biologiche, Università di Pisa, Italy.
Lippi
A
A
Criscuoli
M
M
Breschi
M C
MC
Subissi
A
A
D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006898:Hydroxylamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000201:enzymology; D014018:Tissue Distribution
D000806:Angiotensin-Converting Enzyme Inhibitors; D003509:Cyclohexanecarboxylic Acids; D006898:Hydroxylamines; C076966:idrapril; D007703:Peptidyl-Dipeptidase A