Inhibition of brain angiotensin-converting enzyme by peripheral administration of trandolapril versus lisinopril in Wistar rats.
BACKGROUND
Peripheral administration of blockers of the renin-angiotensin system (RAS) may affect the RAS in the brain to a variable degree. In the present study, we determined inhibition of angiotensin-converting enzyme (ACE) in the brain after peripheral administration of a lipophilic (trandolapril) versus hydrophilic (lisinopril) ACE inhibitor.


METHODS
Trandolapril (0.2, 1, and 5 mg/kg/day, subcutaneously) was compared with lisinopril (2, 10, and 50 mg/kg/day, subcutaneously), each for 6 days. At 4 and 24 h after the last dose, (125)I-351A binding on brain ACE was measured.


RESULTS
Trandolapril and lisinopril caused similar inhibition of ligand binding outside the blood-brain barrier (BBB). However, inside the BBB, trandolapril was more effective at low and medium doses (for lisinopril, 28% to 51% inhibition at a dose of 2 mg, 63% to 72% at 10 mg, and 84% to 86% at 50 mg; and for trandolapril, 62% to 68% inhibition at a dose of 0.2 mg, 84% to 87% at 1 mg, and 88% to 93% at 5 mg). In contrast, in the brain structures caudate putamen and globus pallidus, lisinopril inhibited ligand binding better than trandolapril (for lisinopril 30% to 44% at a dose of 2 mg and 71% to 74% at 10 mg, versus for trandolapril 21% to 27% at 0.2 mg and 51% to 63% at 1 mg). At 24 h after the last dose, inhibition by trandolapril persisted more than inhibition by lisinopril both outside and inside the BBB.


CONCLUSIONS
These results suggest that peripheral administration of even hydrophilic ACE inhibitors can result in marked inhibition of brain ACE inside the BBB but that different brain structures show variable inhibition.
Tan
Junhui
J
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Wang
Jun Ming
JM
Leenen
Frans H H
FH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000201:enzymology*; D004151:Dipeptides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005917:Globus Pallidus / Q000201:enzymology; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008024:Ligands; D017706:Lisinopril / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism*; D011699:Putamen / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D007211:Indoles; D008024:Ligands; C042037:L-proline, N2-((1S)-1-carboxy-3-phenylpropyl)-N6-((4-hydroxyphenyl)iminomethyl)-L-lysyl-; C052035:trandolapril; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A