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.