Prevention and intervention studies with telmisartan, ramipril and their combination in different rat stroke models

• Published in: PloS one Vol. 6; no. 8; p. e23646
• Main Authors: Thoene-Reineke, Christa, Rumschüssel, Kay, Schmerbach, Kristin, Krikov, Maxim, Wengenmayer, Christina, Godes, Michael, Mueller, Susanne, Villringer, Arno, Steckelings, Ulrike, Namsolleck, Pawel, Unger, Thomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.08.2011; Public Library of Science (PLoS)
• Subjects: Animal cognition; Animal models; Animals; Antihypertensive Agents - therapeutic use; Benzimidazoles - therapeutic use; Benzoates - therapeutic use; Biology; Blood pressure; Brain research; Cell survival; Cerebral blood flow; Cognitive ability; Drinking water; Drug dosages; Free radicals; Hypertension; Incidence; Intervention; Ischemia; Magnetic resonance imaging; Male; Medicine; Neurons; Neuroprotection; Occlusion; Pharmacology; Prevention; Proteins; Ramipril; Ramipril - therapeutic use; Random Allocation; Rats; Rats, Inbred SHR; Rats, Wistar; Reperfusion; Rodents; Salts; Sodium chloride; Stroke; Stroke - drug therapy; Stroke - prevention & control; Survival; Traumatic brain injury; TrkB receptors; Tumor necrosis factor-α; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023646

The effects of AT1 receptor blocker, telmisartan, and the ACE inhibitor, ramipril, were tested head-to head and in combination on stroke prevention in hypertensive rats and on potential neuroprotection in acute cerebral ischemia in normotensive rats. Prevention study: Stroke-prone spontaneously hypertensive rats (SHR-SP) were subjected to high salt and randomly assigned to 4 groups: (1) untreated (NaCl, n = 24), (2) telmisartan (T; n = 27), (3) ramipril (R; n = 27) and (4) telmisartan + ramipril (T+R; n = 26). Drug doses were selected to keep blood pressure (BP) at 150 mmHg in all groups. Neurological signs and stroke incidence at 50% mortality of untreated SHR-SP were investigated. Intervention study: Normotensive Wistar rats were treated s.c. 5 days prior to middle cerebral artery occlusion (MCAO) for 90 min with reperfusion. Groups (n = 10 each): (1) sham, (2) vehicle (V; 0.9% NaCl), (3) T (0.5 mg/kg once daily), (4) R (0.01 mg/kg twice daily), (5) R (0.1 mg/kg twice daily) or (6) T (0.5 mg/kg once daily) plus R (0.01 mg/kg twice daily). Twenty-four and 48 h after MCAO, neurological outcome (NO) was determined. Forty-eight h after MCAO, infarct volume by MRI, neuronal survival, inflammation factors and neurotrophin receptor (TrkB) were analysed. Stroke incidence was reduced, survival was prolonged and neurological outcome was improved in all treated SHR-SP with no differences between treated groups. In the acute intervention study, T and T+R, but not R alone, improved NO, reduced infarct volume, inflammation (TNFα), and induced TrkB receptor and neuronal survival in comparison to V. T, R or T+R had similar beneficial effects on stroke incidence and NO in hypertensive rats, confirming BP reduction as determinant factor in stroke prevention. In contrast, T and T+R provided superior neuroprotection in comparison to R alone in normotensive rats with induced cerebral ischemia.