Prevention and Intervention Studies with Telmisartan, Ramipril and Their Combination in Different Rat Stroke Models

Abstract

ObjectivesThe 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.Methods 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.ResultsStroke 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.ConclusionsT, 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.

Potential of the Angiotensin Receptor Blockers (ARBs) Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke

“…SHRSPs develop severe hypertension with age and die from ischemic stroke or hemorrhagic stroke in greater than 80% of the animals [47]. Telmisartan reduces the incidence of stroke, prolongs survival, and improves neurological outcome in SHRSPs [49]. Irbesartan also increases the survival rate in SHRSPs fed a high-salt and low-protein diet, and ameliorates the appearance of stroke symptoms, showing an association with the prevention of microscopic lesions [50].…”

“…BDNF acts on certain neurons of the central and peripheral nervous systems to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses [53,54]. Telmisartan improves neurological outcome, reduces infarct size and TNF-α levels, and induces expression of the TrkB receptor and neuronal survival in a rat MCAO model [49]. Irbesartan also improves neurological outcome, reduces infarct size, decreases the number of apoptotic cells in the peri-infarct cortex, and attenuates the invasion of activated microglia and macrophages in the peri-infarct cortex in the rat MCAO model [55].…”

Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat

“…Doses were selected on the basis of previous studies in the laboratory and those reported in the literature. [20][21][22][23] The animals were selected randomly based on their body weight into nine groups and each group comprised six animals. The study was performed in multiple phases as shown in the experimental protocol (Scheme 1).…”

The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: A Narrative Review of Preclinical and Clinical Studies

“…Deguchi et al demonstrated that TMS dose-dependently (0.3 mg/kg/day or 3 mg/kg/day) ameliorated metabolic syndrome related changes in the post stroke brain of SR-SHR with direct neuroprotective effects [34]. Moreover, incidence of stroke was reduced along with prolonged survival and improved neurological outcome following TMS application (0.5 mg/kg once daily) [35]. Pretreatment of rats with TMS (1 mg/kg) seven days before inducing cerebral ischemia also showed significant reduced infarct size and histopathologically normal appearance of neurons in the periinfarct cortical regions [36].…”