Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke‐prone spontaneously hypertensive rats

Abstract

An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

Different protective and reparative effects of olmesartan in stroke according to time of administration and withdrawal

“…This result was further confirmed with the H&E technique. These results are in agreement with previous data showing reduced infarct size in animals treated with ARBs after cerebral ischemia (Engelhorn et al, ; Hosomi et al, ; Hamai et al, ; Oyama et al, ; Omote et al, ).…”

“…Various markers are altered in the brain in response to oxidative stress. A recent study demonstrated that OLM provided greater benefits than a simple lowering of blood pressure by its ability to reduce oxidative stresses with neurovascular protection (Omote et al, ). A previous study on mice demonstrated that temporary pretreatment with valsartan attenuated brain damage and decreased oxidative stress (Li et al, ).…”

“…Recent data suggest that modulation of the rennin–angiotensin system, in addition to its specific antihypertensive effects, alters other biological functions (Takizawa et al, ; Chrysant, ; Guimond and Gallo‐Payet, ). The effects of this modulation include anti‐inflammatory effects (Larrayoz et al, ; Benicky et al, ; Saavedra, ; Omote et al, ), inhibition of apoptosis and reactive microglia at the edge of the infarct core (Lou et al, ), and a significant reduction of oxidative stress after both transient and permanent ischemia (Li et al, ; Takizawa et al, ). Tissue integrity also appears to be altered, and levels of certain matrix metalloproteinases are diminished in the brains of rats after continuous OLM administration (Hosomi et al, ).…”

Observational Study of Brain Atrophy and Cognitive Decline Comparing a Sample of Community-Dwelling People Taking Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Over Time

“…The specific targeting of ARB to Angiotensin II receptors (AT1 and possibly AT2) may result in greater vasodilation and improved cerebral blood flow than ACEi [35,36]. Head-to-head studies comparing ACEi and ARB are lacking but results from animal models of stroke suggest that ARB may also have an anti-inflammatory action and neuroprotective role in humans [37,38]. The results for a small number of studies suggest that ARB use is associated with lower AD pathology on autopsy [39] possibly via a beneficial effect on brain tau concentrations [40].…”

Azelnidipine and glucose tolerance: possible indications and treatment selection for hypertensive patients with metabolic disorders

“…In SHRs, azelnidipine treatment decreased spontaneous infarct volume in a dose-dependent manner. The number of MCP-1-and ionized calcium-binding adapter molecule 1-positive cells at the boundary zone of spontaneous infarction were reduced by azelnidipine treatment [78].…”