Comparison between early and delayed systemic treatment with candesartan of rats after ischaemic stroke

Brdon, Jan; Kaiser, Sabine; Hagemann, Friederike; Zhao, Yi; Čulman, Juraj; Gohlke, Peter

doi:10.1097/01.hjh.0000254376.80864.d3

Cited by 40 publications

(31 citation statements)

References 46 publications

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“…Gohlke et al 21 have shown earlier that oral administration of 0.1 mg kg À1 candesartan inhibited the central response to angiotensin II. This finding is in agreement with other studies showing that postischemic low-dose, but not moderate-or high-dose, administration of candesartan is neuroprotective against transient focal ischemia in both normotensive 5 and hypertensive rats. 6 Furthermore, our results show that lowering the BP shortly after reperfusion in SHR results in a decline in cerebral blood flow in the affected cortex, which could overshadow any potential beneficial Candesartan 10 mg kg À1 12 37.6 ± 0.3 38.0 ± 0.5 37.9 ± 0.5 38.0 ± 0.4 37.9 ± 0.4…”

Section: Discussionsupporting

confidence: 83%

“…1 In experimental animal stroke models, recent studies have shown that postischemic administration of an angiotensin II type 1 receptor (AT 1 ) blocker (ARB) after transient middle cerebral artery (MCA) occlusion improves neurological outcomes and reduces infarct size. [2][3][4][5] However, it remains unclear whether the beneficial effects of ARBs are dose dependent. Several studies have suggested that high doses of ARBs are not beneficial because they cause hypotension.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have suggested that high doses of ARBs are not beneficial because they cause hypotension. 5,6 Molecular mechanisms underlying the protective effects of ARBs on the postischemic brain could include the suppression of inflammation, 3,[7][8][9] oxidative stress, 10 and apoptosis. 11 Recently, Rho-kinase has attracted attention because it is a potential target for the attenuation of ischemic brain injury.…”

Section: Introductionmentioning

confidence: 99%

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Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats

et al. 2009

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Lowering the blood pressure (BP) during the acute period following ischemic stroke is still a controversial treatment. In this study, we investigated the effect of postischemic treatment using the angiotensin II type 1 receptor blocker, candesartan, on brain damage in focal cerebral ischemia. Spontaneously hypertensive rats underwent transient occlusion of the middle cerebral artery for 1 h. Candesartan (0.1, 1 and 10 mg kg À1 ) or vehicle was administered orally 3 and 24 h after ischemia. Blood pressure and neurological function were monitored, and infarct volume was evaluated 48 h after occlusion. Cerebral blood flow was measured using laser Doppler flowmetry before and after treatment with candesartan. Activation of Rho-kinase in cerebral microvessels was evaluated by immunohistochemistry. Systolic blood pressure was markedly lowered with both moderate and high doses, but it did not fall with a low dose of candesartan. The infarct volume was reduced in rats treated with the low dose of candesartan but not in those treated with the moderate or high doses. Cerebral blood flow decreased in parallel with the reduction in BP 3 h after treatment using the moderate dose, but it did not change after treatment with the low dose of candesartan, compared with vehicle. Rho-kinase was activated in the brain vessels of the ischemic cortex, but treatment with candesartan suppressed it. Our results show that oral administration of candesartan after transient focal ischemia reduced infarct volume at doses that showed little effect on BP. The neurovascular protective effects of candesartan may be caused by the inhibition of Rho-kinase in brain microvessels.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats

et al. 2009

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“…In addition, early administration of candesartan (3 h after onset of ischemia) to normotensive rats has been shown to be neuroprotective, but only when excessive BP lowering is avoided (Brdon et al, 2007). We are the first group to add the additional benefit of a reduction in vascular damage and hemorrhage to the benefits of candesartan in SHRs as well as identifying an interaction between preexisting hypertension and stroke in the response to BP lowering with candesartan.…”

Section: Discussionmentioning

confidence: 99%

Vascular Protection with Candesartan after Experimental Acute Stroke in Hypertensive Rats: A Dose-Response Study

Kozak

Kozák²,

Johnson

et al. 2008

J Pharmacol Exp Ther

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We have shown that candesartan decreases the acute strokeinduced elevation of mean arterial blood pressure (MAP) in Wistar rats and improves functional outcome. The aim of the present study was to determine whether the same benefit could be achieved in spontaneously hypertensive rats (SHR). Animals were subjected to middle cerebral artery occlusion (MCAO) or sham for 3 h followed by reperfusion. Either candesartan (0.1, 0.3, or 1.0 mg/kg) or saline was administered. MAP of the rats was monitored by means of telemetry, and neurological function was assessed. Infarct size, edema formation, and hemoglobin content in the ischemic hemisphere were evaluated 24 h after the stroke. MAP of SHR increased immediately upon MCAO from 135 (baseline) to 189 mm Hg, and it remained elevated until reperfusion. Candesartan decreased MAP in a dose-dependent manner, with a drop below baseline after a dose of 1.0 mg/kg. SHRs experienced greater blood pressure (BP)-lowering effects of candesartan after stroke compared with a sham condition (p Ͻ 0.0001). Neurological deficit after stroke was reduced in candesartan-treated animals, revealing a dose-dependent effect (p Ͻ 0.01). Infarct size, edema formation, and hemoglobin content were all reduced by candesartan at doses of 0.1 and 0.3 mg/kg (p Ͻ 0.05 for all). Candesartan (1 mg/kg) was not different from saline. Low doses of candesartan provide neurovascular protection after stroke in SHRs. Caution is warranted because acute stroke increases the sensitivity to BP lowering, which, in turn, increases the likelihood of overshooting.

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“…9 We have previously suggested that antihypertensive medications that increase angiotensin II levels such as thiazide diuretics, calcium antagonists, and ARBs could be more cerebroprotective than agents that lower angiotensin II levels such as ␤-blockers and angiotensin-converting enzyme inhibitors. 10 This hypothesis was based on experimental findings 11,12 but also was supported by a recent meta-analysis of 206 632 patients in 26 prospective randomized clinical trials. 13 Angiotensin II-decreasing drugs proved to be less stroke protective than antihypertensive drugs that increased angiotensin II levels.…”

Section: Article P 2969mentioning

confidence: 87%

Cerebroprotection by Hypertension in Ischemic Stroke

Messerli

2007

Circulation

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Comparison between early and delayed systemic treatment with candesartan of rats after ischaemic stroke

Cited by 40 publications

References 46 publications

Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats

Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats

Vascular Protection with Candesartan after Experimental Acute Stroke in Hypertensive Rats: A Dose-Response Study

Cerebroprotection by Hypertension in Ischemic Stroke

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