Blockade of Central Angiotensin AT ₁ Receptors Improves Neurological Outcome and Reduces Expression of AP-1 Transcription Factors After Focal Brain Ischemia in Rats

Abstract

Background and Purpose-Angiotensin-converting enzyme inhibitors have been shown to protect against stroke in hypertensive rats and to improve neurological outcome after cerebral ischemia in normotensive rats. The present study was designated to test the hypothesis that blockade of brain AT 1 receptors improves the recovery from focal cerebral ischemia and reduces expression of AP-1 transcription factors c-Fos and c-Jun, which have been associated with programmed cell death and neurodegeneration. Methods-Experiments were carried out in normotensive male Wistar rats. Focal cerebral ischemia was induced by middle cerebral artery occlusion lasting for 90 minutes and followed by reperfusion. The selective AT 1 receptor antagonist irbesartan was infused intracerebroventricularly over a 5-day period before the induction of ischemia at a dose that inhibited brain but not vascular AT 1 receptors. Twenty-four hours after ischemia, neurological outcome was evaluated and expression of c-Fos and c-Jun proteins in the brain was studied immunocytochemically. Results-Focal

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

“…Several clinical and experimental studies presented earlier have provided evidence that AII can be cerebroprotective and its effects on ischaemic stroke are mediated through local stimulation of the AT 2 receptors. [36][37][38][39][40] 28,30,33 and especially in elderly patients with isolated systolic hypertension. 29,31 Other mechanisms by which ARBs could reduce the incidence of new or recurrent stroke include the beneficial effects of some ARBs on blood glucose control by increasing insulin sensitivity, 49,50 their platelet antiaggregating effects, [51][52][53][54] their hypouricemic effects 66,67 and their atrial antifibrillatory effects.…”

Multifunctional Actions of Approved and Candidate Stroke Drugs

“…58 -60 Effects of AT1 receptor blockers on brain AT1 receptors were suggested to mediate these neuroprotective characteristics. 58,61 The ability of different AT1 receptor blockers to cross the blood-brain barrier is controversial, however. 62,63 Candesartan was shown to enhance the TrkB receptor of brain-derived neurotrophic factor (BDNF), a neurotrophin well known for its neuroprotective effects.…”

The renin-angiotensin system in the brain: possible therapeutic implications for AT1-receptor blockers

“…We have demonstrated that long-term blockade of brain AT 1 receptors by irbesartan and losartan improves neurological outcome of focal cerebral ischaemia, markedly reduces the expression of the transcription factors c-Fos and c-Jun in the parietal and piriform cortices on the ligated side of the brain, and completely abolishes ischaemia-induced c-Fos expression in the hippocampus. 43 The AT 1 receptor blockers were infused into the cerebral ventricles over a 5-day period before the induction of ischaemia, at a dose which effectively inhibited brain but not vascular AT 1 receptors. 43 In further studies we showed that systemic pretreatment of normotensive rats with candesartan, at doses which did not affect the arterial blood pressure, improved the recovery from cerebral ischaemia and reduced the volume of ischaemic injury (Figure 2; Groth et al unpublished results).…”

“…43 The AT 1 receptor blockers were infused into the cerebral ventricles over a 5-day period before the induction of ischaemia, at a dose which effectively inhibited brain but not vascular AT 1 receptors. 43 In further studies we showed that systemic pretreatment of normotensive rats with candesartan, at doses which did not affect the arterial blood pressure, improved the recovery from cerebral ischaemia and reduced the volume of ischaemic injury (Figure 2; Groth et al unpublished results). Together, these findings demonstrate that AT 1 receptor blockers may improve the recovery from stroke by restoration of blood flow after ischaemia and by blocking the biochemical and metabolic changes at the ischaemic cascade level.…”